# Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies

Bojana Bogdanović, Daniel Fagret, Catherine Ghezzi, Christopher

Montemagno

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Bojana Bogdanović, Daniel Fagret, Catherine Ghezzi, Christopher Montemagno. Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies. Pharmaceuticals, 2024, 17 (11), pp.1556. 10.3390/ph17111556. inserm-05005519

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Review

# Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies

Bojana Bogdanović<fnref n="1" /> ID, Daniel Fagret<fnref n="1" />, Catherine Ghezzi<fnref n="1" /> and Christopher Montemagno<fnref n="2" />,*, ID

**Abstract:** Integrins, an important superfamily of cell adhesion receptors, play an essential role in cancer progression, metastasis, and angiogenesis, establishing them as prime targets for both diagnostic and therapeutic applications. Despite their significant potential, integrin-targeted therapies have faced substantial challenges in clinical trials, including variable efficacy and unmet high expectations. Nevertheless, the consistent expression of integrins on tumor and stromal cells underscores their ongoing relevance and potential. Traditional RGD-based imaging and therapeutic agents have faced limitations, such as inconsistent target expression and rapid systemic clearance, which have reduced their effectiveness. To overcome these challenges, recent research has focused on advancing RGD-based strategies and exploring innovative solutions. This review offers a thorough analysis of the latest developments in the RGD-integrin field, with a particular focus on addressing previous limitations. It delves into new dual-targeting approaches and cutting-edge RGD-based agents designed to improve both tumor diagnosis and therapeutic outcomes. By examining these advancements, this review illuminates new pathways for enhancing the specificity and efficacy of integrin-targeted therapies, paving the way for more effective cancer diagnosis and treatment strategies.

**Keywords:** RGD-binding integrin; αvβ3; dual targeting; theranostic; solid tumors; PET imaging

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**Citation:** Bogdanović, B.; Fagret, D.; Ghezzi, C.; Montemagno, C. Integrin Targeting and Beyond: Enhancing Cancer Treatment with Dual-Targeting RGD (Arginine-Glycine-Aspartate) Strategies. *Pharmaceuticals* **2024**, *17*, 1556. https://doi.org/10.3390/ph17111556

Academic Editor: Guillermina Ferro-Flores

Received: 30 September 2024

Revised: 11 October 2024

Accepted: 18 October 2024

Published: 20 November 2024

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**Copyright:** © 2024 by the authors.
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4.0/).

## 1. Introduction

Cancer remains a critical global health challenge, with an estimated 19.3 million new cases and 10 million deaths reported worldwide in 2020, according to GLOBOCAN. The disease now accounts for nearly 1 in 6 deaths globally, making it the second leading cause of mortality [1]. Despite progress in early detection and treatments, the global burden of cancer continues to rise, with projections indicating a 47% increase in new cases by 2040, reaching over 28 million annually [1-4]. This surge, driven by population aging and growth, alongside changing risk factors such as lifestyle and environmental exposures, underscores the escalating challenge faced by healthcare systems worldwide.

Despite progress in early detection and conventional treatments like chemotherapy and radiation, the burden of cancer continues to rise, with projections exceeding 35 million new cases by 2050 [2]. This stark reality underscores the urgent need for more precise and effective diagnostic and therapeutic approaches.

Historically, cancer treatment was limited primarily to surgery, which aimed to remove tumors. However, as our understanding of cancer biology has advanced, so too have the available therapies. Today, cancer treatment options include surgery, chemotherapy, radiation therapy, immunotherapy, and targeted therapies. Each of these approaches can be tailored based on the type of cancer, its stage, and the individual patient's needs [5]. Personalized and precision medicine are transforming cancer care by offering more targeted and efficient strategies [6]. This approach delves into the molecular foundations of cancer,

<footnote n="1">¹ INSERM, CHU Grenoble Alpes, Laboratory of Bioclinical Radiopharmaceutics, University Grenoble Alpes, 38000 Grenoble, France; bojana.bogdanovic@univ-grenoble-alpes.fr (B.B.); daniel.fagret@univ-grenoble-alpes.fr (D.F.); catherine.ghezzi@univ-grenoble-alpes.fr (C.G.)</footnote>

<footnote n="2">² Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco</footnote>

<footnote>* Correspondence: cmontemagno@centrescientifique.mc; Tel.: +377-97-77-44-10</footnote>
enabling the identification of unique patient-specific targets, such as overexpressed receptors and tumor-associated proteins. For instance, agents based on peptides, antibodies, and nanoparticles offer highly specific targeting in both preclinical cancer models and patients' disease states through targeted imaging, while also aiming to eliminate cancer cells with therapies that minimize harm to healthy tissue [7]. Despite these promising advancements, current targeting strategies face challenges such as tumor heterogeneity, drug resistance, and non-specific uptake by healthy tissues [8]. These hurdles can compromise both diagnostic accuracy and therapeutic effectiveness, highlighting the need for ongoing research and innovation in this dynamic field.

Integrins, particularly αvβ3, have emerged as prominent targets in precision oncology due to their involvement in critical processes of cancer progression, including angiogenesis, invasion, and metastasis [9]. A broad array of αvβ3-targeting agents has been developed over the years, with many incorporating the well-characterized RGD (arginine-glycine-aspartate) motif, known for its high affinity binding to this integrin [10,11]. These agents range from small peptides to monoclonal antibodies and nanoparticle conjugates. However, despite promising preclinical results, the clinical translation of RGD-based integrin-targeting agents has faced significant challenges, including inadequate tumor selectivity, heterogeneous αvβ3 expression, and the rapid clearance of small RGD peptides [11–14].

To address these limitations, dual-targeting strategies are being actively investigated. By simultaneously engaging two distinct receptors or proteins on cancer cells, in the tumor microenvironment or on immune cells, dual-targeting agents offer improved tissue uptake and enhanced pharmacokinetics compared to their monovalent counterparts [15]. Combining αvβ3 integrin targeting via the RGD motif with additional tumor-specific markers has demonstrated potential for enhancing the precision and efficacy of these agents [16,17]. This review explores the evolving landscape of dual-targeting strategies, focusing on RGD-based integrin-targeting approaches involving αvβ3, and their potential to provide more powerful tools for cancer diagnosis and therapy.

## 2. Integrins—Unveiling Tumor Dynamics

### 2.1. Fundamentals of Integrin Biology

Integrins are a large family of transmembrane adhesion receptors that play a vital role in cell communication and signaling. These receptors are composed of heterodimeric complexes formed by α and β subunits, resulting in 24 unique receptors in humans [18–20]. Each subunit is a type 1 transmembrane protein. These proteins have a large extracellular domain for ligand binding and a smaller transmembrane and intracellular region that participates in cell signaling [21].

Integrins can bind a wide variety of ligands, including insoluble extracellular matrix (ECM) proteins (e.g., fibronectin, laminin, collagen), matricellular proteins (e.g., Cyr61, CTGF, NOV), cell surface proteins (e.g., ICAMs, VCAM-1), and soluble factors (e.g., fibrinogen, complement proteins, VEGF, FGF2, TGFβ) [22]. Integrins exhibit promiscuous binding, where a single integrin can bind multiple ligands, and redundancy, where different integrins can bind the same ligand [22]. This flexibility enables integrins to support diverse cellular functions in dynamic environments, allowing cells to respond in multiple ways to the same ECM proteins. Integrins are grouped into four receptor classes based on their ligand-binding specificities: collagen receptors (recognized by α1β1, α2β1, α10β1 and α11β1), laminin receptors (recognized by α3β1, α6β1, α6β4 and α7β1), leukocyte-specific (recognized by α9β1, α4β1, α4β7, αEβ7, αLβ2, αMβ2, αXβ2 and αDβ2), and Arg-Gly-Asp (RGD) [19,23,24]. The RGD motif, recognized by eight integrins (α5β1, α8β1, αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, and αIIbβ3), is notably found in several molecules, including ECM proteins like fibronectin and vitronectin [25].

Integrins have two main functions: mediating cellular or ECM adhesion and facilitating signal transduction through outside-in and inside-out signaling. Outside-in signaling transmits signals from ECM ligands to elicit specific cellular responses, while inside-out signaling triggers conformational changes to adjust ligand affinity [26,27]. Integrins exhibit
dynamic conformational flexibility, switching between active (high affinity) and inactive (low affinity) states [21,28]. The active state is regulated by intracellular adaptor proteins talin and kindlin binding to the β-subunit cytoplasmic tail and is stabilized by ligand binding at the extracellular domain [29]. To ensure firm adhesion, integrins must cluster into adhesion complexes that link to the cytoskeleton.

Upon activation, integrins recruit several kinases such as SRC family kinases (SFKs), focal adhesion kinase (FAK), and integrin-linked kinase (ILK), which activate downstream pathways, including phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/AKT), mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK), and yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) [26,30]. These signaling cascades affect various aspects of cell behavior, including survival, proliferation, metabolism, differentiation, shape, and motility [31]. While integrins are vital for physiological processes like embryogenesis, immune response, wound healing, and angiogenesis, they are also implicated in pathological conditions such as cancer, cardiovascular diseases, and inflammation [32–36].

## 2.2. RGD-Binding Integrins in Cancer Progression

Dysregulation of integrins is a defining feature of numerous malignancies, with alterations in their expression frequently observed to promote tumor growth, survival, and metastasis [35]. Among them, integrins that recognize the RGD motifs, such as αvβ3, αvβ5, αvβ6, and α5β1, are critically involved in cancer progression [37–40]. These integrins facilitate essential oncogenic processes, including tumor cell adhesion, proliferation, migration, invasion, and contributing to neovascularization, immune evasion, and resistance to therapies [9].

Integrins-αvβ3, -αvβ6, and -α5β1, which are typically expressed at low levels in normal epithelia tissues, are frequently upregulated in tumors [35]. A key function of these integrins is the regulation of neovascularization. This process involves the formation of new blood vessels that supply essential nutrients and oxygen to the tumor, thereby supporting its growth [41,42]. Notably, integrin-αvβ3, which is expressed at minimal levels in quiescent endothelial cells, is significantly upregulated during tumor angiogenesis, where it plays a pivotal role in neovascularization [33,43]. Recent research has expanded our understanding of integrins beyond their conventional roles, implicating them in processes such as epithelial-to-mesenchymal transition (EMT), cancer stemness, and metabolic rewiring [44–46]. Moreover, integrins like αvβ6 and αvβ8 are involved in the activation of TGFβ, a key regulator of tumor immune evasion and suppression of anti-tumor immunity [47–49]. These findings suggest that integrins not only contribute to the structural aspects of tumor progression but also actively modulate the tumor microenvironment and immune landscape.

The role of RGD-recognizing integrins in metastasis is increasingly recognized as a critical area of investigation. Integrin-αvβ3, -αvβ5, and -αvβ6 have been implicated in promoting metastasis to distant organs, such as the lungs and bones. Additionally, αvβ3, αvβ5, and αvβ8 facilitate the transmigration of tumor cells across the blood-brain barrier, enabling the establishment of brain metastasis [50–55]. Integrin-α5β1 has also been identified as a mediator of liver and bone metastasis through pathways involving c-Met, Src, and focal adhesion kinase (FAK) [56].

Emerging evidence also highlights the role of exosomes in mediating metastatic processes, with integrins being highly expressed on these vesicles [57]. For example, αvβ5-expressing exosomes target liver macrophages to enhance liver metastasis, while αvβ6-expressing exosomes from prostate cancer cells promote cell migration and metastasis in a paracrine manner. Similarly, αvβ3 on breast cancer-derived exosomes has been linked to an increased propensity for lung metastasis [51,58,59].

These insights underscore the pivotal role of integrins in cancer progression and underscore their potential as therapeutic targets in oncology. Consequently, significant efforts have been directed toward developing novel anticancer therapies that target integrins,
with the aim of inhibiting tumor progression, preventing metastasis, and overcoming therapeutic resistance.

### 3. RGD Peptides in Focus—Bridging Cancer Diagnosis and Targeted Therapy

#### 3.1. Targeting RGD-Recognizing Integrins for Cancer Diagnosis

The discovery of the integrin-binding RGD domain has driven the development of RGD-based peptides for cancer diagnosis and treatment, representing a significant advancement in oncology therapeutics and imaging strategies [11]. These peptides can directly inhibit integrins or serve as delivery for anticancer drugs and imaging agents, thereby enhancing treatment efficacy while minimizing off-target effects and damage to healthy tissues.

Imaging techniques have become invaluable tools in cancer diagnosis due to their non-invasive nature and ability to provide detailed insights into tumor biology [60]. By conjugating RGD peptides with radioactive or fluorescent probes, it becomes feasible to visualize and monitor tumors with high integrin expression, using advanced imaging modalities such as positron emission (PET) and single-photon emission tomography (SPECT) [61]. Numerous RGD radiotracers have shown promising results in preclinical and clinical studies across a range of cancers including ovarian, breast, lung, head and neck, non-small cell lung, and cervical cancers [62].

Among all RGD-binding integrins, αvβ3 has emerged as a prominent target, garnering extensive interest in the development of tumor-targeting radiotracers. For diagnostic imaging, gamma-emitting radionuclides such as the Technetium-99 m ($^{99m}$Tc) are used in SPECT, while positron-emitting radionuclides such as Fluorine-18 ($^{18}$F) and Gallium-68 ($^{68}$Ga) are employed in PET [60,61,63]. Some RGD-derived tracers dedicated to imaging are summarized in Table 1.

<table><caption>**Table 1.** RGD-derived radiotracers recently evaluated in humans for the non-invasive imaging of integrins.</caption><thead><tr><td>Radiotracers</td><td>Application</td><td>Tumor Type</td><td>Clinical Trial</td><td>References</td></tr></thead><tbody><tr><td><sup>18</sup>F-Galacto-RGD</td><td>PET imaging</td><td>GBM, HNSCC, prostate cancer</td><td>Phase I</td><td>[64–66]</td></tr><tr><td><sup>18</sup>F-Alfatide</td><td>PET imaging</td><td>Lung cancer, GBM</td><td>Phase I</td><td>[67–70]</td></tr><tr><td><sup>68</sup>Ga-NOTA-PRGD2</td><td>PET imaging</td><td>Lung cancer, gliomas</td><td>Phase I</td><td>[71–73]</td></tr><tr><td><sup>68</sup>Ga-DOTA-RGD2</td><td>PET imaging</td><td>HSNCC, breast, thyroid cancer, and chondrosarcoma</td><td>Phase I and Case report</td><td>[74–76]</td></tr><tr><td><sup>68</sup>Ga-NODAGA-E[c(RGDyK)]2</td><td>PET imaging</td><td>Breast, neuroendocrine tumors, and thyroid cancers</td><td>Phases I and II</td><td>[77–79]</td></tr><tr><td><sup>99m</sup>Tc-3PRGD2</td><td>SPECT imaging</td><td>Lung cancer</td><td>Phase III</td><td>NCT04233476</td></tr><tr><td><sup>68</sup>Ga-cycratinide</td><td>PET imaging</td><td>Pancreatic cancer</td><td>First in human</td><td>[80]</td></tr><tr><td><sup>18</sup>F-αvβ6-BP</td><td>PET imaging</td><td>Pancreatic cancer</td><td>First in human</td><td>[81]</td></tr><tr><td><sup>18</sup>F-FP-R01-MG-F2</td><td>PET imaging</td><td>Pancreatic cancer</td><td>Phase I</td><td>[82]</td></tr></tbody></table>

For instance, $^{18}$F-Galacto-RGD PET has been evaluated to detect and visualize αvβ3 integrin expression in various cancers. In glioblastoma (GBM) (SUV range, 0.8–2.8; mean, 1.6 ± 0.5) and in head and neck squamous cell carcinoma (HNSCC) (SUV range, 2.2–5.8; mean, 3.4 ± 1.2), it allows for non-invasive monitoring of αvβ3 integrin expression [64,65]. Additionally, $^{18}$F-Galacto-RGD has been effective in visualizing bone metastases in prostate cancer patients [66].

Similarly, $^{18}$F-Alfatide has shown promise in identifying malignant lung tumors with high tumor-to-background ratios [67]. Additionally, all malignant lymph nodes in patients with lung tumors were successfully visualized on $^{18}$F-Alfatide PET/CT in patients, and
the sensitivity, specificity, and accuracy were 100.0%, 94.9%, and 95.4%, respectively [68].
$^{18}$F-Alfatide has also been positively evaluated for $\alpha v\beta3$ imaging in GBM, with uptake
levels correlating with tumor grade. It has also shown potential for assessing GBM response
standard therapies [69,70].

