A Modular Coassembly Approach to All-In-One Multifunctional Nanoplatform for Synergistic Codelivery of Doxorubicin and Curcumin

Synergistic combination therapy by integrating chemotherapeutics and chemosensitizers into nanoparticles has demonstrated great potential to reduce side effects, overcome multidrug resistance (MDR), and thus improve therapeutic efficacy. However, with regard to the nanocarriers for multidrug codelivery, it remains a strong challenge to maintain design simplicity, while incorporating the desirable multifunctionalities, such as coloaded high payloads, targeted delivery, hemodynamic stability, and also to ensure low drug leakage before reaching the tumor site, but simultaneously the corelease of drugs in the same cancer cell. Herein, we developed a facile modular coassembly approach to construct an all-in-one multifunctional multidrug delivery system for the synergistic codelivery of doxorubicin (DOX, chemotherapeutic agent) and curcumin (CUR, MDR modulator). The acid-cleavable PEGylated polymeric prodrug (DOX-h-PCEC), tumor cell-specific targeting peptide (CRGDK-PEG-PCL), and natural chemosensitizer (CUR) were ratiometrically assembled into in one single nanocarrier (CUR/DOX-h-PCEC@CRGDK NPs). The resulting CUR/DOX-h-PCEC@CRGDK NPs exhibited several desirable characteristics, such as efficient and ratiometric drug loading, high hemodynamic stability and low drug leakage, tumor intracellular acid-triggered cleavage, and subsequent intracellular simultaneous drug corelease, which are expected to maximize a synergistic effect of chemotherapy and chemosensitization. Collectively, the multifunctional nanocarrier is feasible for the creation of a robust nanoplatform for targeted multidrug codelivery and efficient MDR modulation.

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title: Development of antiproliferative long-circulating liposomes co-encapsulating doxorubicin and curcumin, through the use of a quality-by-design approach
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title: Doxorubicin and curcumin co-delivery by lipid nanoparticles for enhanced treatment of diethylnitrosamine-induced hepatocellular carcinoma in mice.
abstract: At present, the treatment of hepatocellular carcinoma (HCC) is an international problem. The delivery of a chemotherapeutic agent and chemosensitizer using nanocarriers has been suggested as a novel and promising strategy in cancer treatment. However, such studies in HCC remain very limited. In this study, we developed doxorubicin (DOX) and curcumin (Cur) co-delivery lipid nanoparticles (DOX/Cur-NPs) and examined its inhibitory effect on diethylnitrosamine (DEN)-induced HCC in mice. DOX/Cur-NPs displayed the physicochemical characterizations with uniform particle size, high encapsulation efficacy and sustained release profile. In DNE-induced HCC mice treated with DOX/Cur-NPs, we observed decreased liver damage assessed by serum ALT and AST levels, liver/body weight ratio, and histopathological analysis. Compared with DOX-loaded nanoparticles (DOX-NPs), DOX/Cur-NPs induced increased Caspase-3 and Bax/Bcl-2 ratio, and decreased C-myc, PCNA and VEGF. The results revealed the synergistic effect of DOX/Cur-NPs on the apoptosis, proliferation and angiogenesis of HCC. The mRNA levels of MDR1, bcl-2 and HIF-1α, and protein levels of P-gp, Bcl-2 and HIF-1α were decreased in DOX/Cur-NPs than those in DOX-NPs, indicating that Cur might reverse multidrug resistance (MDR) through these pathways. In HCC cells, enhanced cytotoxicity and decreased IC50 and resistant index further confirmed the synergistic effects of DOX/Cur-NPs than DOX-NPs. Our studies suggest that simultaneous delivery of DOX and Cur by DOX/Cur-NPs may be a promising treatment for HCC.