$^{68}$Ga-NOTA-PRGD2 PET/CT is another imaging tool that has been evaluated in multiple cancer types. In GBM, it has shown superior accuracy in visualizing $\alpha v\beta3$ integrin expression, assessing tumor grade, and differentiating between high-grade glioma and uncommon meningioma [71,72]. Studies conducted in lung malignancies demonstrated greater specificity for $^{68}$Ga-NOTA-PRGD2 than the current gold standard, $^{18}$F-FDG PET/CT, for the detection of lymph node metastasis with positive and negative predictive values of 90.0% (27/30) and 93.8% (121/129), respectively, whereas those of $^{18}$F-FDG PET/CT were 30.2% (29/96) and 90.5% (57/63), respectively [73]. Such results were also confirmed using $^{68}$Ga-DOTA-RGD2 PET/CT. $^{68}$Ga-DOTA-RGD2 enhances the visualization of angiogenesis in HNSCC and is effective in detecting primary and metastatic lymph nodes in breast cancer, surpassing $^{18}$F-FDG in specificity and accuracy for thyroid cancer detection [74,75]. Notably, in cases of chondrosarcoma, $^{18}$F-FDG showed limited uptake due to low mitotic activity. However, $^{68}$Ga-DOTA-RGD2 PET/CT showed significant uptake, suggesting a potential role for angiogenesis-targeted radiopharmaceuticals in refractory cases [76].

Among the recently developed RGD-based radiotracers, $^{68}$Ga-NODAGA-E[c(RGDyK)]2 has garnered significant attention due to its promising clinical performance. In a first-in-human phase I trial, $^{68}$Ga-NODAGA-E[c(RGDyK)]2 was safely used for imaging integrin $\alpha v\beta3$ in patients with breast cancer and in NEN (neuroendocrine neoplasms) patients, exhibiting low radiation exposure and favorable tumor monitoring [77]. In a phase II study, high tumor uptake was noted across all NEN grades, with a correlation between increased uptake and poorer prognosis [78]. High integrin $\alpha_v\beta_3$ expression (defines as SUVmax > 5.25) had a hazard ratio of 2.11 and 6.95 for progression-free survival and overall survival, respectively (p = 0.01 for both). Additionally, this tracer was employed to assess RGD-binding integrin expression in thyroid cancer patients with negative radioiodine scintigraphy, revealing high expression in metastatic lesions, particularly in bone metastases [79]. Further research is warranted to validate its potential as a predictive tool for selecting patients suitable for integrin $\alpha v\beta3$-targeted therapies.

Finally, a phase 3 clinical trial of $^{99m}$Tc-3PRGD2 (NCT04233476) showed safety and efficacy for the diagnosis of lung cancer, potentially paving the way for its approval as a novel radiopharmaceutical for cancer diagnosis.

Beyond $\alpha v\beta3$, RGD radiotracers targeting other integrins have also been developed and evaluated in clinical translational studies. The $^{68}$Ga-labeled cyclic peptide $^{68}$Ga-cycratinide, designed to target integrin $\alpha v\beta6$ via the RGDLATL sequence, exhibited enhanced serum stability and increased tumor uptake in comparison to the linear form, showing promise in detecting pancreatic neoplastic lesions and postoperative recurrence [80]. The tumor uptake of $^{68}$Ga-cycratinide was significantly higher than that of $^{68}$Ga-linear-pep (2.15 ± 0.46 vs. 0.94 ± 0.58%ID/g; *p* < 0.05). The $\alpha v\beta6$-targeting peptide $^{18}$F-$\alpha v\beta6$-BP has shown effective tumor imaging, underscoring its clinical potential across various malignancies due to its ability to selectively target tumors with high $\alpha v\beta6$ expression [81]. Similarly, the tracer $^{18}$F-FP-R01-MG-F2 has yielded promising results in a pilot-phase PET/CT study, demonstrating safety and favorable radiation dosimetry in patients with pancreatic cancer, further supporting its potential as a diagnostic tool in $\alpha v\beta6$-positive tumors [82].

These advancements in RGD-based radiotracers are poised to enhance cancer detection and monitoring, providing novel insights into tumor biology and opening avenues for more targeted and effective therapies. Moreover, RGD peptides are being developed not only as diagnostic agents but also as therapeutic agents, underscoring their dual potential in oncology.
## 3.2. RGD-Based Peptides for Cancer Therapy

### 3.2.1. Pharmacological Targeting of Integrins

A range of RGD-containing peptides have been developed to inhibit angiogenesis and tumorigenesis. Among these, Cilengitide (cyclo-Arg-Gly-Asp-DPhe-NMe-Val), a cyclic pentapeptide that blocks the RGD binding site, has emerged as a selective inhibitor of αvβ3 and αvβ5 integrins [83]. While preclinical studies demonstrated its efficacy in inhibiting angiogenesis and glioblastoma (GBM) growth, and early-phase clinical trials showed moderate anti-tumor effects, later-phase trials were less successful [84–86]. A phase II trial even suggested improved overall survival rates with Cilengitide [87]. However, subsequent larger-scale trials, including the randomized phase III CENTRIC and phase II CORE studies, failed to show significant improvements in overall survival with the addition of Cilengitide [12,13]. The limited success in these later trials may be attributed to the tumor microenvironment's complexity, which can activate compensatory VEGF pathways and resistance mechanisms [88]. Nevertheless, in a retrospective study, high levels of αvβ3 were associated with anti-tumor response to Cilengitide, suggesting the potential need for patient stratification based on αvβ3 expression [89]. Furthermore, Cilengitide's fast blood clearance underscores the necessity of alternative strategies, such as combining RGD peptides with other molecules, to improve integrin-targeting therapies.

### 3.2.2. RGD-Based Peptides for Drug Delivery

RGD-based peptides are also increasingly explored for their ability to enhance the targeted delivery of therapeutics, including chemotherapy agents, peptides, and nucleic acids, via nanocarriers such as liposomes, nanoparticles, and micelles in pre-clinical studies [90]. RGD peptide-modified nanoparticles, such as solid lipid nanoparticles (SLNs) and pH-sensitive nanoparticles (RGD-NAMs), have demonstrated improved oral bioavailability and tumor targeting [91,92]. RGD-DOX-SLNs loaded with doxorubicin offer superior tumor inhibition and reduced side effects in breast cancer models, while RGD-NAMs enable controlled drug release through temperature- and pH-sensitive mechanisms [91,93]. Moreover, paclitaxel-loaded RGD nanoparticles have shown improved targeting and efficacy in lung cancer treatment, leading to significant tumor reduction and reduced systemic toxicity compared to free drugs [94]. The LCP-RGD nanoparticle, designed with a calcium phosphate core and RGD-modified components, provides an effective platform for co-delivering docetaxel (DTXL) and GRP78 siRNA. This nanoparticle demonstrates high drug and siRNA loading capacity, and enhanced anti-cancer effects, making it a promising tool for overcoming drug resistance in castration-resistant prostate cancer [95].

### 3.2.3. RGD-Based Radiotracers for Targeted Radiotherapy

Certain RGD-based radiopharmaceuticals in nuclear medicine not only assist with diagnosis but also provide therapeutic benefits through targeted radiotherapy, especially in oncology, known as the 'theranostic approach' [96]. In these treatments, α- and β-particle-emitting radionuclides like Iodine-131 (¹³¹I), Lutetium-177 (¹⁷⁷Lu), and Yttrium-90 (⁹⁰Y) are preferred for their high linear energy transfer (LET) [60,61,63]. In preclinical studies, RGD radiotracers like ¹⁷⁷Lu-3PRGD2 and RAFT-RGD labeled with ⁶⁷/⁶⁴Cu, ¹⁷⁷Lu, or ⁹⁰Y have shown significant tumor growth inhibition in αvβ3-positive glioblastoma models [97–100]. ¹⁷⁷Lu-DOTA-E(cRGDfK)2 has demonstrated significant anti-tumor effect, indicating its potential for peptide receptor radionuclide therapy [101]. Similar anti-tumor effects were reported in melanoma using a ¹⁷⁷Lu-PAMAM-DOTA-cRGDfK counterpart [102]. In preclinical models of pancreatic ductal adenocarcinoma expressing both αvβ3 and αvβ6, ²²⁵Ac-DOTA-RGD2 effectively inhibits tumor growth and extends survival with minimal toxicity, supporting the potential of the development of targeted alpha-therapy [103].

Despite promising preclinical results, clinical research on RGD-radiotracers for cancer therapy remains limited. ¹⁷⁷Lu-DOTA-RGD2 was evaluated in a patient with thyroid cancer based on TEP images obtained after ⁶⁸Ga-DOTA-RGD2 injection. Post-therapy
imaging demonstrated reduced tracer uptake and significant clinical improvement [104]. This represents the first reported use of <sup>68</sup>Ga-DOTA-RGD2 and <sup>177</sup>Lu-DOTA-RGD2 in theranostic treatment, paving the way for future studies. Additionally, an ongoing clinical trial is assessing the safety and dosimetry of <sup>177</sup>Lu-AB-3PRGD2 in lung cancer patients, with results expected by late 2024 [105].

These advancements highlight the promise of RGD-based nanoparticles and radio-pharmaceuticals in overcoming cancer therapy challenges, enhancing drug delivery and efficacy while reducing side effects. However, issues related to tumor microenvironment complexity and targeting precision persist, indicating the need for further refinement and optimization of this targeting strategy.

### 3.3. Challenges and Limitations in Integrin Targeting

Integrin-targeted therapies, particularly those utilizing RGD peptides such as cilengitide, have shown substantial promise in preclinical cancer models, including osteosarcoma, medulloblastoma, and glioblastoma [39,84,106]. However, their translation into clinical success has faced numerous challenges. One major issue is the variability in integrin expression across different tumor types and even within different regions of the same tumor [9]. Tumor heterogeneity can result in inconsistent therapeutic outcomes. Some tumor cells may not express the targeted integrins or their ligands, or they may express them at insufficient levels for effective targeting. This heterogeneity is widely recognized as a major factor contributing to therapeutic resistance and treatment failure [107]. By understanding the underlying drivers of this heterogeneity, we could develop novel strategies to overcome treatment resistance.

Another significant challenge is the redundancy of integrin functions, which complicates targeting strategies [22]. Since multiple integrins can bind to the same extracellular matrix (ECM) proteins, blocking a single integrin might not be enough to disrupt tumor growth or metastasis, as other integrins could compensate for its loss. This redundancy necessitates designing therapies that can effectively target multiple integrins or pathways to achieve meaningful therapeutic effects. Additionally, integrins may have context-dependent roles; for example, some may promote tumor growth in primary tumors while inhibiting metastasis, or vice versa [108].

This dynamic behavior of integrins across cancer stages complicates drug development, as integrin expression can change within tumors over time. This makes it difficult to identify consistent therapeutic targets, as a drug effective in early-stage cancer may not work in later stages [109].

Moreover, the sequestration of RGD-targeted drugs by tumor-derived extracellular vesicles (TEVs) presents another obstacle. TEVs, which are prevalent in the tumor microenvironment, may express the same integrins as the tumor cells, leading to the inadvertent absorption of therapeutic agents before they reach their intended targets [57,59,110]. This sequestration reduces the efficacy of the treatments and poses a significant challenge to RGD-targeted therapies.

Given these challenges, a promising strategy is to employ dual targeting approaches that combine RGD with other targeting moieties or therapeutic strategies. This dual approach could help overcome issues related to integrin redundancy and variability by ensuring that a broader spectrum of tumor cells is targeted more effectively, while also reducing the likelihood of therapeutic agents being sequestered by TEVs. In this way, double targeting could significantly improve the outcomes of cancer management with RGD-based therapies, making them more effective in clinical settings (Figure 1).
<figure><img src="image_6.png" /><figcaption>**Figure 1.** Schematic representation of tumors with high RGD-binding integrin expression, which drives tumor progression, metastasis, and angiogenesis. The figure illustrates various strategies targeting RGD-binding integrins, such as drug delivery through nanoparticles and liposomes, imaging and radiotherapy with radiopharmaceuticals, and pharmacological intervention using RGD inhibitors. Additionally, dual-targeting approaches are shown, which combine the targeting of RGD-binding integrins with other molecular targets. These dual-targeting strategies aim to improve the specificity and efficacy of both diagnostic and therapeutic interventions by simultaneously addressing multiple pathways involved in tumor growth and resistance, offering enhanced therapeutic outcomes compared to traditional single-target approaches.</figcaption></figure>

**4. Dual-Targeting Approaches Based on RGD Peptides**

Heterobivalent ligands provide notable advantages over monovalent agents in cancer management by targeting multiple receptors simultaneously or independently. This approach is particularly advantageous for tumors characterized by heterogeneous receptor expression, where single-target strategies may fall short [17]. Monospecific agents, such as RGD-based radiotracers, have shown potential, and their efficacy can be limited by partial receptor expression, resulting in incomplete lesion detection. While the use of separate monospecific agents could address this issue by targeting different receptors individually, this strategy presents several drawbacks, including increased regulatory hurdles, heightened patient discomfort, and elevated costs. In contrast, heterobivalent approaches, which use multifunctional platforms like radiotracers, nanoparticles, and liposomes, simplify the process with a single application, enhancing stability, avidity, and tumor detection [15]. In this review, we delve into RGD-based dual-targeting strategies, mostly focusing on radiotracers (Table 2) that target αvβ3 and other biomarkers to advance cancer diagnosis and treatment.
<table><caption>**Table 2.** Dual-targeting heterobivalent radiotracers incorporating RGD motifs for tumor imaging and therapy currently in development.</caption><thead><tr><th>Targets</th><th>RGD-Based Molecule</th><th>Radioisotope</th><th>Application</th><th>Tumor Model (In Vivo)</th><th>Clinical Trial</th><th>References</th></tr></thead><tbody><tr><td rowspan="3">GRPR and αvβ3</td><td>NOTA-BBN-RGD</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>PC3 mice</td><td>Prostate (First in human(FIH)) and breast cancer (Phase I)</td><td>[111–113], NCT02749019</td></tr><tr><td>RGD-Glu-[DO3A]-6-Ahx-RM2</td><td><sup>86</sup>Y/<sup>90</sup>Y</td><td>PET imaging and therapy</td><td>PC3 mice</td><td>/</td><td>[114]</td></tr><tr><td>RM26-RGD (LNC1015)</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>PC3 mice</td><td>Breast (FIH), brain (Phase I), and prostate cancer (Phase I)</td><td>[115,116], NCT05549024</td></tr><tr><td>SSTR and αvβ3</td><td>NOTA-3P-TATE-RGD</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>H69 and A549 mice</td><td>SCLC and NSCLC (Phase I), GEP-NETs (Phase I), and RAIR-TC (Phase I)</td><td>[117–120]</td></tr><tr><td rowspan="5">FAP and αvβ3</td><td>FAPI-RGD (LNC1007)</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>Panc02 mice</td><td>Various solid tumors (Phases I/II)</td><td>[121–126]</td></tr><tr><td>AIF-LNC1007</td><td><sup>18</sup>F</td><td>PET imaging</td><td>U87MG mice</td><td>Breast cancer (Phase I)</td><td>[127,128], NCT06471712</td></tr><tr><td>DOTA-FAPI-RGD</td><td><sup>68</sup>Ga/<sup>177</sup>Lu</td><td>PET/SPECT imaging and therapy</td><td>U87MG mice</td><td>/</td><td>[129]</td></tr><tr><td>FAP-RGD</td><td><sup>68</sup>Ga/<sup>177</sup>Lu</td><td>PET/SPECT imaging and therapy</td><td>HT1080-FAP and U87MG mice</td><td>/</td><td>[130]</td></tr><tr><td>DOTA-EB-FAPI-RGD (LNC1009)</td><td><sup>177</sup>Lu</td><td>SPECT imaging and therapy</td><td>U87MG mice</td><td>/</td><td>[131]</td></tr><tr><td rowspan="2">PSMA and αvβ3</td><td rowspan="2">iPSMA-RGD</td><td><sup>177</sup>Lu</td><td>SPECT imaging and therapy</td><td>/</td><td>/</td><td>[132]</td></tr><tr><td><sup>225</sup>Ac</td><td>Therapy</td><td>HCT116 mice</td><td>/</td><td>[133]</td></tr><tr><td rowspan="2">APN/CD13 and αvβ3</td><td>NGR-RGD (HX01)</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>Various tumor models</td><td>Solid tumors (Phase I)</td><td>[134–136], NCT06416774</td></tr><tr><td>HX01-L6</td><td><sup>68</sup>Ga/<sup>177</sup>Lu</td><td>PET/SPECT imaging and therapy</td><td>BxPC-3 mice</td><td>/</td><td>[137]</td></tr><tr><td rowspan="3">NRP-1 and αvβ3</td><td>AIF-NOTA-RGD-ATWLPPR</td><td><sup>18</sup>F</td><td>PET imaging</td><td>U87MG mice</td><td>/</td><td>[138]</td></tr><tr><td>DOTA-RGD-A7R</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>MCF-7 mice</td><td>/</td><td>[139,140]</td></tr><tr><td>iRGD-C6-lys-C6-DA7R</td><td><sup>211</sup>At</td><td>Therapy</td><td>U87MG mice</td><td>/</td><td>[141]</td></tr><tr><td rowspan="3">EGFR and αvβ3</td><td>NOTA-RGD-GE11</td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>NCI-H292 mice</td><td>/</td><td>[142]</td></tr><tr><td>NODA-GA-PEG3-GE11-PEG3-RGD</td><td><sup>64</sup>Cu</td><td>PET imaging</td><td>BxPC3 mice</td><td>/</td><td>[143]</td></tr><tr><td></td><td><sup>68</sup>Ga</td><td>PET imaging</td><td>A431 mice</td><td>/</td><td>[144]</td></tr><tr><td rowspan="2">uPAR and αvβ3</td><td>AE105-NOTA-RGD</td><td><sup>68</sup>Ga/<sup>64</sup>Cu</td><td>PET imaging</td><td>U87MG mice</td><td>/</td><td>[145]</td></tr><tr><td>AE105-PEG8-NOTA-PEG4-RGD</td><td><sup>68</sup>Ga/<sup>64</sup>Cu</td><td>PET imaging</td><td>U87MG and PANC-1 mice</td><td>/</td><td>[146,147]</td></tr><tr><td>MC1R and αvβ3</td><td>SiFAlin-GG-Nle-c(DHfRWK)-PEG8-RGD</td><td><sup>18</sup>F</td><td>PET imaging</td><td>B16F1 mice</td><td>/</td><td>[148]</td></tr></tbody></table>

## 4.1. Dual-Targeting RGD-Based Radiotracers for Imaging and Targeted Therapy

### 4.1.1. Dual Targeting of GRPR and αvβ3

Gastrin-releasing peptide receptor (GRPR) is a G protein-coupled receptor that binds to the neuropeptide gastrin-releasing peptide (GRP), playing a critical role in stimulating gastric acid secretion and regulating gastrointestinal motility [149]. GRPR contributes to tumor growth and progression and is overexpressed in various cancers, including prostate, breast, small cell lung (SCLC), colon, gastrointestinal, and pancreatic cancer, as well as glioblastomas and neuroblastomas [150]. Due to its expression pattern, GRPR is an attrac-
tive target for cancer imaging and therapy. Theranostic agents targeting GRPR are currently under clinical investigation [151].

One dual-targeting tracer developed for GRPR and αvβ3 was developed, the BBN-RGD. After successful preclinical studies in mouse models of pancreatic tumors, which demonstrated higher tumor uptake of ⁶⁸Ga-BBN-RGD compared to ⁶⁸Ga-BBN or ⁶⁸Ga-RGD alone, a first-in-human trial evaluated the safety and diagnostic effectiveness of ⁶⁸Ga-NOTA-BBN-RGD in prostate cancer patients [111,112]. The study showed no adverse effects and confirmed the radiotracer's safety, with a radiation dose well below FDA limits. ⁶⁸Ga-NOTA-BBN-RGD PET/CT detected more primary tumors (3/4 vs. 2/4 for ⁶⁸Ga-BBN), metastatic lymph nodes (14 vs. 5), and bone lesions (20 vs. 12) compared to ⁶⁸Ga-BBN alone, indicating superior diagnostic performance. This result prompted additional evaluation of the radiotracer in breast cancer patients [113]. The findings revealed substantial ⁶⁸Ga-NOTA-BBN-RGD accumulation in primary tumors and metastases, correlating with GRPR and αvβ3 expression. In 11 patients who underwent two PET scans in this study, ⁶⁸Ga-BBN-RGD PET/CT identified 13 suspected primary tumor lesions in 9 patients, along with 8 metastatic lymph nodes, 9 bone metastases, and 4 lung metastases. In comparison, ⁶⁸Ga-BBN PET/CT detected 11 suspected primary tumor lesions in 7 patients, along with 3 metastatic lymph nodes, 3 bone metastases, and 2 lung metastases.

Another dual-targeting tracer, RGD-Glu-[DO3A]-6-Ahx-RM2, was developed by linking RGD and RM2 peptides with a DOTA chelating, radiolabeled with ⁶⁶Y or ⁹⁰Y and tested in preclinical models [114]. Biodistribution studies in mice bearing pancreatic tumors revealed significant tumor uptake and retention of the tracer. Micro PET imaging supported these findings, showing effective targeting and retention, which positions RGD-Glu-[DO3A]-6-Ahx-RM2 as a promising candidate for further imaging studies in larger animal models and potentially in clinical settings.

Finally, the recently developed radiotracer RM26-RGD (LNC1015) has shown strong potential as a dual-targeting agent for GRPR and αvβ3 in PET imaging [115]. In preclinical studies using a pancreatic xenograft model, ⁶⁸Ga-RM26-RGD demonstrated high stability, favorable binding affinity, and superior tumor uptake compared to the monomeric tracers ⁶⁸Ga-RGD and ⁶⁸Ga-RM26. Early clinical trials in breast cancer patients corroborated these findings, revealing significantly higher tumor uptake and improved tumor-to-background ratios compared to ¹⁸F-FDG. Additionally, in a cohort of 23 brain tumor patients, ⁶⁸Ga-RM26-RGD demonstrated high tumor uptake and favorable tumor-to-background ratios compared to the monomeric tracers ⁶⁸Ga-RM26 and ⁶⁸Ga-BBN, with a moderate positive correlation with tumor grade [116]. Currently, this tracer is being further evaluated in a clinical trial for PET/CT imaging of breast, brain, and prostate cancers, where its diagnostic efficacy is being compared to ¹⁸F-FDG, ⁶⁸Ga-RGD, and ⁶⁸Ga-RM26 (NCT05549024). Overall, these findings highlight the potential of dual-targeting radiotracers that focus on αvβ3 integrin and GRPR to improve the accuracy of cancer diagnosis and staging in specific cancer types.

### 4.1.2. Dual Targeting of SSTR and αvβ3

Somatostatin receptors (SSTRs) are a class of G protein-coupled receptors that bind somatostatin, a peptide hormone that inhibits the release of several other hormones and regulates various physiological [152]. There are five known subtypes of SSTRs (SSTR1-5), which are expressed in various tissues including the brain, gastrointestinal tract, and pancreas. SSTRs are overexpressed in many neuroendocrine tumors, making them critical targets for both diagnostic imaging and therapy [153]. Radiolabelled somatostatin analogs, such as ⁶⁸Ga-DOTATATE and ¹⁷⁷Lu-DOTATATE (Luthatera®), are commonly used in PET imaging and targeted radionuclide therapy, respectively, to detect and treat SSTR-expressing tumors. Luthatera® became the first FDA-approved peptide receptor radionuclide therapy (PRRT) following the NETTER-1 trial, which demonstrated a remarkable progression-free survival (PFS) in comparison to octreotide [154]. Despite these
advances, resistance to PRRT can develop, necessitating the exploration of alternative therapeutic strategies, such as dual-targeting approaches.

The radiotracer ⁶⁸Ga-NOTA-3P-TATE-RGD has been recently evaluated for its dual-targeting properties towards SSTR2 and αvβ3. This tracer exhibited binding affinities comparable to its monomeric counterparts in both in vitro and in vivo models of small (SCLC) and non-small cell lung cancers (NSCLC), suggesting its broad applicability for detecting cancers involving both SSTR2 and integrin αvβ3 [117]. In a proof-of-concept study involving 32 patients with NSCLC and SCLC, ⁶⁸Ga-NOTA-3P-TATE-RGD provided high-quality imaging with significantly improved tumor-to-background (T/B) ratios compared to its monomeric forms [118]. Immunohistochemical analysis further confirmed the presence of SSTR2 and variable integrin αvβ3 levels in tumor lesions, highlighting the tracer's effectiveness in dual targeting.

In a subsequent study involving 35 patients with neuroendocrine tumors (NETs), ⁶⁸Ga-NOTA-3P-TATE-RGD identified more liver lesions (634 vs. 532, *p* = 0.021) and showed superior T/B ratios in the liver compared to ⁶⁸Ga-DOTATATE (8.4 ± 5.5 vs. 4.7 ± 3.7, *p* < 0.001), proving particularly effective in detecting FDG-avid NETs [119]. Finally, in a cohort of 12 patients with radioiodine-refractory thyroid carcinoma (RAIR-TC)—a type of thyroid cancer resistant to traditional iodine-based treatments—⁶⁸Ga-NOTA-3P-TATE-RGD demonstrated slightly higher T/B ratios for lymph node metastases and was comparable to ¹⁸F-FDG in detecting other metastases [120,155]. Overall, ⁶⁸Ga-NOTA-3P-TATE-RGD emerges as a versatile dual-targeting radiotracer that enhances imaging and detection across various cancers, improving diagnostic precision and therapeutic management.

### 4.1.3. Dual Targeting of FAP and αvβ3

Fibroblast activation protein (FAP) is a serine protease predominantly expressed in the stroma of solid tumors including breast, pancreatic, and colorectal cancers, while being minimally present in normal tissues [156]. Its elevated expression correlates with tumor progression and poor prognosis, making it a promising target for imaging and therapy. FAP is commonly targeted with radiotracers such as Fibroblast Activation Protein Inhibitors (FAPIs), which specifically bind to FAP, enabling precise imaging and potential therapeutic intervention in tumor-associated stromal cells [157–159].

The dual-targeting PET tracer ⁶⁸Ga-NOTA-FAPI-RGD, designed to target both FAP and integrin αvβ3, demonstrated significantly enhanced tumor uptake, retention, and TBR compared to its monomeric counterparts ⁶⁸Ga-FAPI-02 and ⁶⁸Ga-RGDfK in preclinical pancreatic tumor models [121]. Indeed, tumor uptake of ⁶⁸Ga-NOTA-FAPI-RGD was 5.33 ± 0.27% ID/g, compared to 2.89 ± 0.09% ID/g for ⁶⁸Ga-RGDfK and 1.16 ± 0.07% ID/g for ⁶⁸Ga-FAPI-02 at 2 h post-injection. This result led to a preliminary clinical study involving six newly diagnosed cancer patients, where ⁶⁸Ga-NOTA-FAPI-RGD showed favorable pharmacokinetics with rapid and high tumor uptake, prolonged retention, effective dosimetry and comparable maximal uptake to ¹⁸F-FDG, underscoring its strong diagnostic potential [121].

In a pilot study involving 51 patients with suspected lung malignancies, ⁶⁸Ga-NOTA-FAPI-RGD outperformed ¹⁸F-FDG, ⁶⁸Ga-RGD, and ⁶⁸Ga-FAPI-04 in detecting primary tumors and metastases, and exhibited superior accuracy in evaluating mediastinal lymph nodes [122]. Further clinical evaluation in 22 patients across various cancer types revealed that ⁶⁸Ga-FAPI-RGD had higher tumor uptake and TBR compared to ¹⁸F-FDG and ⁶⁸Ga-FAPI-46, leading to an improved detection of primary tumors, lymph node, and bone metastases. This study also evaluated the safety and effectiveness of the tracer [123]. The enhanced imaging capability of ⁶⁸Ga-NOTA-FAPI-RGD was attributed to its dual targeting of FAP and integrin αvβ3, making it more effective in detecting both tumor and stromal components.

In comparative studies, ⁶⁸Ga-NOTA-FAPI-RGD (LNC1007) exhibited superior detection of primary tumors and metastases in 61 patients across different cancers compared to ¹⁸F-FDG and ⁶⁸Ga-FAPI-02 PET/CT [124]. It also showed enhanced performance in renal
cell carcinoma (RCC) imaging, surpassing ¹⁸F-FDG and ⁶⁸Ga-PSMA in detecting primary lesions, skeletal, and peritoneal metastasis, with strong correlations to FAP expression [125]. Additionally, the tracer effectively distinguishes between aggressive and less aggressive RCC. Finally, a recent case report showed ⁶⁸Ga-NOTA-FAPI-RGD successfully identifying metastasis in a case of radioiodine-refractory thyroid cancer, with superior uptake and clearer lesion delineation compared to ¹⁸F-FDG, highlighting its potential for targeted treatment [126].

A comparison of ⁶⁸Ga- and ¹⁸F-AIF-LNC1007 revealed similar pharmacokinetics, with both tracers showing high tumor uptake and prolonged retention in preclinical glioblastoma models [127]. Clinical evaluations of ¹⁸F-AIF-LNC1007 in six cancer patients confirmed its stability, effective imaging performance, and increasing TBR over time. In a study involving 33 patients with breast cancer, ¹⁸F-AIF-LNC1007 was compared with ¹⁸F-FDG and ¹⁸F-FAPI-04. It showed higher uptake in primary tumors and metastases than ¹⁸F-FDG but showed lower TBR for bone metastases [128]. In contrast, ¹⁸F-FAPI-04 had better performance in maximal uptake for all lesions, including bone metastases, while ¹⁸F-FDG excelled in imaging liver metastases and correlated well with metastatic tumor volume in small bone lesions. A clinical trial is currently recruiting to evaluate the pharmacokinetics, biodistribution, dosimetry, and safety of ¹⁸F-LNC1007 in healthy volunteers and cancer patients with minimal tumor burden (NCT06471712).

While FAPI-RGD-based tracers have demonstrated exceptional performance in clinical diagnostics, ongoing research aims to optimize their structure for enhanced efficacy in targeted radiotherapy. The DOTA-FAPI-RGD tracer, labeled with either ⁶⁸Ga or ¹⁷⁷Lu, has shown high yields, stability, strong binding, and rapid internalization in FAP/αVβ3-positive glioblastoma cells [129]. In preclinical models, this tracer achieved high tumor uptake, rapid clearance, and clear imaging. The ¹⁷⁷Lu-labeled version of this heterodimeric ligand shows promise for therapeutic applications. Preclinical studies involving ⁶⁸Ga- or ¹⁷⁷Lu-labeled FAP-RGD, synthesized from FAP-2286 and c(RGDfK), demonstrated strong binding affinity, increased tumor uptake, and prolonged retention compared to their monomeric counterparts [130]. These studies confirm the tracer's favorable imaging properties and effective antitumor responses, highlighting its potential for targeted radiotherapy.

A recent work of Wen et al., highlighted the potential of ¹⁷⁷Lu-DOTA-EB-FAPI-RGD (LNC1009), a modification of LNC1007 with an Evans Blue motility to enhance tumor targeting, showed great promise for the imaging and therapy of solid tumors that are FAP⁺/αVβ₃⁻, FAP/αVβ₃⁺, or FAP⁺/αVβ₃⁺ [131].

The promising results from dual-targeting PET tracers like ⁶⁸Ga-FAPI-RGD, ¹⁸F-AIF-LNC1007, or ¹⁷⁷Lu-LNC1009 highlight their potential to significantly improve both diagnostic accuracy and therapeutic outcomes by enhancing tumor visualization and targeting capabilities, particularly in complex cancer cases. However, further investigations are warranted to determine their clinical value.