title: Nanomedicine based curcumin and doxorubicin combination treatment of glioblastoma with scFv-targeted micelles: In vitro evaluation on 2D and 3D tumor models.
abstract: NF-κB is strongly associated with poor prognosis of different cancer types and an important factor responsible for the malignant phenotype of glioblastoma. Overcoming chemotherapy-induced resistance caused by activation of PI3K/Akt and NF-κB pathways is crucial for successful glioblastoma therapy. We developed an all-in-one nanomedicine formulation for co-delivery of a chemotherapeutic agent (topoisomerase II inhibitor, doxorubicin) and a multidrug resistance modulator (NF-κB inhibitor, curcumin) for treatment of glioblastoma due to their synergism. Both agents were incorporated into PEG-PE-based polymeric micelles. The glucose transporter-1 (GLUT1) is overexpressed in many tumors including glioblastoma. The micellar system was decorated with GLUT1 antibody single chain fragment variable (scFv) as the ligand to promote blood brain barrier transport and glioblastoma targeting. The combination treatment was synergistic (combination index, CI of 0.73) against U87MG glioblastoma cells. This synergism was improved by micellar encapsulation (CI: 0.63) and further so with GLUT1 targeting (CI: 0.46). Compared to non-targeted micelles, GLUT1 scFv surface modification increased the association of micelles (>20%, P<0.01) and the nuclear localization of doxorubicin (∼3-fold) in U87MGcells, which also translated into enhanced cytotoxicity. The increased caspase 3/7 activation by targeted micelles indicates successful apoptosis enhancement by combinatory treatment. Moreover, GLUT1 targeted micelles resulted in deeper penetration into the 3D spheroid model. The increased efficacy of combination nanoformulations on the spheroids compared to a single agent loaded, or to non-targeted formulations, reinforces the rationale for selection of this combination and successful utilization of GLUT1 scFv as a targeting agent for glioblastoma treatment.

title: Co‐assembly of doxorubicin and curcumin targeted micelles for synergistic delivery and improving anti‐tumor efficacy
abstract: No caption available.  Chemotherapeutic drugs have a series of limitations in anti‐tumor treatment, mainly including multidrug resistance (MDR) and serious adverse reactions. Co‐delivery system with two or more synergistic therapeutic drugs is an effective strategy to settle these limitations. In this study, active tumor‐targeted co‐delivery micelles (DOX + Cur)‐PMs, with two synergistic drugs of a therapeutic drug of doxorubicin (DOX) and a chemosensitizer of curcumin (Cur) co‐encapsulated into hyaluronic acid‐vitamin E succinate (HA‐VES) graft copolymer, were prepared and delivered simultaneously into tumor cells for improving therapeutic effects of DOX. (DOX + Cur)‐PMs had uniform particle size, high encapsulation efficacy, sustained release profile and good colloidal stability. In vitro cytotoxicity study, (DOX + Cur)‐PMs exerted the strongest cytotoxicity and highest cell apoptosis‐inducing activities against DOX‐resistant MCF‐7/Adr cells. Moreover, (DOX + Cur)‐PMs more efficiently internalized into cancer cells and enhanced the cellular uptake of DOX via energy‐dependent and caveolae‐mediated endocytosis, and significantly reversed MDR effects via CD44 targeting delivery and the synergic effect of released Cur. More importantly, in vivo results illustrated that (DOX + Cur)‐PMs not only displayed better tumor accumulation and tumor targeting, and more efficiently inhibited the growth of tumor in 4T1 tumor‐bearing mice, but also induced significantly less pathological damage to the cardiac tissue in comparison with free DOX, even DOX‐PMs and DOX‐PMs + Cur. In summary, this targeted combinational micellar delivery system with DOX and Cur could be a promising vehicle in tumor therapy.

title: Synergistically Improved Anti-tumor Efficacy by Co-delivery Doxorubicin and Curcumin Polymeric Micelles.
abstract: P-gp mediated drug efflux has been recognized as a major obstacle limiting the success of cancer chemotherapy. To overcome this issue, doxorubicin (DOX) and curcumin (Cur; P-gp inhibitor and apoptosis inhibitor) co-encapsulated pegylated polymeric micelles ((DOX+Cur)-PMs) were designed, prepared and characterized to simultaneously deliver chemotherapeutic drug and multidrug resistance (MDR) modulator to tumor sites. The (DOX+Cur)-PMs were spherical nano-size particle, with a loading content of 6.83%, and high colloidal stability. Co-delivery micelles exhibited excellent cytotoxicity by reversing MDR, promoting cellular uptake and enhancing cellular apoptosis in MCF7/Adr cells. The tumor growth inhibitory effect of (DOX+Cur)-PMs in 4T1-bearing mice was more effective compared with the combination solution of DOX and Cur and even DOX-PMs. In conclusion, simultaneous delivery of DOX and Cur by (DOX+Cur)-PMs has been demonstrated to be a promising approach for overcoming MDR and improving antitumor efficacy.