### 4.1.4. Dual Targeting of PSMA and αVβ3

This dual-target strategy also takes advantage of the recent development of PSMA-derived tracers. PSMA is a glycoprotein predominantly expressed on the surface of prostate epithelial cells and is significantly overexpressed in prostate cancer, particularly in advanced and metastatic forms [160]. PSMA contributes to cancer progression by promoting tumor cell growth, invasion, and angiogenesis, and it interacts with the extracellular matrix, which facilitates metastasis [161,162]. Its limited expression in normal tissues makes PSMA an ideal target for both diagnostic imaging and targeted therapies, improving the precision and effectiveness of prostate cancer management [163–165].

As heterobivalent peptides gain prominence in targeted radionuclide therapy, the ¹⁷⁷Lu-iPSMA-RGD peptide, which targets both PSMA and αVβ3 integrins, serves as a key example, designed to enhance tumor targeting and improve therapeutic results. The peptide demonstrated a strong binding affinity to PSMA and αVβ3 integrins in vitro, as well as an effective reduction in cell viability and induced apoptosis in U87MG glioblastoma
cells [132]. While iPSMA-RGD showed potential for dual targeting, it did not outperform the individual components in receptor recognition, warranting further preclinical studies to assess its therapeutic potential.

For colorectal cancer, ²²⁵Ac-iPSMA-RGD showed increased cytotoxicity in HCT116 cells, inducing significant DNA damage, apoptosis, and cell death [133]. In mice, tumor growth was markedly reduced with ²²⁵Ac-iPSMA-RGD compared to untreated controls. Eleven days after treatment, ²²⁵Ac-iPSMA-RGD achieved a greater tumor reduction than ²²⁵Ac-RGD and ²²⁵Ac-PSMA. These findings, reflecting the ablative doses of the radiopharmaceuticals, suggest that ²²⁵Ac-iPSMA-RGD has strong potential for treating colorectal cancer, similar to the effectiveness seen with higher doses in metastatic prostate cancer. The clinical applicability of such treatments needs to be further investigated.

### 4.1.5. Dual Targeting of APN/CD13 and αvβ3

Aminopeptidase N (APN), also known as CD13, is a cell surface metalloprotease involved in various physiological and pathological processes, including tumor growth and angiogenesis [166]. It is highly expressed on the surface of tumor-associated endothelial cells and certain cancer cells, making it a valuable target for cancer imaging and therapy. APN interacts indirectly with integrins by influencing the extracellular matrix and modulating cell adhesion and migration processes, which are crucial for tumor progression [167].

The dual-targeting PET imaging tracer ⁶⁸Ga-NGR-RGD was designed to target both integrin αvβ3 and APN (CD13) [134]. In breast cancer models, this tracer demonstrated high stability and specificity, achieving superior tumor uptake and contrast compared to single-target tracers and detecting metastatic lung lesions. Further evaluation in ovarian cancer models showed that ⁶⁸Ga-NGR-RGD provided better contrast and more clearly delineated peritoneal and liver metastases than ¹⁸F-FDG [135]. Renamed ⁶⁸Ga-HX01, it was tested in various tumor models, including those for pancreas, breast, gallbladder, lung, ovary, colorectal, liver, stomach, and glioma cancers, outperforming single-target probes and ¹⁸F-FDG with higher tumor uptake and improved tumor-to-background ratios [136].

The promising results led to the initiation of a clinical translation. A Phase Ia study was conducted to evaluate the safety, biodistribution, radiation dose, and pharmacokinetics of ⁶⁸Ga-HX01 in healthy Chinese adults, while a Phase Ib study focused on its safety and tumor imaging capabilities in patients with malignant solid tumors (NCT06416774). Despite these advances, ⁶⁸Ga-HX01 seems to face challenges with fast clearance and limited tumor retention. To address these issues, a new radiopharmaceutical, ⁶⁸Ga-HX01-L6, was developed by adding an albumin binder to the HX01 structure [137]. ⁶⁸Ga-HX01-L6 demonstrated significantly improved tumor uptake and retention in pancreas xenograft models. When labeled with ¹⁷⁷Lu, it showed rapid clearance from normal tissues and high tumor uptake, positioning it as a promising candidate for therapeutic applications. Further studies are needed to fully evaluate its therapeutic potential and confirm its role in clinical settings.

### 4.1.6. Dual Targeting of NRP-1 and αvβ3

Neuropilin-1 (NRP-1) is a cell surface receptor that plays a crucial role in cell signaling, angiogenesis, and tumor progression [168]. Overexpressed in several cancers, NRP-1 enhances tumor growth by promoting angiogenesis and cell migration, often in conjunction with vascular endothelial growth factor (VEGF) [169]. Its interaction with these factors makes NRP-1 a valuable target for imaging and therapies aimed at disrupting tumor vasculature and limiting cancer spread [168,170,171].

A radiolabeled heterodimeric peptide, ¹⁸F-AIF-NOTA-RGD-ATWLPPR, was designed to target both integrin αvβ3 and NRP-1 in tumors [138]. This peptide showed enhanced tumor uptake and targeting compared to monomeric RGD and ATWLPPR (A7R). In vitro and in vivo studies using GBM tumor models showed that the heterodimer's uptake was only partially inhibited by an excess of either unlabeled RGD or ATWLPPR, but it was
completely blocked when both were present, leading to improved pharmacokinetics and imaging quality.

In another study, a tetrameric RGD-A7R peptide conjugate labeled with a fluorescent probe exhibited superior tumor uptake, imaging contrast, and pharmacokinetics compared to monomeric peptides [172].

A recent study introduced the heterodimeric tracer ⁶⁸Ga-DOTA-RGD-A7R, which targets both αvβ3 and NRP-1 [139]. In breast cancer xenograft mouse models, this tracer showed excellent stability, clear tumor imaging on PET/CT, and superior tumor uptake compared to its individual components. Blocking studies validated the specificity of ⁶⁸Ga-DOTA-RGD-ATWLPPR for its intended targets [139,140]. These studies highlight the potential of dual-targeting tracers, such as ¹⁸F-AIF-NOTA-RGD-ATWLPPR and ⁶⁸Ga-DOTA-RGD-ATWLPPR, in enhancing the precision of cancer imaging and therapy by effectively targeting both integrin αvβ3 and NRP-1, offering new avenues for advancing cancer diagnosis and treatment. However, no clinical studies have been conducted until today.

### 4.1.7. Dual Targeting of Growth Factors Receptors (GFRs) and αvβ3

Growth factor receptors are well-established targets in oncology, with dual-targeting agents incorporating RGD peptides developed to enhance the efficacy of their inhibitors. Among them, studies have focused on Vascular endothelial growth factor receptor (VEGFR). VEGFR promotes tumor growth by facilitating new blood vessel formation, while integrin αvβ3, often co-expressed with VEGFR, helps stabilize these vessels [173]. Radiotracers targeting both VEGFR and integrin αvβ3 provide detailed imaging of the tumor's blood supply and active regions.

A notable example is the development of a peptide targeting VRGFR and αvβ3, iRGD-C6-lys-C6-DA7R radiolabelled with ²¹¹At, investigated recently for targeted radio-therapy [141]. The peptide demonstrated stability, strong binding to U87MG glioma cells, and significant in vitro antitumor effects, including reduced cell viability and increased apoptosis. Biodistribution studies revealed rapid tumor uptake and clearance from normal tissues via the kidneys. In vivo, it effectively inhibited tumor growth and extended survival in glioma-bearing mice with minimal toxicity. These results suggest that VEGFR targeting alongside αvβ3 is a promising strategy for detecting and treating glioma and potentially other cancers.

Similarly, epidermal growth factor receptor (EGFR), another crucial actor of tumor cell growth and survival, was targeted by such an approach. Radiotracers that target EGFR alongside integrin αvβ3 offer insights into both the tumor cells and their vascular support, providing a more comprehensive view of tumor biology. This dual-targeting approach could bolster diagnostic accuracy and treatment planning by integrating multiple aspects of tumor dynamics.

Innovative heterodimeric peptides have been introduced, such as ⁶⁸Ga-NOTA-RGD-GE11, which combine integrin αvβ3-specific cyclic RGD peptides with the EGFR-targeting peptide GE11 [142]. This dual targeting showed significantly improved tumor uptake compared to its monomeric counterparts, ⁶⁸Ga-NOTA-RGD and ⁶⁸Ga-NOTA-GE11, in lung tumor models. At 2 h post-injection, the tumor uptake values for ⁶⁸Ga-NOTA-RGD-GE11, ⁶⁸Ga-NOTA-RGD, and ⁶⁸Ga-NOTA-GE11 were 3.446 ± 0.548, 2.756 ± 0.483, and 2.408 ± 0.327% ID/g. Similarly, the ⁶⁴Cu-labeled tracer, ⁶⁴Cu-NOTA-RGD-GE11, exhibited superior tumor uptake in pancreatic xenografts and showed enhanced specificity, with uptake significantly blocked by non-radioactive peptides [143]. Additional development of NODA-GA-PEG3-GE11-PEG3-c(RGDyK) and c(RGDfK) tracers highlighted the feasibility of creating radiolabelled heterobivalent peptides (HBPLs) [144]. Although these HBPLs were successfully labeled with ⁶⁸Ga, exhibited high hydrophilicity, and demonstrated stability, they showed strong binding to integrin αvβ3 but lacked specific interaction with EGFR in vitro. In vivo studies in squamous cell carcinoma models have confirmed that uptake was mediated exclusively by integrin αvβ3. Given the mixed results of the dual-
targeting approach with GE11, future research should explore alternative EGFR-specific
peptides to enhance dual-targeting effectiveness and improve tumor imaging.

4.1.8. Dual Targeting of uPAR and αvβ3

uPAR is a cell surface receptor crucial for cell migration, tissue remodeling, and inflammation. uPAR is frequently overexpressed in cancers such as breast, prostate, and lung cancer, where it is associated with increased tumor invasion and poor prognosis [174]. This makes uPAR a valuable biomarker for imaging and monitoring tumor activity through PET and SPECT radiotracers.

In a proof-of-concept study, researchers developed heterodimeric ligands targeting both uPAR and integrin αvβ3 using an innovative bifunctional chelator (BFC) scaffold [145]. These ligands combined the peptide ligands AE105 (for uPAR) and cyclo(RGDyK) and were radiolabelled with ⁶⁴Cu and ⁶⁸Ga. The heterodimers demonstrated enhanced stability and superior imaging performance compared to single-target radiotracers. PET imaging of U87MG tumor-bearing mice with the ⁶⁴Cu-labeled tracer showed improved tumor targeting capabilities, with higher tumor uptake and clearer images than those achieved with individual-target tracers.

Subsequent studies further optimized these heterodimeric probes [146]. The tracers continued to exhibit better binding affinity and higher receptor density than their monomeric counterparts. Among the tested variants, the heterodimer with a PEG8 linker delivered the best results, showing strong tumor retention and stability in both in vitro and in vivo assays when labeled with ⁶⁴Cu and ⁶⁸Ga [146,147]. PET imaging of U87MG and PANC-1 tumor xenografts demonstrated that this PEG8-linked heterodimer significantly outperformed monomeric tracers, achieving higher tumor uptake and a superior signal-to-background ratio, highlighting its potential as a highly effective imaging agent for tumors expressing both uPAR and integrin αvβ3.

4.1.9. Dual Targeting of MC1R and αvβ3

This dual-targeting approach was also recently evaluated for melanoma imaging and targeting. Melanocortin-1 receptor (MC1R) is a G protein-coupled receptor primarily expressed in melanocytes, where it regulates melanin production. Activation of MC1R stimulates the synthesis of eumelanin, providing photoprotection to the skin. MC1R is critical in melanoma, with its variants increasing UV sensitivity and cancer risk. In tumors, MC1R affects immune response, tumor growth, and metastasis by influencing cellular adhesion and migration [175,176]. Its dysregulation can facilitate melanoma progression and spread.

A recent study focused on developing a heterobivalent radiotracer targeting both the MC1R and integrin αvβ3, which play critical roles in melanoma progression and metastasis [148]. Six ligands, incorporating c(RGDfK) and GG-Nle-c(DHfRWK) (Gly-Gly-Nle-cyclic Asp-His-DPhe-Arg-Trp-Lys), were synthesized and radiolabelled with ¹⁸F to enhance tumor-targeting sensitivity and visualization. Among them, one compound (¹⁸F-SiFAlin-GG-Nle-c(DHfRWK)-PEG8-RGD) demonstrated strong receptor affinity, hydrophilicity, and superior tumor uptake and TBR in melanoma and glioblastoma mouse models. This makes it a promising radiotracer for PET/CT imaging of malignant melanoma. However, studies in patients should be performed to fully characterize the potential of such radiotracer.

4.2. Dual-Targeting RGD-Based Nanoparticles and Liposomes; Implications for Brain Tumor Management

In addition to major recent developments in the theranostic field, advancements in tar-
geted delivery systems have emerged, particularly for glioma therapy. Several innovations
rely on RGD-derived peptides to enhance both tumor specificity and blood–brain barrier
(BBB) penetration. Polyamidoamine (PAMAM) dendrimers, known for their stability and
nanoscale size, are optimized for glioma therapy through PEGylation, which promotes pas-
sive targeting via the Enhanced Permeability and Retention (EPR) effect. Further, RGDyC
modification provides active targeting by binding to integrin αvβ3 receptors on tumor
cells [177]. In a rat glioma model, the RGDyC-modified PEG-PAMAM/ATO (arsenic
trioxide) system showed superior therapeutic efficacy and significant anti-tumor effects
as compared to ATO alone and mPEG-PAMAM/ATO due to improved BBB penetration
and targeted delivery [178]. RGDyC-modified PEG-PAMAM/ATO was also associated
with reduced secondary effects in this model. However, despite these combined passive
and active targeting strategies, effectively delivering therapeutics across the BBB remains
a challenge.

To address this issue, PAMAM was further modified with both the iRGD peptide for
tumor-specific targeting via integrin αvβ3 and the TGN peptide, which binds to transferrin
receptors on BBB endothelial cells to enhance brain penetration [179]. The resulting system
(iRGD/TGN-PEG-PAMAM) loaded with ATO showed high entrapment efficiency, pH-
sensitive release, and significantly improved drug delivery across the BBB. In vitro and
in vivo studies have confirmed an enhanced accumulation and activation of ATO in glioma
tissue, leading to increased therapeutic efficacy and reduced side effects. This dual-targeting
approach demonstrates a promising strategy for targeted glioma therapy by optimizing
both tumor specificity and BBB penetration.

Building on these advancements, a hepatitis B core protein-based virus-like particle (TGN/RGD-VLP) was developed to co-deliver paclitaxel (PTX) and siRNA to glioblastoma models [180]. This approach effectively targeted both the αvβ3 integrin and TGN, resulting in enhanced drug delivery to tumor sites. The combined therapy (PTX/siRNA@TGN/RGD-VLP) outperformed PTX alone, significantly reducing tumor growth, promoting necrosis and apoptosis, extending median survival, and minimizing weight loss.

Further advancing targeted delivery for glioma therapy, a study developed chitosan-
PLGA nanoparticles functionalized with AS1411 aptamer, targeting nucleolin overex-
pressed on brain cancer cells, and RGD peptide, to enhance the targeted co-delivery of
docetaxel (DTX) and up conversion nanoparticles (UCNP) for brain cancer therapy and
imaging [181]. These nanoparticles, with an average size of less than 200 nm, exhibited high
DTX and UCNP encapsulation and sustained DTX release over 72 h. The dual-functional
nanoparticles significantly improved cellular uptake and cytotoxicity, showing an 89-fold
greater efficacy than unmodified particles. Additionally, they increased DTX bioavailability
and UCNP accumulation in brain tissues, leading to substantial tumor growth suppression
in brain tumor-bearing mice without notable toxicity. The DUCPN-RGD-AS1411 nanoparti-
cles demonstrate potential for effective brain cancer treatment and real-time imaging.

In a related development, a novel approach utilized dual-target liposomes to en-
hance drug delivery across the BBB. These liposomes were modified with a glucose-RGD
(Glu-RGD) derivative to target glioma cells and facilitate BBB penetration [182]. The Glu-
RGD-modified liposomes, encapsulating PTX, showed significantly improved targeting
efficiency and accumulation at tumor sites compared to unmodified PTX and other lipo-
some formulations. The liposomes demonstrated enhanced drug delivery with a 4.41-fold
increase in uptake efficiency and a 4.72-fold increase in concentration efficiency at tu-
mor sites. This method further underscores the progress in developing effective delivery
systems that combine BBB penetration with targeted therapy for gliomas.

These advancements underscore the ongoing efforts to overcome the challenges of
blood-brain barrier penetration and dual tumor targeting, paving the way for future
innovations in brain cancer management. Future challenges will include the variability of
the blood-brain barrier's permeability among patients and potential differences in tumor
biology between animal models and human cancers. Additionally, the long-term safety and
effectiveness of these nanoparticle-based therapies need thorough evaluation. To confirm
their potential, comprehensive clinical studies are necessary to assess their performance in
human subjects, ensuring that these innovations can be safely and effectively applied in
clinical settings.
**5. Conclusions**

Despite their promise, RGD-derived molecules designed for the treatment of solid
tumors have faced several challenges, including rapid clearance, potential immunogenicity,
and heterogeneity in integrin expression. Dual-targeting strategies based on RGD in cancer
imaging and therapy have made notable progress, using radiotracers to target multiple
biomarkers or receptors, which could enhance both diagnostic precision and therapeutic
efficacy. Additionally, recent advancements in targeted delivery systems, such as RGD-
based nanoparticles and liposomes, have improved drug delivery across the blood-brain
barrier (BBB) and boosted therapeutic effectiveness, highlighting the need for continued
development. However, challenges persist, including variability in BBB permeability and
differences between animal models and human cancers. Future research should focus
on refining dual-targeting approaches by investigating specific mechanisms that could
enhance tumor selectivity while minimizing off-target effects. For many dual-targeting
strategies, the therapeutic efficacy has yet to be fully validated in preclinical models, where
studies on biodistribution and pharmacodynamics could offer valuable insights into their
potential effectiveness. Additionally, it is essential to optimize these systems to balance
potency and safety. Finally, comprehensive clinical trials are needed to assess not only the
safety and efficacy of these innovations but also their long-term immunogenicity, patient-
specific responses, and potential for personalized treatment adaptations. These trials will
be crucial for translating dual-targeting therapies from experimental settings to widespread
clinical use.

In conclusion, dual-targeting strategies and advanced delivery systems could lead to
significant progress in cancer management, promising better diagnosis, treatment precision,
and improved patient outcomes. Clinical trials involving RGD-based dual molecules are
crucial to establishing their role in cancer therapy.

**Author Contributions:** Conceptualization, B.B. and C.M.; writing—original draft preparation, B.B.; writing—review and editing, B.B., D.F., C.G. and C.M.; figure preparation, B.B.; supervision, D.F., C.G. and C.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflicts of interest.

**References**

1. Bray, F.; Laversanne, M.; Sung, H.; Ferlay, J.; Siegel, R.L.; Soerjomataram, I.; Jemal, A. Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. *CA Cancer J. Clin.* **2024**, *74*, 229–263. [CrossRef] [PubMed]

2. Global Cancer Burden Growing, amidst Mounting Need for Services. Available online: https://www.who.int/news/item/01-02-2024-global-cancer-burden-growing--amidst-mounting-need-for-services (accessed on 20 September 2024).

3. Global Cancer Facts & Figures. Available online: https://www.cancer.org/research/cancer-facts-statistics/global-cancer-facts-and-figures.html (accessed on 11 October 2024).

4. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. *CA Cancer J. Clin.* **2021**, *71*, 209–249. [CrossRef]

5. Sonkin, D.; Thomas, A.; Teicher, B.A. Cancer Treatments: Past, Present, and Future. *Cancer Genet.* **2024**, *286–287*, 18–24. [CrossRef]

6. Rulten, S.L.; Grose, R.P.; Gatz, S.A.; Jones, J.L.; Cameron, A.J.M. The Future of Precision Oncology. *Int. J. Mol. Sci.* **2023**, *24*, 12613. [CrossRef] [PubMed]

7. Bai, J.-W.; Qiu, S.-Q.; Zhang, G.-J. Molecular and Functional Imaging in Cancer-Targeted Therapy: Current Applications and Future Directions. *Signal Transduct. Target. Ther.* **2023**, *8*, 89. [CrossRef]

8. Liu, B.; Zhou, H.; Tan, L.; Siu, K.T.H.; Guan, X.-Y. Exploring Treatment Options in Cancer: Tumor Treatment Strategies. *Signal Transduct. Target. Ther.* **2024**, *9*, 175. [CrossRef] [PubMed]

9. Hamidi, H.; Ivaska, J. Every Step of the Way: Integrins in Cancer Progression and Metastasis. *Nat. Rev. Cancer* **2018**, *18*, 533–548. [CrossRef] [PubMed]

10. Danhier, F.; Le Breton, A.; Préat, V. RGD-Based Strategies to Target Alpha(v) Beta(3) Integrin in Cancer Therapy and Diagnosis. *Mol. Pharm.* **2012**, *9*, 2961–2973. [CrossRef]

11. Javid, H.; Oryani, M.A.; Rezagholinejad, N.; Esparham, A.; Tajaldini, M.; Karimi-Shahri, M. RGD Peptide in Cancer Targeting: Benefits, Challenges, Solutions, and Possible Integrin-RGD Interactions. *Cancer Med.* **2024**, *13*, e6800. [CrossRef]
12. Stupp, R.; Hegi, M.E.; Gorlia, T.; Erridge, S.C.; Perry, J.; Hong, Y.-K.; Aldape, K.D.; Lhermitte, B.; Pietsch, T.; Grujicic, D.; et al. Cilengitide Combined with Standard Treatment for Patients with Newly Diagnosed Glioblastoma with Methylated MGMT Promoter (CENTRIC EORTC 26071-22072 Study): A Multicentre, Randomised, Open-Label, Phase 3 Trial. *Lancet Oncol.* **2014**, *15*, 1100–1108. [CrossRef]

13. Nabors, L.B.; Fink, K.L.; Mikkelsen, T.; Grujicic, D.; Tarnawski, R.; Nam, D.H.; Mazurkiewicz, M.; Salacz, M.; Ashby, L.; Zagonel, V.; et al. Two Cilengitide Regimens in Combination with Standard Treatment for Patients with Newly Diagnosed Glioblastoma and Unmethylated MGMT Gene Promoter: Results of the Open-Label, Controlled, Randomized Phase II CORE Study. *Neuro Oncol.* **2015**, *17*, 708–717. [CrossRef] [PubMed]

14. Gu, Y.; Dong, B.; He, X.; Qiu, Z.; Zhang, J.; Zhang, M.; Liu, H.; Pang, X.; Cui, Y. The Challenges and Opportunities of Avβ3-Based Therapeutics in Cancer: From Bench to Clinical Trials. *Pharmacol. Res.* **2023**, *189*, 106694. [CrossRef] [PubMed]

15. Taghipour, Y.D.; Zarebkohan, A.; Salehi, R.; Rahimi, F.; Torchilin, V.P.; Hamblin, M.R.; Seifalian, A. An Update on Dual Targeting Strategy for Cancer Treatment. *J. Control Release* **2022**, *349*, 67–96. [CrossRef]

16. Ehlerding, E.B.; Sun, L.; Lan, X.; Zeng, D.; Cai, W. Dual-Targeted Molecular Imaging of Cancer. *J. Nucl. Med.* **2018**, *59*, 390–395. [CrossRef]

17. Judmann, B.; Braun, D.; Wängler, B.; Schirrmacher, R.; Fricker, G.; Wängler, C. Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy. *Pharmaceuticals* **2020**, *13*, 173. [CrossRef]

18. Takada, Y.; Ye, X.; Simon, S. The Integrins. *Genome Biol.* **2007**, *8*, 215. [CrossRef] [PubMed]

19. Barczyk, M.; Carracedo, S.; Gullberg, D. Integrins. *Cell Tissue Res.* **2010**, *339*, 269–280. [CrossRef]

20. Kadry, Y.A.; Calderwood, D.A. Chapter 22: Structural and Signaling Functions of Integrins. *Biochim. Biophys. Acta Biomembr.* **2020**, *1862*, 183206. [CrossRef]

21. Ginsberg, M.H. Integrin Activation. *BMB Rep.* **2014**, *47*, 655. [CrossRef]

22. Alday-Parejo, B.; Stupp, R.; Rüegg, C. Are Integrins Still Practicable Targets for Anti-Cancer Therapy? *Cancers* **2019**, *11*, 978. [CrossRef]

23. Humphries, J.D.; Byron, A.; Humphries, M.J. Integrin Ligands at a Glance. *J. Cell Sci.* **2006**, *119*, 3901–3903. [CrossRef] [PubMed]

24. Pang, X.; He, X.; Qiu, Z.; Zhang, H.; Xie, R.; Liu, Z.; Gu, Y.; Zhao, N.; Xiang, Q.; Cui, Y. Targeting Integrin Pathways: Mechanisms and Advances in Therapy. *Signal Transduct. Target. Ther.* **2023**, *8*, 1. [CrossRef] [PubMed]

25. Ludwig, B.S.; Kessler, H.; Kossatz, S.; Reuning, U. RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field. *Cancers* **2021**, *13*, 1711. [CrossRef]

26. Harburger, D.S.; Calderwood, D.A. Integrin Signalling at a Glance. *J. Cell Sci.* **2009**, *122*, 159–163. [CrossRef] [PubMed]

27. Luo, B.-H.; Springer, T.A. Integrin Structures and Conformational Signaling. *Curr. Opin. Cell Biol.* **2006**, *18*, 579–586. [CrossRef]

28. Calderwood, D.A. Integrin Activation. *J. Cell Sci.* **2004**, *117*, 657–666. [CrossRef]

29. Sun, Z.; Costell, M.; Fässler, R. Integrin Activation by Talin, Kindlin and Mechanical Forces. *Nat. Cell Biol.* **2019**, *21*, 25–31. [CrossRef]

30. Legate, K.R.; Wickström, S.A.; Fässler, R. Genetic and Cell Biological Analysis of Integrin Outside-in Signaling. *Genes. Dev.* **2009**, *23*, 397–418. [CrossRef]

31. Bachmann, M.; Kukkurainen, S.; Hytönen, V.P.; Wehrle-Haller, B. Cell Adhesion by Integrins. *Physiol. Rev.* **2019**, *99*, 1655–1699. [CrossRef]

32. Mezu-Ndubuisi, O.J.; Maheshwari, A. The Role of Integrins in Inflammation and Angiogenesis. *Pediatr. Res.* **2021**, *89*, 1619–1626. [CrossRef]

33. Avraamides, C.J.; Garmy-Susini, B.; Varner, J.A. Integrins in Angiogenesis and Lymphangiogenesis. *Nat. Rev. Cancer* **2008**, *8*, 604–617. [CrossRef] [PubMed]

34. Desgrosellier, J.S.; Cheresh, D.A. Integrins in Cancer: Biological Implications and Therapeutic Opportunities. *Nat. Rev. Cancer* **2010**, *10*, 9–22. [CrossRef] [PubMed]

35. Liu, F.; Wu, Q.; Dong, Z.; Liu, K. Integrins in Cancer: Emerging Mechanisms and Therapeutic Opportunities. *Pharmacol. Ther.* **2023**, *247*, 108458. [CrossRef]

36. Borowska, K.; Jedrych, B.; Czerny, K.; Zabielski, S. Udział integryn w procesach fizjo- i patologicznych [The role of integrins in the physiologic and pathogenic processes]. *Pol. Merkur. Lekarski* **2006**, *21*, 362–366.

37. Hou, J.; Yan, D.; Liu, Y.; Huang, P.; Cui, H. The Roles of Integrin A5β1 in Human Cancer. *OncoTargets Ther.* **2020**, *13*, 13329–13344. [CrossRef]

38. Bergonzini, C.; Kroese, K.; Zweemer, A.J.; Danen, E.H. Targeting Integrins for Cancer Therapy—Disappointments and Opportunities. *Front. Cell Dev. Biol.* **2022**, *10*, 863850. [CrossRef] [PubMed]

39. Echavidre, W.; Durivault, J.; Gotorbe, C.; Blanchard, T.; Pagnuzzi, M.; Vial, V.; Raes, F.; Broisat, A.; Villeneuve, R.; Amblard, R.; et al. Integrin-Avβ3 Is a Therapeutically Targetable Fundamental Factor in Medulloblastoma Tumorigenicity and Radioresistance. *Cancer Res. Commun.* **2023**, *3*, 2483–2496. [CrossRef]

40. Pachane, B.C.; Selistre-de-Araujo, H.S. The Role of Avβ3 Integrin in Cancer Therapy Resistance. *Biomedicines* **2024**, *12*, 1163. [CrossRef]

41. Adair, T.H.; Montani, J.-P. Overview of Angiogenesis. In *Angiogenesis*; Morgan & Claypool Life Sciences: San Rafael, CA, USA, 2010.

42. Lugano, R.; Ramachandran, M.; Dimberg, A. Tumor Angiogenesis: Causes, Consequences, Challenges and Opportunities. *Cell. Mol. Life Sci.* **CMLS** **2020**, *77*, 1745–1770. [CrossRef]
43. Bussolati, B.; Deambrosis, I.; Russo, S.; Deregibus, M.C.; Camussi, G. Altered Angiogenesis and Survival in Human Tumor-Derived Endothelial Cells. *FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol.* **2003**, *17*, 1159–1161. [CrossRef]

44. Ata, R.; Antonescu, C.N. Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer. *Int. J. Mol. Sci.* **2017**, *18*, 189. [CrossRef] [PubMed]

45. Cooper, J.; Giancotti, F.G. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. *Cancer Cell* **2019**, *35*, 347–367. [CrossRef] [PubMed]

46. Harryman, W.L.; Marr, K.D.; Nagle, R.B.; Cress, A.E. Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers. *Front. Cell Dev. Biol.* **2022**, *10*, 837585. [CrossRef] [PubMed]

47. Bagati, A.; Kumar, S.; Jiang, P.; Pyrdol, J.; Zou, A.E.; Godicelj, A.; Mathewson, N.D.; Cartwright, A.N.R.; Cejas, P.; Brown, M.; et al. Integrin Avß6-TGFß-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer. *Cancer Cell* **2021**, *39*, 54–67.e9. [CrossRef]

48. Dodagatta-Marri, E.; Ma, H.-Y.; Liang, B.; Li, J.; Meyer, D.S.; Chen, S.-Y.; Sun, K.-H.; Ren, X.; Zivak, B.; Rosenblum, M.D.; et al. Integrin Avß8 on T Cells Suppresses Anti-Tumor Immunity in Multiple Models and Is a Promising Target for Tumor Immunotherapy. *Cell Rep.* **2021**, *36*, 109309. [CrossRef]

49. Liao, J.; Chen, R.; Lin, B.; Deng, R.; Liang, Y.; Zeng, J.; Ma, S.; Qiu, X. Cross-Talk between the TGF-β and Cell Adhesion Signaling Pathways in Cancer. *Int. J. Med. Sci.* **2024**, *21*, 1307–1320. [CrossRef]

50. Vogetseder, A.; Thies, S.; Ingold, B.; Roth, P.; Weller, M.; Schraml, P.; Goodman, S.L.; Moch, H. Av-Integrin Isoform Expression in Primary Human Tumors and Brain Metastases. *Int. J. Cancer* **2013**, *133*, 2362–2371. [CrossRef]

51. Hoshino, A.; Costa-Silva, B.; Shen, T.-L.; Rodrigues, G.; Hashimoto, A.; Tesic Mark, M.; Molina, H.; Kohsaka, S.; Di Giannatale, A.; Ceder, S.; et al. Tumour Exosome Integrins Determine Organotropic Metastasis. *Nature* **2015**, *527*, 329–335. [CrossRef]

52. Wu, Y.J.; Pagel, M.A.; Muldoon, L.L.; Fu, R.; Neuwelt, E.A. High Av Integrin Level of Cancer Cells Is Associated with Development of Brain Metastasis in Athymic Rats. *Anticancer Res.* **2017**, *37*, 4029–4040. [CrossRef]

53. Huang, R.; Rofstad, E.K. Integrins as Therapeutic Targets in the Organ-Specific Metastasis of Human Malignant Melanoma. *J. Exp. Clin. Cancer Res.* **2018**, *37*, 92. [CrossRef]

54. Yan, P.; Zhu, H.; Yin, L.; Wang, L.; Xie, P.; Ye, J.; Jiang, X.; He, X. Integrin Avß6 Promotes Lung Cancer Proliferation and Metastasis through Upregulation of IL-8-Mediated MAPK/ERK Signaling. *Transl. Oncol.* **2018**, *11*, 619–627. [CrossRef] [PubMed]

55. Fan, D.; Zhang, C.; Luo, Q.; Li, B.; Ai, L.; Li, D.; Jia, W. In Vivo Evaluation of Integrin Avß6-Targeting Peptide in NSCLC and Brain Metastasis. *Front. Oncol.* **2023**, *13*, 1070967. [CrossRef] [PubMed]

56. Mitra, A.; Sawada, K.; Tiwari, P.; Mui, K.; Gwin, K.; Lengyel, E. Ligand Independent Activation of C-Met by Fibronectin and A5ß1-Integrin Regulates Ovarian Cancer Invasion and Metastasis. *Oncogene* **2011**, *30*, 1566–1576. [CrossRef]

57. Stefańska, K.; Józkowiak, M.; Angelova Volponi, A.; Shibli, J.A.; Golkar-Narenji, A.; Antosik, P.; Bukowska, D.; Piotrowska-Kempisty, H.; Mozdziak, P.; Dziegiel, P.; et al. The Role of Exosomes in Human Carcinogenesis and Cancer Therapy—Recent Findings from Molecular and Clinical Research. *Cells* **2023**, *12*, 356. [CrossRef]

58. Zhao, L.; Ma, X.; Yu, J. Exosomes and Organ-Specific Metastasis. *Mol. Ther. Methods Clin. Dev.* **2021**, *22*, 133–147. [CrossRef]

59. Grigoryeva, E.S.; Tashireva, L.A.; Savelieva, O.E.; Zavyalova, M.V.; Popova, N.O.; Kuznetsov, G.A.; Andryuhova, E.S.; Perelmuter, V.M. The Association of Integrins B3, B4, and αVβ5 on Exosomes, CTCs and Tumor Cells with Localization of Distant Metastasis in Breast Cancer Patients. *Int. J. Mol. Sci.* **2023**, *24*, 2929. [CrossRef]

60. Nuclear Medicine. Available online: https://www.nibib.nih.gov/science-education/science-topics/nuclear-medicine (accessed on 19 June 2024).