title: pH-Responsive prodrug nanoparticles based on a sodium alginate derivative for selective co-release of doxorubicin and curcumin into tumor cells.
abstract: In order to realize a combination of chemotherapy and selective drug release into tumor cells, novel pH-sensitive prodrugnanoparticles were designed and prepared via the self-assembly of a synthetic amphiphilic macromolecular prodrug for the selective co-delivery of doxorubicin (Dox) and curcumin (Cur). Dox was covalently conjugated to the oxidized sodium alginate through a Schiff base reaction to produce an amphiphilic macromolecular prodrug, and the prodrug was subsequently self-assembled into nanoparticles (Dox-NPs) in an aqueous solution, which were responsive to the acidic environment in tumor cells. Additionally, a second chemotherapeutic agent, Cur, was encapsulated in the core of nanoparticles (Cur-Dox-NPs) via hydrophobic effects, with a significant drug loading capacity. Cur-Dox-NPs exhibited an efficient release of both Dox and Cur in acidic media and further studies of their intracellular uptake and drug release confirmed that Dox-NPs were easily taken up by cells and selectively released the drug into the human breast cancer cell line MCF-7. In vitro cytotoxicity studies of the NPs showed a remarkable efficacy against MCF-7 cell lines, whereas an improved safety profile was observed in the human breast epithelial cell line MCF-10A. Furthermore, in vivo studies in zebrafish further confirmed an efficient absorption of Dox-NPs. In vivo cardiotoxicity experiments on a zebrafish model showed that Dox-NPs exhibited an improved cardiotoxicity profile in comparison with free Dox. This study demonstrated that this novel pH-sensitive prodrug-nanoparticle system may provide a simple and efficient platform for the selective co-delivery of multiple drugs to tumor cells.

title: Co-delivery of doxorubicin and pH-sensitive curcumin prodrug by transferrin-targeted nanoparticles for breast cancer treatment.
abstract: The natural product curcumin and the chemotherapeutic agent doxorubicin have been used in the treatment of many cancers, including breast cancer. However, fast clearance and unspecific distribution in the body after intravenous injection are still challenges to be overcome by an ideal nano-sized drug delivery system in cancer treatment. In this study we design transferrin (Tf) decorated nanoparticles (NPs) to co-deliver CUR and DOX for breast cancer treatment. A pH-sensitive prodrug, transferrin-poly(ethylene glycol)-curcumin (Tf-PEG-CUR), was synthesized and used for the self‑assembling of NPs (Tf-PEG-CUR NPs). DOX is incorporated into the Tf-PEG-CUR NPs to obtain Tf-PEG-CUR/DOX NPs. In vitro cytotoxicity studies and in vivo antitumor activity were carried out using MCF-7 cells and mice bearing MCF-7 cells, respectively. Tf-PEG-CUR/DOX NPs has a particle size of 89 nm and a zeta potential of -15.6 mV. This system displayed remarkably higher efficiency than other systems both in vitro and in vivo. DOX and CUR were successfully loaded into nanocarriers. The in vitro cell viability assays revealed the combination of Tf-PEG-CUR and DOX NPs exhibited higher cytotoxicity in vitro in MCF-7 cells compared with Tf-PEG-CUR NPs alone. Using the breast cancer xenograft mouse model, we demonstrate that this co-encapsulation approach resulted in an efficient tumor-targeted drug delivery, decreased cytotoxic effects and exhibited stronger antitumor effect.

title: Amifostine-conjugated pH-sensitive calcium phosphate-covered magnetic-amphiphilic gelatin nanoparticles for controlled intracellular dual drug release for dual-targeting in HER-2-overexpressing breast cancer.
abstract: We developed a surfactant-free method utilizing amifostine to stably link a targeting ligand (Herceptin) to amphiphilic gelatin (AG)-iron oxide@calcium phosphate (CaP) nanoparticles with hydrophobic curcumin (CUR) and hydrophilic doxorubicin (DOX) encapsulated in the AG core and CaP shell (AGIO@CaP-CD), respectively. This multi-functional nanoparticle system has a pH-sensitive CaP shell and degradable amphiphilic gelatin (AG) core, which enables controllable sequential release of the two drugs. The dual-targeting system of AGIO@CaP-CD (HER-AGIO@CaP-CD) with a bioligand and magnetic targeting resulted in significantly elevated cellular uptake in HER2-overexpressing SKBr3 cells and more efficacious therapy than delivery of targeting ligand alone due to the synergistic cell multi-drug resistance/apoptosis-inducing effect of the CUR and DOX combination. This nanoparticle combined with Herceptin and iron oxide nanoparticles not only provided a dual-targeting functionality, but also encapsulated CUR and DOX as a dual-drug delivery system for the combination therapy. This study further demonstrated that the therapeutic efficacy of this dual-targeting co-delivery system can be improved by modifying the application duration of magnetic targeting, which makes this combination therapy system a powerful new tool for in vitro/in vivo cancer therapy, especially for HER2-positive cancers.