61. Tafti, D.; Banks, K.P. Nuclear Medicine Physics. In *StatPearls [Internet]*, StatPearls Publishing: Treasure Island, FL, USA, 2023.

62. Li, L.; Chen, X.; Yu, J.; Yuan, S. Preliminary Clinical Application of RGD-Containing Peptides as PET Radiotracers for Imaging Tumors. *Front. Oncol.* **2022**, *12*, 837952. [CrossRef]

63. Blower, P.J. A Nuclear Chocolate Box: The Periodic Table of Nuclear Medicine. *Dalton Trans.* **2015**, *44*, 4819–4844. [CrossRef] [PubMed]

64. Beer, A.J.; Grosu, A.-L.; Carlsen, J.; Kolk, A.; Sarbia, M.; Stangier, I.; Watzlowik, P.; Wester, H.-J.; Haubner, R.; Schwaiger, M. [18F]Galacto-RGD Positron Emission Tomography for Imaging of Alphavbeta3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck. *Clin. Cancer Res.* **2007**, *13*, 6610–6616. [CrossRef]

65. Schnell, O.; Krebs, B.; Carlsen, J.; Miederer, I.; Goetz, C.; Goldbrunner, R.H.; Wester, H.-J.; Haubner, R.; Pöpperl, G.; Holtmannspötter, M.; et al. Imaging of Integrin Avß3 Expression in Patients with Malignant Glioma by [18F] Galacto-RGD Positron Emission Tomography. *Neuro-Oncol.* **2009**, *11*, 861–870. [CrossRef]

66. Beer, A.J.; Schwarzenböck, S.M.; Zantl, N.; Souvatzoglou, M.; Maurer, T.; Watzlowik, P.; Kessler, H.; Wester, H.-J.; Schwaiger, M.; Krause, B.J. Non-Invasive Assessment of Inter-and Intrapatient Variability of Integrin Expression in Metastasized Prostate Cancer by PET. *Oncotarget* **2016**, *7*, 28151–28159. [CrossRef] [PubMed]

67. Guo, H.; Zhou, J.; Yao, S.; Li, J.; Fu, Z.; Liu, S. The Application Value of 18F-Alfatide-RGD PET/CT in the Preliminary Diagnosis of Patients with Non-Small Cell Lung Cancer. *J. Radioanal. Nucl. Chem.* **2022**, *331*, 4141–4148. [CrossRef]

68. Zhou, Y.; Gao, S.; Huang, Y.; Zheng, J.; Dong, Y.; Zhang, B.; Zhao, S.; Lu, H.; Liu, Z.; Yu, J.; et al. A Pilot Study of 18F-Alfatide PET/CT Imaging for Detecting Lymph Node Metastases in Patients with Non-Small Cell Lung Cancer. *Sci. Rep.* **2017**, *7*, 2877. [CrossRef] [PubMed]
69. Liu, N.; Zhao, W.; Hu, X.-D.; Gao, S.; Yu, Q.; Wang, S.; Hou, W.; Zhu, S.; Lu, H.; Yuan, S. A Pilot Study on Imaging of Integrin Avβ3 with RGD PET/CT in Patients with Glioma. *J. Nucl. Med.* **2015**, *56*, 324.

70. Li, L.; Liu, N.; Zhang, H.; Tao, R.; Zhao, S.; Chen, Z.; Fu, Z.; Li, W.; Xu, L.; Liu, Y.; et al. Potential 18F-RGD PET/CT and DCE-MRI Imaging-Based Biomarkers for Postoperative Survival Prediction Among Patients with Newly Diagnosed Glioblastoma Treated with Bevacizumab and Chemoradiotherapy. *Front. Oncol.* **2022**, *12*, 848266. [CrossRef]

71. Li, D.; Zhao, X.; Zhang, L.; Li, F.; Ji, N.; Gao, Z.; Wang, J.; Kang, P.; Liu, Z.; Shi, J.; et al. (68)Ga-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study. *Mol. Pharm.* **2014**, *11*, 3923-3929. [CrossRef]

72. Li, D.; Zhang, J.; Ji, N.; Zhao, X.; Zheng, K.; Qiao, Z.; Li, F.; Lang, L.; Iagaru, A.; Niu, G.; et al. Combined 68Ga-NOTA-PRGD2 and 18F-FDG PET/CT Can Discriminate Uncommon Meningioma Mimicking High-Grade Glioma. *Clin. Nucl. Med.* **2018**, *43*, 648-654. [CrossRef]

73. Zheng, K.; Liang, N.; Zhang, J.; Lang, L.; Zhang, W.; Li, S.; Zhao, J.; Niu, G.; Li, F.; Zhu, Z.; et al. 68Ga-NOTA-PRGD2 PET/CT for Integrin Imaging in Patients with Lung Cancer. *J. Nucl. Med.* **2015**, *56*, 1823-1827. [CrossRef]

74. Parihar, A.S.; Mittal, B.R.; Kumar, R.; Shukla, J.; Bhattacharya, A. 68Ga-DOTA-RGD2 Positron Emission Tomography/Computed Tomography in Radioiodine Refractory Thyroid Cancer: Prospective Comparison of Diagnostic Accuracy with 18F-FDG Positron Emission Tomography/Computed Tomography and Evaluation Toward Potential Theranostics. *Thyroid* **2020**, *30*, 557-567. [CrossRef]

75. Lobeek, D.; Rijpkema, M.; Terry, S.Y.A.; Molkenboer-Kuenen, J.D.M.; Joosten, L.; van Genugten, E.A.J.; van Engen-van Grunsven, A.C.H.; Kaanders, J.H.A.M.; Pegge, S.A.H.; Boerman, O.C.; et al. Imaging Angiogenesis in Patients with Head and Neck Squamous Cell Carcinomas by [68Ga]Ga-DOTA-E-[c(RGDfK)]2 PET/CT. *Eur. J. Nucl. Med. Mol. Imaging* **2020**, *47*, 2647-2655. [CrossRef]

76. Krishnaraju, V.S.; Kumar, R.; Sood, A.; Shukla, J.; Subramanian, K.; Kakkar, N.; Panda, N.; Mittal, B.R. Angiogenesis-Targeted 68Ga-DOTA-RGD2 PET/CT Imaging: A Potential Theranostic Application in the Case of Chondrosarcoma. *Nucl. Med. Mol. Imaging* **2021**, *55*, 141-145. [CrossRef] [PubMed]

77. Clausen, M.M.; Carlsen, E.A.; Christensen, C.; Madsen, J.; Brandt-Larsen, M.; Klausen, T.L.; Holm, S.; Loft, A.; Berthelsen, A.K.; Kroman, N.; et al. First-in-Human Study of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET for Integrin Avβ3 Imaging in Patients with Breast Cancer and Neuroendocrine Neoplasms: Safety, Dosimetry and Tumor Imaging Ability. *Diagnostics* **2022**, *12*, 851. [CrossRef] [PubMed]

78. Carlsen, E.A.; Loft, M.; Loft, A.; Czyzewska, D.; Andreassen, M.; Langer, S.W.; Knigge, U.; Kjaer, A. Prospective Phase II Trial of [68Ga]Ga-NODAGA-E[c(RGDyK)]2 PET/CT Imaging of Integrin Avβ3 for Prognostication in Patients with Neuroendocrine Neoplasms. *J. Nucl. Med.* **2023**, *64*, 252-259. [CrossRef] [PubMed]

79. Gondhane, A.; Verma, P.; Chandak, A.; Basu, S. Prospective Evaluation of 68Ga-NODAGA-RGD PET-CT in Patients of Carcinoma Thyroid with Thyroglobulin Elevated Negative Radioiodine Scintigraphy (TENIS) with a Head-to-Head Comparison with FDG-PET/CT. *Nucl. Med. Commun.* **2024**, *45*, 412-419. [CrossRef]

80. Feng, X.; Wang, Y.; Lu, D.; Xu, X.; Zhou, X.; Zhang, H.; Zhang, T.; Zhu, H.; Yang, Z.; Wang, F.; et al. Clinical Translation of a 68Ga-Labeled Integrin Avβ6-Targeting Cyclic Radiotracer for PET Imaging of Pancreatic Cancer. *J. Nucl. Med.* **2020**, *61*, 1461-1467. [CrossRef]

81. Hausner, S.H.; Bold, R.J.; Cheuy, L.Y.; Chew, H.K.; Daly, M.E.; Davis, R.A.; Foster, C.C.; Kim, E.J.; Sutcliffe, J.L. Preclinical Development and First-in-Human Imaging of the Integrin Avβ6 with [18F]Avβ6-Binding Peptide in Metastatic Carcinoma. *Clin. Cancer Res.* **2019**, *25*, 1206-1215. [CrossRef]

82. Nakamoto, R.; Ferri, V.; Duan, H.; Hatami, N.; Goel, M.; Rosenberg, J.; Kimura, R.; Wardak, M.; Haywood, T.; Kellow, R.; et al. Pilot-Phase PET/CT Study Targeting Integrin Avβ6 in Pancreatic Cancer Patients Using the Cystine-Knot Peptide-Based 18F-FP-R01-MG-F2. *Eur. J. Nucl. Med. Mol. Imaging* **2022**, *50*, 184-193. [CrossRef] [PubMed]

83. Mas-Moruno, C.; Rechenmacher, F.; Kessler, H. Cilengitide: The First Anti-Angiogenic Small Molecule Drug Candidate. Design, Synthesis and Clinical Evaluation. *Anticancer. Agents Med. Chem.* **2010**, *10*, 753-768. [CrossRef]

84. Maurer, G.D.; Tritschler, I.; Adams, B.; Tabatabai, G.; Wick, W.; Stupp, R.; Weller, M. Cilengitide Modulates Attachment and Viability of Human Glioma Cells, but Not Sensitivity to Irradiation or Temozolomide in Vitro. *Neuro-Oncol.* **2009**, *11*, 747-756. [CrossRef]

85. Stupp, R.; Hegi, M.E.; Neyns, B.; Goldbrunner, R.; Schlegel, U.; Clement, P.M.J.; Grabenbauer, G.G.; Ochsenbein, A.F.; Simon, M.; Dietrich, P.-Y.; et al. Phase I/IIa Study of Cilengitide and Temozolomide with Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients with Newly Diagnosed Glioblastoma. *JCO* **2010**, *28*, 2712-2718. [CrossRef]

86. Kim, Y.-H.; Lee, J.K.; Kim, B.; DeWitt, J.P.; Lee, J.E.; Han, J.H.; Kim, S.-K.; Oh, C.W.; Kim, C.-Y. Combination Therapy of Cilengitide with Belotecan against Experimental Glioblastoma. *Int. J. Cancer* **2013**, *133*, 749-756. [CrossRef] [PubMed]

87. Nabors, L.B.; Mikkelsen, T.; Hegi, M.E.; Ye, X.; Batchelor, T.; Lesser, G.; Peereboom, D.; Rosenfeld, M.R.; Olsen, J.; Brem, S.; et al. A Safety Run-in and Randomized Phase 2 Study of Cilengitide Combined with Chemoradiation for Newly Diagnosed Glioblastoma (NABTT 0306). *Cancer* **2012**, *118*, 5601-5607. [CrossRef] [PubMed]

88. Reynolds, A.R.; Hart, I.R.; Watson, A.R.; Welti, J.C.; Silva, R.G.; Robinson, S.D.; Da Violante, G.; Gourlaouen, M.; Salih, M.; Jones, M.C.; et al. Stimulation of Tumor Growth and Angiogenesis by Low Concentrations of RGD-Mimetic Integrin Inhibitors. *Nat. Med.* **2009**, *15*, 392-400. [CrossRef]
89. Weller, M.; Nabors, L.B.; Gorlia, T.; Leske, H.; Rushing, E.; Bady, P.; Hicking, C.; Perry, J.; Hong, Y.-K.; Roth, P.; et al. Cilengitide in Newly Diagnosed Glioblastoma: Biomarker Expression and Outcome. *Oncotarget* **2016**, *7*, 15018–15032. [CrossRef]

90. Sanati, M.; Afshari, A.R.; Aminyavari, S.; Kesharwani, P.; Jamialahmadi, T.; Sahebkar, A. RGD-Engineered Nanoparticles as an Innovative Drug Delivery System in Cancer Therapy. *J. Drug Deliv. Sci. Technol.* **2023**, *84*, 104562. [CrossRef]

91. Kim, H.-S.; Kang, J.-H.; Jang, J.; Lee, E.-J.; Kim, J.H.; Byun, J.; Shin, U.S. Dual Stimuli-Responsive Mesoporous Silica Nanoparticles for Efficient Loading and Smart Delivery of Doxorubicin to Cancer with RGD-Integrin Targeting. *Eur. J. Pharm. Sci.* **2023**, *188*, 106525. [CrossRef] [PubMed]

92. Yu, H.-T.; Meng, D.; Feng, M.-X.; Ruan, K.-Y.; Dong, J.-J.; Bin-Shen; Xiao, Y.-P.; Zhang, X.-H.; Shi, L.-L.; Jiang, X.-H. RGD-Modified Solid Lipid Nanoparticles Improve Oral Doxorubicin Absorption: In Vitro and in Vivo Study. *J. Drug Deliv. Sci. Technol.* **2024**, *91*, 105293. [CrossRef]

93. Zheng, G.; Zheng, M.; Yang, B.; Fu, H.; Li, Y. Improving Breast Cancer Therapy Using Doxorubicin Loaded Solid Lipid Nanoparticles: Synthesis of a Novel Arginine-Glycine-Aspartic Tripeptide Conjugated, pH Sensitive Lipid and Evaluation of the Nanomedicine in Vitro and in Vivo. *Biomed. Pharmacother.* **2019**, *116*, 109006. [CrossRef]

94. Wang, G.; Wang, Z.; Li, C.; Duan, G.; Wang, K.; Li, Q.; Tao, T. RGD Peptide-Modified, Paclitaxel Prodrug-Based, Dual-Drugs Loaded, and Redox-Sensitive Lipid-Polymer Nanoparticles for the Enhanced Lung Cancer Therapy. *Biomed. Pharmacother.* **2018**, *106*, 275–284. [CrossRef]

95. Zhang, X.; He, Z.; Xiang, L.; Li, L.; Zhang, H.; Lin, F.; Cao, H. Codelivery of GRP78 siRNA and Docetaxel via RGD-PEG-DSPE/DOPA/CaP Nanoparticles for the Treatment of Castration-Resistant Prostate Cancer. *Drug Des. Devel Ther.* **2019**, *13*, 1357–1372. [CrossRef]

96. Sgouros, G.; Bodei, L.; McDevitt, M.R.; Nedrow, J.R. Radiopharmaceutical Therapy in Cancer: Clinical Advances and Challenges. *Nat. Rev. Drug Discov.* **2020**, *19*, 589–608. [CrossRef] [PubMed]

97. Bozon-Petitprin, A.; Bacot, S.; Gauchez, A.S.; Ahmadi, M.; Bourre, J.C.; Marti-Battle, D.; Perret, P.; Broisat, A.; Riou, L.M.; Claron, M.; et al. Targeted Radionuclide Therapy with RAFT-RGD Radiolabelled with (90)Y or (177)Lu in a Mouse Model of Avβ3-Expressing Tumours. *Eur. J. Nucl. Med. Mol. Imaging* **2015**, *42*, 252–263. [CrossRef]

98. Jin, Z.-H.; Furukawa, T.; Degardin, M.; Sugyo, A.; Tsuji, A.B.; Yamasaki, T.; Kawamura, K.; Fujibayashi, Y.; Zhang, M.-R.; Boturyn, D.; et al. αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-Cyclam-RAFT-c(-RGDfK-)4. *Mol. Cancer Ther.* **2016**, *15*, 2076–2085. [CrossRef]

99. Jin, Z.-H.; Furukawa, T.; Ohya, T.; Degardin, M.; Sugyo, A.; Tsuji, A.B.; Fujibayashi, Y.; Zhang, M.-R.; Higashi, T.; Boturyn, D.; et al. 67Cu-Radiolabeling of a Multimeric RGD Peptide for αVβ3 Integrin-Targeted Radionuclide Therapy: Stability, Therapeutic Efficacy, and Safety Studies in Mice. *Nucl. Med. Commun.* **2017**, *38*, 347–355. [CrossRef]

100. Shi, J.; Fan, D.; Dong, C.; Liu, H.; Jia, B.; Zhao, H.; Jin, X.; Liu, Z.; Li, F.; Wang, F. Anti-Tumor Effect of Integrin Targeted (177)Lu-3PRGD2 and Combined Therapy with Endostar. *Theranostics* **2014**, *4*, 256–266. [CrossRef] [PubMed]

101. Pirooznia, N.; Abdi, K.; Beiki, D.; Emami, F.; Arab, S.S.; Sabzevari, O.; Soltani-Gooshkhaneh, S. 177Lu-Labeled Cyclic RGD Peptide as an Imaging and Targeted Radionuclide Therapeutic Agent in Non-Small Cell Lung Cancer: Biological Evaluation and Preclinical Study. *Bioorg. Chem.* **2020**, *102*, 104100. [CrossRef] [PubMed]

102. Vats, K.; Sharma, R.; Sharma, A.K.; Sarma, H.D.; Satpati, D. Assessment of 177 Lu-Labeled Carboxyl-Terminated Polyamidoamine (PAMAM) Dendrimer-RGD Peptide Conjugate. *J. Pept. Sci.* **2022**, *28*, e3366. [CrossRef]

103. Yoshimoto, M.; Washiyama, K.; Ohnuki, K.; Kojima, M.; Miller, B.; Yoshii, Y.; Fujii, H. Pre-Clinical Evaluation of 225Ac-DOTA-E[c(RGDfK)]2 for Targeted Alpha Therapy in PDCA Mice Model. *J. Nucl. Med.* **2023**, *64*, P276.

104. Parihar, A.S.; Sood, A.; Kumar, R.; Bhusari, P.; Shukla, J.; Mittal, B.R. Novel Use of 177Lu-DOTA-RGD2 in Treatment of 68Ga-DOTA-RGD2-Avid Lesions in Papillary Thyroid Cancer with TENIS. *Eur. J. Nucl. Med. Mol. Imaging* **2018**, *45*, 1836–1837. [CrossRef]

105. Study Details | 177Lu-AB-3PRGD2 in Patients with Integrin αVβ3 Positive Tumors | ClinicalTrials.Gov. Available online: https://clinicaltrials.gov/study/NCT05013086 (accessed on 9 August 2024).

106. Gvozdenovic, A.; Boro, A.; Meier, D.; Bode-Lesniewska, B.; Born, W.; Muff, R.; Fuchs, B. Targeting Avβ3 and Avβ5 Integrins Inhibits Pulmonary Metastasis in an Intratibial Xenograft Osteosarcoma Mouse Model. *Oncotarget* **2016**, *7*, 55141–55154. [CrossRef]

107. Ramón y Cajal, S.; Sesé, M.; Capdevila, C.; Aasen, T.; De Mattos-Arruda, L.; Diaz-Cano, S.J.; Hernández-Losa, J.; Castellví, J. Clinical Implications of Intratumor Heterogeneity: Challenges and Opportunities. *J. Mol. Med.* **2020**, *98*, 161–177. [CrossRef] [PubMed]

108. Truong, H.H.; Xiong, J.; Ghotra, V.P.S.; Nirmala, E.; Haazen, L.; Le Dévédec, S.E.; Balcioğlu, H.E.; He, S.; Snaar-Jagalska, B.E.; Vreugdenhil, E.; et al. B1 Integrin Inhibition Elicits a Prometastatic Switch Through the TGFβ–miR-200–ZEB Network in E-Cadherin–Positive Triple-Negative Breast Cancer. *Sci. Signal.* **2014**, *7*, ra15. [CrossRef]

109. Su, C.; Li, J.; Zhang, L.; Wang, H.; Wang, F.; Tao, Y.; Wang, Y.; Guo, Q.; Li, J.; Liu, Y.; et al. The Biological Functions and Clinical Applications of Integrins in Cancers. *Front. Pharmacol.* **2020**, *11*, 579068. [CrossRef]

110. Krishn, S.R.; Singh, A.; Bowler, N.; Duffy, A.N.; Friedman, A.; Fedele, C.; Kurtoglu, S.; Tripathi, S.K.; Wang, K.; Hawkins, A.; et al. Prostate Cancer Sheds the Avβ3 Integrin in Vivo through Exosomes. *Matrix Biol.* **2019**, *77*, 41–57. [CrossRef] [PubMed]

111. Liu, Z.; Niu, G.; Wang, F.; Chen, X. (68)Ga-Labeled NOTA-RGD-BBN Peptide for Dual Integrin and GRPR-Targeted Tumor Imaging. *Eur. J. Nucl. Med. Mol. Imaging* **2009**, *36*, 1483–1494. [CrossRef] [PubMed]
112. Zhang, J.; Niu, G.; Lang, L.; Li, F.; Fan, X.; Yan, X.; Yao, S.; Yan, W.; Huo, L.; Chen, L.; et al. Clinical Translation of a Dual Integrin Avβ3- and Gastrin-Releasing Peptide Receptor-Targeting PET Radiotracer, 68Ga-BBN-RGD. *J. Nucl. Med.* **2017**, *58*, 228-234. [CrossRef]

113. Zhang, J.; Mao, F.; Niu, G.; Peng, L.; Lang, L.; Li, F.; Ying, H.; Wu, H.; Pan, B.; Zhu, Z.; et al. 68Ga-BBN-RGD PET/CT for GRPR and Integrin Avβ3 Imaging in Patients with Breast Cancer. *Theranostics* **2018**, *8*, 1121-1130. [CrossRef]

114. Bandara, N.; Stott Reynolds, T.J.; Schehr, R.; Bandari, R.P.; Diebolder, P.J.; Krieger, S.; Xu, J.; Miao, Y.; Rogers, B.E.; Smith, C.J. Matched-Pair, 86Y/90Y-Labeled, Bivalent RGD/Bombesin Antagonist, [RGD-Glu-[DO3A]-6-Ahx-RM2], as a Potential Theranostic Agent for Prostate Cancer. *Nucl. Med. Biol.* **2018**, *62–63*, 71–77. [CrossRef] [PubMed]

115. Wen, X.; Wang, R.; Xu, P.; Shi, M.; Shang, Q.; Zeng, X.; Zeng, X.; Liu, J.; Wang, X.; Zhu, Z.; et al. Synthesis, Preclinical, and Initial Clinical Evaluation of Integrin αVβ3 and Gastrin-Releasing Peptide Receptor (GRPR) Dual-Targeting Radiotracer [68Ga]Ga-RGD-RM26-03. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 2023–2035. [CrossRef]

116. Li, D.; Li, Z.; Chen, X.; Zhang, J.; Zhu, Z.; Wang, R.; Wang, J. Dual Integrin 1±v123 and Gastrin-Releasing Peptide Receptor Targeting PET Tracer 68Ga-DOTA-RM26-RGD in Glioma: A Pilot Study. *J. Nucl. Med.* **2024**, *65*, 241697.

117. Liu, B.; Zhang, Z.; Wang, H.; Yao, S. Preclinical Evaluation of a Dual Sstr2 and Integrin Avβ3-Targeted Heterodimer [68Ga]-NOTA-3PEG4-TATE-RGD. *Bioorg. Med. Chem.* **2019**, *27*, 115094. [CrossRef] [PubMed]

118. Zheng, Y.; Zhu, Z. A Proof-of-Concept Study of 68Ga-NOTA-3P-TATE-RGD PET/CT for Dual-Target Imaging of Somatostatin Receptor and Integrin Avβ3 to Detect Lung Cancer in a Single Scan. *J. Nucl. Med.* **2018**, *59*, 1141.

119. Jiang, Y.; Liu, Q.; Wang, G.; Sui, H.; Wang, R.; Wang, J.; Zhu, Z. A Prospective Head-to-Head Comparison of 68 Ga-NOTA-3P-TATE-RGD and 68 Ga-DOTATATE in Patients with Gastroenteropancreatic Neuroendocrine Tumours. *Eur. J. Nucl. Med. Mol. Imaging* **2022**, *49*, 4218–4227. [CrossRef] [PubMed]

120. Xiang, J.; Sun, D.; Sun, Y.-Q.; Wang, J.; Li, L.; Zhu, Z.; Lin, Y. Initial Experience with 68Ga-NOTA-3P-TATE-RGD PET Imaging in Patients with Radioiodine Refractory Thyroid Carcinoma. *J. Nucl. Med.* **2024**, *65*, 241978.

121. Zang, J.; Wen, X.; Lin, R.; Zeng, X.; Wang, C.; Shi, M.; Zeng, X.; Zhang, J.; Wu, X.; Zhang, X.; et al. Synthesis, Preclinical Evaluation and Radiation Dosimetry of a Dual Targeting PET Tracer [68Ga]Ga-FAPI-RGD. *Theranostics* **2022**, *12*, 7180–7190. [CrossRef]

122. Wang, R.; Jakobsson, V.; Wang, J.; Zhao, T.; Peng, X.; Li, B.; Xue, J.; Liang, N.; Zhu, Z.; Chen, X.; et al. Dual Targeting PET Tracer [68Ga]Ga-FAPI-RGD in Patients with Lung Neoplasms: A Pilot Exploratory Study. *Theranostics* **2023**, *13*, 2979–2992. [CrossRef]

123. Zhao, L.; Wen, X.; Xu, W.; Pang, Y.; Sun, L.; Wu, X.; Xu, P.; Zhang, J.; Guo, Z.; Lin, Q.; et al. Clinical Evaluation of 68Ga-FAPI-RGD for Imaging of Fibroblast Activation Protein and Integrin Avβ3 in Various Cancer Types. *J. Nucl. Med.* **2023**, *64*, 1210–1217. [CrossRef] [PubMed]

124. Zang, J.; Lin, R.; Wen, X.; Wang, C.; Zhao, T.; Jakobsson, V.; Yang, Y.; Wu, X.; Guo, Z.; Chen, X.; et al. A Head-to-Head Comparison of 68Ga-LNC1007 and 2-18F-FDG/68Ga-FAPI-02 PET/CT in Patients with Various Cancers. *Clin. Nucl. Med.* **2023**, *48*, 861–868. [CrossRef]

125. Lin, R.; Wang, C.; Chen, S.; Lin, T.; Cai, H.; Chen, S.; Yang, Y.; Zhang, J.; Xu, F.; Zhang, J.; et al. [68Ga]Ga-LNC1007 PET/CT in the Evaluation of Renal Cell Carcinoma: Comparison with 2-[18F]FDG/[68Ga]Ga-PSMA PET/CT. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 535–547. [CrossRef]

126. Chen, Y.; Zang, J.; Wu, Z.; Miao, W. 68Ga-FAPI-RGD PET/CT Detected Skull Metastasis Better Than 18F-FDG in a Patient With Radioiodine-Refractory Differentiated Thyroid Cancer. *Clin. Nucl. Med.* **2024**, *49*, 964–965. [CrossRef]

127. Liu, N.; Wan, Q.; Wu, X.; Zhao, T.; Jakobsson, V.; Yuan, H.; Chen, X.; Zhang, J.; Zhang, W. A Comparison of [18F]AIF- and 68Ga-Labeled Dual Targeting Heterodimer FAPI-RGD in Malignant Tumor: Preclinical Evaluation and Pilot Clinical PET/CT Imaging. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 1685–1697. [CrossRef] [PubMed]

128. Gao, H.; Zhang, W.; Zhang, J.; Chen, X. 18F-AIF-LNC1007 in the Evaluation of Breast Cancer: Comparison with 18F-FDG/18F-FAPI-04 PET/CT. *J. Nucl. Med.* **2024**, *65*, 242585.

129. Yan, Q.; Zhong, J.; Liu, Y.; Peng, S.; Feng, P.; Zhong, Y.; Hu, K. Synthesis and Preclinical Evaluation of a Heterodimeric Radioligand Targeting Fibroblast Activation Protein and Integrin-Avβ3. *Eur. J. Med. Chem.* **2023**, *251*, 115279. [CrossRef]

130. Liu, K.; Jiang, T.; Rao, W.; Chen, B.; Yin, X.; Xu, P.; Hu, S. Peptidic Heterodimer-Based Radiotracer Targeting Fibroblast Activation Protein and Integrin Avβ3. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 1544–1557. [CrossRef]

131. Wen, X.; Yang, H.; Liu, J.; Guo, Z.; Zhang, J.; Chen, X. Development of Dual Targeting Heterodimer 177Lu-LNC1009 for Cancer Theranostics. *J. Nucl. Med.* **2024**, *65*, 241873.