title: Magnetic core-shell nanocapsules with dual-targeting capabilities and co-delivery of multiple drugs to treat brain gliomas.
abstract: Lactoferrin (Lf)-tethered magnetic double emulsion nanocapsules (Lf-MDCs) are assembled from polyvinyl alcohol (PVA), polyacrylic acid (PAA), and iron oxide (IO) nanoparticles. The core-shell nanostructure of the Lf-MDCs (particle diameters from 100 to 150 nm) can simultaneously accommodate a hydrophilic drug, doxorubicin (Dox), and a hydrophobic drug, curcumin (Cur), in the core and shell, respectively, of the nanocapsules for an efficient drug delivery system. The release patterns of the two drugs can be regulated by manipulating the surface charges and drug-loading ratios, providing the capability for a stepwise adjuvant release to treat cancer cells. The results demonstrate that the dual (Dox+Cur)-drug-loaded nanocapsule can be effectively delivered into RG2 glioma cells to enhance the cytotoxicity against the cells through a synergistic effect. The combined targeting, i.e., magnetic guidance and incorporation of Lf ligands, of these Lf-MDCs results in significantly elevated cellular uptake in the RG2 cells that overexpress the Lf receptor. Interestingly, an intravenous injection of the co-delivered chemotherapeutics follows by magnetic targeting in brain tumor-bearing mice not only achieve high accumulation at the targeted site but also more efficiently suppress cancer growth in vivo than does the delivery of either drug alone.

title: Effective co-delivery of doxorubicin and dasatinib using a PEG-Fmoc nanocarrier for combination cancer chemotherapy.
abstract: A simple PEGylated peptidic nanocarrier, PEG5000-lysyl-(α-Fmoc-ε-Cbz-lysine)2 (PLFCL), was developed for effective co-delivery of doxorubicin (DOX) and dasatinib (DAS) for combination chemotherapy. Significant synergy of DOX and DAS in inhibition of cancer cell proliferation was demonstrated in various types of cancer cells, including breast, prostate, and colon cancers. Co-encapsulation of the two agents was facilitated by incorporation of 9-Fluorenylmethoxycarbonyl (Fmoc) and carboxybenzyl (Cbz) groups into a nanocarrier for effective carrier-drug interactions. Spherical nanomicelles with a small size of ∼30 nm were self-assembled by PLFCL. Strong carrier/drug intermolecular π-π stacking was demonstrated in fluorescence quenching and UV absorption. Fluorescence study showed more effective accumulation of DOX in nuclei of cancer cells following treatment with DOX&DAS/PLFCL in comparison with cells treated with DOX/PLFCL. DOX&DAS/PLFCL micelles were also more effective than other treatments in inhibiting the proliferation and migration of cultured cancer cells. Finally, a superior anti-tumor activity was demonstrated with DOX&DAS/PLFCL. A tumor growth inhibition rate of 95% was achieved at a respective dose of 5 mg/kg for DOX and DAS in a murine breast cancer model. Our nanocarrier may represent a simple and effective system that could facilitate clinical translation of this promising multi-agent regimen in combination chemotherapy.

title: Physical and chemical stability of drug nanoparticles.
abstract: As nano-sizing is becoming a more common approach for pharmaceutical product development, researchers are taking advantage of the unique inherent properties of nanoparticles for a wide variety of applications. This article reviews the physical and chemical stability of drug nanoparticles, including their mechanisms and corresponding characterization techniques. A few common strategies to overcome stability issues are also discussed.

title: Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology.
abstract: Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000's. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential "retention" in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers.