132. Escudero-Castellanos, A.; Ocampo-García, B.E.; Ferro-Flores, G.; Isaac-Olivé, K.; Santos-Cuevas, C.L.; Olmos-Ortiz, A.; García-Quiroz, J.; García-Becerra, R.; Díaz, L. Preparation and in Vitro Evaluation of 177Lu-iPSMA-RGD as a New Heterobivalent Radiopharmaceutical. *J. Radioanal. Nucl. Chem.* **2017**, *314*, 2201–2207. [CrossRef]

133. Ocampo-García, B.; Cruz-Nova, P.; Jiménez-Mancilla, N.; Luna-Gutiérrez, M.; Oros-Pantoja, R.; Lara-Almazán, N.; Pérez-Velasco, D.; Santos-Cuevas, C.; Ferro-Flores, G. 225Ac-iPSMA-RGD for Alpha-Therapy Dual Targeting of Stromal/Tumor Cell PSMA and Integrins. *Int. J. Mol. Sci.* **2023**, *24*, 16553. [CrossRef]

134. Gai, Y.; Jiang, Y.; Long, Y.; Sun, L.; Liu, Q.; Qin, C.; Zhang, Y.; Zeng, D.; Lan, X. Evaluation of an Integrin Avβ3 and Aminopeptidase N Dual-Receptor Targeting Tracer for Breast Cancer Imaging. *Mol. Pharm.* **2020**, *17*, 349–358. [CrossRef]

135. Long, Y.; Shao, F.; Ji, H.; Song, X.; Lv, X.; Xia, X.; Liu, Q.; Zhang, Y.; Zeng, D.; Lan, X.; et al. Evaluation of a CD13 and Integrin Avβ3 Dual-Receptor Targeted Tracer 68Ga-NGR-RGD for Ovarian Tumor Imaging: Comparison With 18F-FDG. *Front. Oncol.* **2022**, *12*, 884554. [CrossRef]
136. Lv, X.; Song, X.; Long, Y.; Zeng, D.; Lan, X.; Gai, Y. Preclinical Evaluation of a Dual-Receptor Targeted Tracer [68Ga]Ga-HX01 in 10 Different Subcutaneous and Orthotopic Tumor Models. *Eur. J. Nucl. Med. Mol. Imaging* **2023**, *51*, 54–67. [CrossRef]

137. Yang, B.; Shan, C.; Song, X.; Lv, X.; Long, Y.; Zeng, D.; An, R.; Lan, X.; Gai, Y. Development and Evaluation of Albumin Binder-Conjugated Heterodimeric Radiopharmaceuticals Targeting Integrin Avβ3 and CD13 for Cancer Therapy. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 3334–3345. [CrossRef] [PubMed]

138. Wu, H.; Chen, H.; Pan, D.; Ma, Y.; Liang, S.; Wan, Y.; Fang, Y. Imaging Integrin Avβ3 and NRP-1 Positive Gliomas with a Novel Fluorine-18 Labeled RGD-ATWLPPR Heterodimeric Peptide Probe. *Mol. Imaging Biol.* **2014**, *16*, 781–792. [CrossRef]

139. Yao, L.; Li, Y.; Chen, H.; Wen, X.; Pang, Y.; Chen, Z.; Guo, Z.; Zhang, X.; Wu, H.; Guo, W. Dual Targeting of Integrin Avβ3 and VEGF Receptor Improves PET Imaging of Breast Cancer. *Res. Sq.* **2021**. [CrossRef]

140. Yao, L.; Li, Y.; Chen, H.; Wen, X.; Pang, Y.; Chen, Z.; Guo, Z.; Zhang, X.; Wu, H.; Guo, W. Dual Targeting of Integrin Avβ3 and Neuropilin-1 Receptors Improves Micropositron Emission Tomography Imaging of Breast Cancer. *Mol. Pharm.* **2022**, *19*, 1458–1467. [CrossRef]

141. Liu, W.; Ma, H.; Liang, R.; Chen, X.; Li, H.; Lan, T.; Yang, J.; Liao, J.; Qin, Z.; Yang, Y.; et al. Targeted Alpha Therapy of Glioma Using 211At-Labeled Heterodimeric Peptide Targeting Both VEGFR and Integrins. *Mol. Pharm.* **2022**, *19*, 3206–3216. [CrossRef]

142. Chen, C.-J.; Chan, C.-H.; Lin, K.-L.; Chen, J.-H.; Tseng, C.-H.; Wang, P.-Y.; Chien, C.-Y.; Yu, H.-M.; Lin, W.-J. 68Ga-Labelled NOTA-RGD-GE11 Peptide for Dual Integrin and EGFR-Targeted Tumour Imaging. *Nucl. Med. Biol.* **2019**, *68–69*, 22–30. [CrossRef] [PubMed]

143. Li, H.; Peng, W.; Zhen, Z.; Zhang, W.; Liao, S.; Wu, X.; Wang, L.; Xuan, A.; Gao, Y.; Xu, J. Integrin Avβ3 and EGFR Dual-Targeted [64Cu]Cu-NOTA-RGD-GE11 Heterodimer for PET Imaging in Pancreatic Cancer Mouse Model. *Nucl. Med. Biol.* **2023**, *124–125*, 108364. [CrossRef]

144. Braun, D.; Judmann, B.; Cheng, X.; Wängler, B.; Schirrmacher, R.; Fricker, G.; Wängler, C. Synthesis, Radiolabeling, and In Vitro and In Vivo Characterization of Heterobivalent Peptidic Agents for Bispecific EGFR and Integrin Avβ3 Targeting. *ACS Omega* **2023**, *8*, 2793–2807. [CrossRef]

145. Gai, Y.; Xiang, G.; Ma, X.; Hui, W.; Ouyang, Q.; Sun, L.; Ding, J.; Sheng, J.; Zeng, D. Universal Molecular Scaffold for Facile Construction of Multivalent and Multimodal Imaging Probes. *Bioconjug Chem.* **2016**, *27*, 515–520. [CrossRef]

146. Gai, Y.; Sun, L.; Xiang, G.; Ma, X.; Zeng, D. Optimized Peptide Heterodimer for uPAR-Avβ3 Dual-Targeted Cancer Imaging. *J. Nucl. Med.* **2016**, *57*, 1064.

147. Gai, Y.; Sun, L.; Xiang, G.; Ma, X.; Zeng, D. PET Imaging of Pancreatic Cancer Using uPAR-Avβ3 Dual-Targeted Heterodimer. *J. Nucl. Med.* **2016**, *57*, 1149.

148. Cheng, X.; Hübner, R.; von Kiedrowski, V.; Fricker, G.; Schirrmacher, R.; Wängler, C.; Wängler, B. Design, Synthesis, In Vitro and In Vivo Evaluation of Heterobivalent SiFAlin-Modified Peptidic Radioligands Targeting Both Integrin Avβ3 and the MC1 Receptor—Suitable for the Specific Visualization of Melanomas? *Pharmaceuticals* **2021**, *14*, 547. [CrossRef] [PubMed]

149. PubChem GRPR—Gastrin Releasing Peptide Receptor (Human). Available online: https://pubchem.ncbi.nlm.nih.gov/gene/GRPR/human (accessed on 27 August 2024).

150. Pooja, D.; Gunukula, A.; Gupta, N.; Adams, D.J.; Kulhari, H. Bombesin Receptors as Potential Targets for Anticancer Drug Delivery and Imaging. *Int. J. Biochem. Cell Biol.* **2019**, *114*, 105567. [CrossRef] [PubMed]

151. Echavidre, W.; Fagret, D.; Faraggi, M.; Picco, V.; Montemagno, C. Recent Pre-Clinical Advancements in Nuclear Medicine: Pioneering the Path to a Limitless Future. *Cancers* **2023**, *15*, 4839. [CrossRef] [PubMed]

152. Theodoropoulou, M.; Stalla, G.K. Somatostatin Receptors: From Signaling to Clinical Practice. *Front. Neuroendocrinol.* **2013**, *34*, 228–252. [CrossRef]

153. Kumar, U. Somatostatin and Somatostatin Receptors in Tumour Biology. *Int. J. Mol. Sci.* **2024**, *25*, 436. [CrossRef]

154. Hennrich, U.; Kopka, K. Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. *Pharmaceuticals* **2019**, *12*, 114. [CrossRef]

155. Aashiq, M.; Silverman, D.A.; Na'ara, S.; Takahashi, H.; Amit, M. Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. *Cancers* **2019**, *11*, 1382. [CrossRef]

156. Dziadek, S.; Kraxner, A.; Cheng, W.-Y.; Ou Yang, T.-H.; Flores, M.; Theiss, N.; Tsao, T.-S.; Andersson, E.; Harring, S.V.; Bröske, A.-M.E.; et al. Comprehensive Analysis of Fibroblast Activation Protein Expression across 23 Tumor Indications: Insights for Biomarker Development in Cancer Immunotherapies. *Front. Immunol.* **2024**, *15*, 1352615. [CrossRef]

157. Sidrak, M.M.A.; De Feo, M.S.; Corica, F.; Gorica, J.; Conte, M.; Filippi, L.; Schillaci, O.; De Vincentis, G.; Frantellizzi, V. Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review. *Int. J. Mol. Sci.* **2023**, *24*, 3863. [CrossRef]

158. Watabe, T.; Liu, Y.; Kaneda-Nakashima, K.; Shirakami, Y.; Lindner, T.; Ooe, K.; Toyoshima, A.; Nagata, K.; Shimosegawa, E.; Haberkorn, U.; et al. Theranostics Targeting Fibroblast Activation Protein in the Tumor Stroma: 64Cu- and 225Ac-Labeled FAPI-04 in Pancreatic Cancer Xenograft Mouse Models. *J. Nucl. Med.* **2020**, *61*, 563–569. [CrossRef] [PubMed]

159. Dong, Y.; Zhou, H.; Alhaskawi, A.; Wang, Z.; Lai, J.; Yao, C.; Liu, Z.; Hasan Abdullah Ezzi, S.; Goutham Kota, V.; Hasan Abdulla Hasan Abdulla, M.; et al. The Superiority of Fibroblast Activation Protein Inhibitor (FAPI) PET/CT Versus FDG PET/CT in the Diagnosis of Various Malignancies. *Cancers* **2023**, *15*, 1193. [CrossRef] [PubMed]

160. Queisser, A.; Hagedorn, S.A.; Braun, M.; Vogel, W.; Duensing, S.; Perner, S. Comparison of Different Prostatic Markers in Lymph Node and Distant Metastases of Prostate Cancer. *Mod. Pathol.* **2015**, *28*, 138–145. [CrossRef] [PubMed]
161. Sheehan, B.; Guo, C.; Neeb, A.; Paschalis, A.; Sandhu, S.; de Bono, J.S. Prostate-Specific Membrane Antigen Biology in Lethal Prostate Cancer and Its Therapeutic Implications. *Eur. Urol. Focus* **2022**, *8*, 1157–1168. [CrossRef]

162. Conway, R.E.; Petrovic, N.; Li, Z.; Heston, W.; Wu, D.; Shapiro, L.H. Prostate-Specific Membrane Antigen Regulates Angiogenesis by Modulating Integrin Signal Transduction. *Mol. Cell Biol.* **2006**, *26*, 5310–5324. [CrossRef]

163. Mokoala, K.; Lawal, I.; Lengana, T.; Kgatle, M.; Giesel, F.L.; Vorster, M.; Sathekge, M. PSMA Theranostics: Science and Practice. *Cancers* **2021**, *13*, 3904. [CrossRef]

164. Ahmadzadehfar, H.; Seifert, R.; Afshar-Oromieh, A.; Kratochwil, C.; Rahbar, K. Prostate Cancer Theranostics With 177Lu-PSMA. *Semin. Nucl. Med.* **2024**, *54*, 581–590. [CrossRef]

165. Mattana, F.; Muraglia, L.; Barone, A.; Colandrea, M.; Saker Diffalah, Y.; Provera, S.; Cascio, A.S.; Omodeo Salè, E.; Ceci, F. Prostate-Specific Membrane Antigen-Targeted Therapy in Prostate Cancer: History, Combination Therapies, Trials, and Future Perspective. *Cancers* **2024**, *16*, 1643. [CrossRef]

166. Lendeckel, U.; Karimi, F.; Al Abdulla, R.; Wolke, C. The Role of the Ectopeptidase APN/CD13 in Cancer. *Biomedicines* **2023**, *11*, 724. [CrossRef]

167. Guo, Q.; Li, X.; Cui, M.-N.; Sun, J.-L.; Ji, H.-Y.; Ni, B.-B.; Yan, M.-X. CD13: A Key Player in Multidrug Resistance in Cancer Chemotherapy. *Oncol. Res.* **2020**, *28*, 533–540. [CrossRef]

168. Dumond, A.; Pagès, G. Neuropilins, as Relevant Oncology Target: Their Role in the Tumoral Microenvironment. *Front. Cell Dev. Biol.* **2020**, *8*, 662. [CrossRef] [PubMed]

169. Herzog, B.; Pellet-Many, C.; Britton, G.; Hartzoulakis, B.; Zachary, I.C. VEGF Binding to NRP1 Is Essential for VEGF Stimulation of Endothelial Cell Migration, Complex Formation between NRP1 and VEGFR2, and Signaling via FAK Tyr407 Phosphorylation. *Mol. Biol. Cell* **2011**, *22*, 2766–2776. [CrossRef] [PubMed]

170. Chuckran, C.A.; Liu, C.; Bruno, T.C.; Workman, C.J.; Vignali, D.A. Neuropilin-1: A Checkpoint Target with Unique Implications for Cancer Immunology and Immunotherapy. *J. Immunother. Cancer* **2020**, *8*, e000967. [CrossRef]

171. Liu, Q.; Cai, S.; Ye, J.; Xie, Q.; Liu, R.; Qiu, L.; Lin, J. Preclinical Evaluation of 68 Ga-Labeled Peptide CK2 for PET Imaging of NRP-1 Expression in Vivo. *Eur. J. Nucl. Med. Mol. Imaging* **2024**, *51*, 1826–1840. [CrossRef]

172. Thoreau, F.; Vanwonterghem, L.; Henry, M.; Coll, J.-L.; Boturyn, D. Design of RGD-ATWLPPR Peptide Conjugates for the Dual Targeting of αVβ3 Integrin and Neuropilin-1. *Org. Biomol. Chem.* **2018**, *16*, 4101–4107. [CrossRef]

173. Bazzazi, H.; Zhang, Y.; Jafarnejad, M.; Popel, A.S. Computational Modeling of Synergistic Interaction between αVβ3 Integrin and VEGFR2 in Endothelial Cells: Implications for the Mechanism of Action of Angiogenesis-Modulating Integrin-Binding Peptides. *J. Theor. Biol.* **2018**, *455*, 212–221. [CrossRef]

174. Metrangolo, V.; Ploug, M.; Engelholm, L.H. The Urokinase Receptor (uPAR) as a "Trojan Horse" in Targeted Cancer Therapy: Challenges and Opportunities. *Cancers* **2021**, *13*, 5376. [CrossRef]

175. Mun, Y.; Kim, W.; Shin, D. Melanocortin 1 Receptor (MC1R): Pharmacological and Therapeutic Aspects. *Int. J. Mol. Sci.* **2023**, *24*, 12152. [CrossRef] [PubMed]

176. Guida, S.; Guida, G.; Goding, C.R. MC1R Functions, Expression, and Implications for Targeted Therapy. *J. Investig. Dermatol.* **2022**, *142*, 293–302.e1. [CrossRef]

177. Huang, A.-H.; Han, S.-P.; Lu, Y.-P.; Ma, R.; Zheng, H.-S.; Li, F.-Z. [Preparation and in vitro evaluation of arsenic trioxide glioma targeting drug delivery system loaded by PAMAM dendrimers co-modified with RGDyC and PEG]. *Zhongguo Zhong Yao Za Zhi* **2018**, *43*, 1618–1625. [CrossRef]

178. Lu, Y.; Han, S.; Zheng, H.; Ma, R.; Ping, Y.; Zou, J.; Tang, H.; Zhang, Y.; Xu, X.; Li, F. A Novel RGDyC/PEG Co-Modified PAMAM Dendrimer-Loaded Arsenic Trioxide of Glioma Targeting Delivery System. *Int. J. Nanomed.* **2018**, *13*, 5937–5952. [CrossRef] [PubMed]

179. Shi, X.; Ma, R.; Lu, Y.; Cheng, Y.; Fan, X.; Zou, J.; Zheng, H.; Li, F.; Piao, J.-G. iRGD and TGN Co-Modified PAMAM for Multi-Targeted Delivery of ATO to Gliomas. *Biochem. Biophys. Res. Commun.* **2020**, *527*, 117–123. [CrossRef] [PubMed]

180. Yang, J.; Zhang, Q.; Liu, Y.; Zhang, X.; Shan, W.; Ye, S.; Zhou, X.; Ge, Y.; Wang, X.; Ren, L. Nanoparticle-Based Co-Delivery of siRNA and Paclitaxel for Dual-Targeting of Glioblastoma. *Nanomedicine* **2020**, *15*, 1391–1409. [CrossRef] [PubMed]

181. Chauhan, M.; Sonali; Shekhar, S.; Yadav, B.; Garg, V.; Dutt, R.; Mehata, A.K.; Goswami, P.; Koch, B.; Muthu, M.S.; et al. AS1411 Aptamer/RGD Dual Functionalized Theranostic Chitosan-PLGA Nanoparticles for Brain Cancer Treatment and Imaging. *Biomater. Adv.* **2024**, *160*, 213833. [CrossRef]

182. Fu, Q.; Zhao, Y.; Yang, Z.; Yue, Q.; Xiao, W.; Chen, Y.; Yang, Y.; Guo, L.; Wu, Y. Liposomes Actively Recognizing the Glucose Transporter GLUT1 and Integrin Av B3 for Dual-Targeting of Glioma. *Arch. Pharm.* **2019**, *352*, e1800219. [CrossRef]

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