title: The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect.
abstract: The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors related to their anatomical and pathophysiological differences from normal tissues. For example, angiogenesis leads to high vascular density in solid tumors, large gaps exist between endothelial cells in tumor blood vessels, and tumor tissues show selective extravasation and retention of macromolecular drugs. This EPR effect served as a basis for development of macromolecular anticancer therapy. We demonstrated methods to enhance this effect artificially in clinical settings. Of great importance was increasing systolic blood pressure via slow angiotensin II infusion. Another strategy involved utilization of NO-releasing agents such as topical nitroglycerin, which releases nitrite. Nitrite is converted to NO more selectively in the tumor tissues, which leads to a significantly increased EPR effect and enhanced antitumor drug effects as well. This review discusses molecular mechanisms of factors related to the EPR effect, the unique anatomy of tumor vessels, limitations and techniques to avoid such limitations, augmenting tumor drug delivery, and experimental and clinical findings.

title: Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs
abstract: Penetrating Attack on Tumors While considerable research effort in oncology is focused on the design of new cancer drugs, an important but relatively understudied research area is the development of methods that optimize the delivery and tumor penetration of existing cancer drugs. Previous work has characterized a peptide (iRGD) that selectively targets and penetrates tumor tissue by virtue of its specific interaction with tumor blood vessels. Now, studying mouse models, Sugahara et al. (p. 1031, see the cover) show that coinjection of the iRGD peptide increases the tumor penetration and antitumor activity of several cancer drugs, including the cytotoxic agent doxorubicin and the therapeutic antibody trastuzumab (Herceptin), without increasing their harmful effects on healthy tissue. Importantly, these effects did not require chemical conjugation of the cancer drugs to the peptide. Anticancer drugs are more effective in mice when they are injected with a peptide that helps the drugs penetrate the tumor. Poor penetration of anticancer drugs into tumors can be an important factor limiting their efficacy. We studied mouse tumor models to show that a previously characterized tumor-penetrating peptide, iRGD, increased vascular and tissue permeability in a tumor-specific and neuropilin-1–dependent manner, allowing coadministered drugs to penetrate into extravascular tumor tissue. Importantly, this effect did not require the drugs to be chemically conjugated to the peptide. Systemic injection with iRGD improved the therapeutic index of drugs of various compositions, including a small molecule (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and a monoclonal antibody (trastuzumab). Thus, coadministration of iRGD may be a valuable way to enhance the efficacy of anticancer drugs while reducing their side effects, a primary goal of cancer therapy research.

title: Targeted Chemo-Photodynamic Combination Platform Based on the DOX Prodrug Nanoparticles for Enhanced Cancer Therapy.
abstract: Chemo-photodynamic combination therapy has been received widespread attention in cancer treatment due to its excellent characteristics, such as reducing the adverse side effects of chemo-drugs and improving the therapeutic effects for various cancers. In this study, RGD and DOX was conjugated to PEG by thiol-ene addition and Schiff's base reaction, respectively, to prepare the targeted and pH-sensitive antitumor prodrug nanoparticles (RGD-PEG-DOX NPs, RGD-NPs). Subsequently, the photosensitizer chlorin e6 (Ce6) was encapsulated into RGD-NPs, thus obtaining a simple and efficient chemo-photodynamic combination platform (RGD-PEG-DOX/Ce6 NPs, RGD-NPs/Ce6). This nanoparticle possessed high drug loading property of both the chemo-drug and photosensitizer and could simultaneously release them under the mild acidic microenvironment of cancer cells, which was expected to realize the synchronization therapy of chemotherapy and photodynamic therapy (PDT). Compared with free DOX and Ce6, RGD-NPs/Ce6 could significantly improve the cellular uptake capacities of DOX and Ce6, resulting in the increased contents of ROS in cancer cells and effective cytotoxicity for tumor cells (MDA-MB-231 cells and MCF-7 cells) upon a laser radiation. The in vivo experiment showed that RGD-NPs/Ce6 displayed superior tumor targeting, accumulation, and retention ability than the other groups (free DOX, free Ce6 and NPs/Ce6), and thus significantly enhancing the antitumor effect in vivo with a laser radiation. In addition, the cardiotoxicity induced by DOX was thoroughly wiped out after being loaded and delivered by the nanoparticles according to the pathological analysis. Therefore, the targeted chemo-photodynamic combination therapeutic platform may be a promising candidate for enhanced cancer therapy.

title: Release of Doxorubicin by a Folate-Grafted, Chitosan-Coated Magnetic Nanoparticle
abstract: In clinical tumor therapy, chemotherapeutic routes have caused severe side effects; current delivery methods are unsatisfactory. Successful design of a remotely folate (FA)-grafted chitosan (CS)-coated magnetic nanoparticle (MNP) with low toxicity, has been achieved. A chemotherapeutic drug such as doxorubicin (DOX), is loaded in the MNP-based matrix (FA-grafted CS-DOX-TPP-MNP), which is coated by an activated target tumor molecule of FA-grafted CS biopolymer with the inclusion of tripolyphosphate (TPP) as a linker. The resultant nano-complexes exhibited random aggregates (~240 nm) and zeta potential (−24.9 mV). In vivo experiments using athymic BALB/c nude mice with human glioblastoma U87 cells in a subcutaneous tumor model revealed that magnetic guidance of FA-grafted CS-DOX-TPP-MNP, injected via the tail vein, significantly decreased tumor growth. This manuscript demonstrates the feasibility of magnetizing control of FA-grafted CS-DOX-TPP-MNP to enhance the localization of drug release.

title: Tumor-penetrating peptide modified and pH-sensitive polyplexes for tumor targeted siRNA delivery
abstract: A pH-sensitive ternary block copolymer comprising poly(ethylene glycol)methyl ether methacrylate (PEGMA), and pH-sensitive segments poly(2-(dimethylamino) ethylmethacrylate) (PDMA) and poly(2-(diisopropyl amino)ethyl methacrylate) (PDPA) (mal-PEGMA-b-PDPA-b-PDMA, PMDM) was synthesized. The copolymer effectively complexed with siRNA at pH 5.0 to form a polyplex which showed decreased positive charge along with the increase of pH value due to deprotonation of the PDPA block. The nearly non-charged polyplex at pH 7.4 exhibited enhanced stability and inertness in serum-containing media, which is favorable for a prolonged circulation time and reduced cytotoxicity. The pH-sensitivity of PDMA and PDPA also enhanced the lysosomal escape of polyplexes after endocytosis. Moreover, modification of the tumor-penetrating peptide iRGD endowed the polyplexes with effective intratumoral delivery and high transfection efficiency. A study using the luciferase expression assay achieved highly effective target gene silencing both in vitro and in vivo, which revealed the potential of our iRGD-modified and pH-sensitive siRNA polyplex as a promising siRNA delivery system in cancer treatment.

title: Functionalized nanoscale micelles improve drug delivery for cancer therapy in vitro and in vivo.
abstract: Poor penetration of therapeutic drugs into tumors is a major challenge in anticancer therapy, especially in solid tumors, leading to reduced therapeutic efficacy in vivo. In the study, we used a new tumor-penetrating peptide, CRGDK, to conjugate onto the surface of doxorubicin encapsulated nanoscale micelles. The CRGDK peptide triggered specific binding to neuropilin-1, leading to enhanced cellular uptake and cytotoxicity in vitro and highly accumulation and penetration in the tumors in vivo.

title: Neuropilin-1-targeted gold nanoparticles enhance therapeutic efficacy of platinum(IV) drug for prostate cancer treatment.
abstract: Platinum-based anticancer drugs such as cisplatin, oxaliplatin, and carboplatin are some of the most potent chemotherapeutic agents but have limited applications due to severe dose-limiting side effects and a tendency for cancer cells to rapidly develop resistance. The therapeutic index can be improved through use of nanocarrier systems to target cancer cells efficiently. We developed a unique strategy to deliver a platinum(IV) drug to prostate cancer cells by constructing glutathione-stabilized (Au@GSH) gold nanoparticles. Glutathione (GSH) has well-known antioxidant properties, which lead to cancer regression. Here, we exploit the advantages of both the antioxidant properties and high surface-area-to-volume ratio of Au@GSH NPs to demonstrate their potential for delivery of a platinum(IV) drug by targeting the neuropilin-1 receptor (Nrp-1). A lethal dose of a platinum(IV) drug functionalized with the Nrp-1-targeting peptide (CRGDK) was delivered specifically to prostate cancer cells in vitro. Targeted peptide ensures specific binding to the Nrp-1 receptor, leading to enhanced cellular uptake level and cell toxicity. The nanocarriers were themselves nontoxic, but exhibited high cytotoxicity and increased efficacy when functionalized with the targeting peptide and drug. The uptake of drug-loaded nanocarriers is dependent on the interaction with Nrp-1 in cell lines expressing high (PC-3) and low (DU-145) levels of Nrp-1, as confirmed through inductively coupled plasma mass spectrometry and confocal microscopy. The nanocarriers have effective anticancer activity, through upregulation of nuclear factor kappa-B (NF-κB) protein (p50 and p65) expression and activation of NF-κB-DNA-binding activity. Our preliminary investigations with platinum(IV)-functionalized gold nanoparticles along with a targeting peptide hold significant promise for future cancer treatment.

title: Facile synthesis of RGD-conjugated unimolecular micelles based on a polyester dendrimer for targeting drug delivery.
abstract: Arginyl-glycyl-aspartic acid (RGD)-conjugated core-shell amphiphilic copolymers consisting of a polyester dendrimer poly(propargyl alcohol-4-mercaptobutyric acid) (PPMA) core and hydrophilic poly(ethylene glycol) (PEG) shells (PPMA-MPEG/PEG-RGD) were synthesized as unimolecular micelles for targeted drug delivery. During the synthesis, the PPMA core was firstly constructed at the end of a polystyrene (PS) support via the combination of a highly efficient thio-yne click reaction and esterification. The presence of PS segments in l-PS-PPMA hybrid copolymers facilitated the easy separation of the product from the excessive unreacted monomers by simple precipitation. After five reaction cycles, the fifth-generation PPMA with 64 terminal carboxylic acid groups (PPMAG5-64-COOH) was formed, in which the characteristic alkoxyamine linker between PS and PPMA segments was easily cleaved at an elevated temperature. The resultant PPMA-64-COOH was further coupled with MPEG/MAPEG followed by functionalization with RGD-SH to produce the targeted copolymer PPMA-MPEG/PEG-RGD. Due to the unique single molecular core-shell architecture, PPMA-MPEG/PEG-RGD copolymers exist as stable unimolecular micelles in aqueous solution. In addition, the hydrophobic core in PPMA-MPEG/PEG-RGD unimolecular micelles exhibited strong capability for the encapsulation of hydrophobic anticancer drugs, and it showed the pH-dependent controlled release behavior of the payload. Furthermore, in vitro cytotoxicity assay revealed the good biocompatibility of PPMA-MPEG/PEG-RGD unimolecular micelles. These results indicated that as-developed unimolecular micelles are promising candidates as tumor-targeted drug delivery nanocarriers.

title: Passive versus active tumor targeting using RGD- and NGR-modified polymeric nanomedicines.
abstract: Enhanced permeability and retention (EPR) and the (over-) expression of angiogenesis-related surface receptors are key features of tumor blood vessels. As a consequence, EPR-mediated passive and Arg-Gly-Asp (RGD) and Asn-Gly-Arg (NGR) based active tumor targeting have received considerable attention in the last couple of years. Using several different in vivo and ex vivo optical imaging techniques, we here visualized and quantified the benefit of RGD- and NGR-based vascular vs EPR-mediated passive tumor targeting. This was done using ∼ 10 nm sized polymeric nanocarriers, which were either labeled with DY-676 (peptide-modified polymers) or with DY-750 (peptide-free polymers). Upon coinjection into mice bearing both highly leaky CT26 and poorly leaky BxPC3 tumors, it was found that vascular targeting did work, resulting in rapid and efficient early binding to tumor blood vessels, but that over time, passive targeting was significantly more efficient, leading to higher overall levels and to more efficient retention within tumors. Although this situation might be different for larger carrier materials, these insights indicate that caution should be taken not to overestimate the potential of active over passive tumor targeting.

title: Sequential thermo-induced self-gelation and acid-triggered self-release process of drug-conjugated nanoparticles: a strategy for the sustained and controlled drug delivery to tumors.
abstract: A novel strategy was purposed to sustainedly deliver drug-loaded nanoparticles (NPs) to tumor sites and further enhance intracellular drug release. NPs with the ability of sequential self-gelation and self-release in response to a tumor-specific microenvironment were developed, which involved the conjugation of doxorubicin (DOX) on a thermosensitive amphiphilic copolymer (poly(ε-caprolactone)-b-poly(ethylene glycol)-b-poly(ε-caprolactone), PCEC) via acid-cleavable hydrazone linkages. The conjugate (PCEC-co-DOX) can self-assemble into micelle-like NPs in water. Moreover, the freeze-dried PCEC-co-DOX NP powder with good dispersibility in water can easily be constructed into an injectable NP aqueous dispersion at ambient temperature, making it convenient for storage and clinical applications. After injection, the dispersion can in situ thermosensitively self-gelate, anchoring large amounts of NPs at the tumor site. Subsequently, the formed NP self-supported gel can sustainedly release NPs themselves in an acidic tumor microenvironment. The released DOX-co-PCEC NPs were taken up by tumor cells and finally realized in intracellular drug release by the acid-triggered cleavage of the hydrazone bond. Compared with the repeated injection of free DOX, a single peritumoral injection of DOX-co-PCEC NP aqueous dispersion achieved a similar tumor inhibition effect but exhibited lower systemic toxicity. In vivo biodistribution studies indicated that DOX delivered by the DOX-co-PCEC NP hydrogel accumulated mainly in tumor tissue rather than in healthy tissue in mice treated with a single peritumoral injection. These results suggest that the design presented here provides a promising nanomedicine platform for cancer therapy.

title: Thermosensitive in situ hydrogel of paclitaxel conjugated poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone)
abstract: This paper aimed at engineering a multifunctional drug delivery system to provide efficient drug loading and sustained and site-specific drug release for prolonged formulation. Paclitaxel conjugated poly(e-caprolactone)-poly(ethylene glycol)-poly(e-caprolactone)(PCEC/PTX) was synthesized by conjugating paclitxel(PTX) to carboxylic acid-terminated poly(e-caprolactone)-b-poly(ethylene glycol)-b-poly(e-caprolactone)(PCEC). PCEC/PTX could self-assemble into nanoparticles (NPs) with high PTX content (20%, w/w) in the cores. The PCEC/PTX NPs performed pH sensitive drug release and presented a similar anticancer efficacy as PTX. Significantly, the aqueous solution of PCEC/PTX NPs freeze-dried powder presented a thermosensitive reversible sol-to-gel transition property around body temperature, which provided a possibility of injectable site-specific administration. Not only free PTX but also PTX-loaded NPs could be released from PCEC/PTX hydrogel. The in vitrocell uptake results of Rhodamine B conjugated PCEC NPs indicated the PCEC/PTX NPs could be endocytosized by cancer cells efficiently. The in vivo gel degradation studies showed that PCEC/PTX hydrogel could sustain at least 28 days after subcutaneous injection. These results suggested PCEC/PTX hydrogel could be employed as an injectable anti-cancer drug for site-specific administration to achieve the sustained release of PTX.

title: Carbohydrate coated, folate functionalized colloidal graphene as a nanocarrier for both hydrophobic and hydrophilic drugs.
abstract: Although graphene based drug delivery has gained significant recent interest, the synthesis of colloidal graphene based nanocarriers with high drug loading capacities and with targeting ligands at the outer surface is a challenging issue. We have synthesized carbohydrate coated and folate functionalized colloidal graphene which can be used as a nanocarrier for a wide variety of hydrophobic and hydrophilic drugs. The synthesized colloidal graphene is loaded with paclitaxol, camptothecin, doxorubicin, curcumin and used for their targeted delivery to cancer cells. We demonstrate that this drug loaded functional graphene nanocarrier can successfully deliver drugs into target cells and offers an enhanced therapeutic performance. The reported approach can be extended to the cellular delivery of other hydrophobic and hydrophilic drugs and the simultaneous delivery of multiple drugs.

title: A strategy for oral chemotherapy via dual pH-sensitive polyelectrolyte complex nanoparticles to achieve gastric survivability, intestinal permeability, hemodynamic stability and intracellular activity.
abstract: Efficient oral administration of anticancer agents requires a nanocarrier to long survive in the stomach, effectively penetrate across the small intestine, tightly retain the drug during bloodstream and quickly release drug in tumor cells. Herein a kind of dual pH-sensitive polyelectrolyte complex nanoparticles (CNPs) was developed by employing electrostatic interaction between positively charged chitosan (CS) and negative poly (L-glutamic acid) grafted polyethylene glycol-doxorubicin conjugate nanoparticles (PG-g-PEG-hyd-DOX NPs) with acid-labile hydrazone linkages. The obtained NPs and CNPs were characterized for their morphology, particle size, ζ-potential, pH-sensitivity under the simulated physiological conditions, drug release, as well as in vivo antitumor activity and biodistribution. The results indicated that CNPs can remain intact structure in pH range from 3.0 to 6.5. After detaching CS layer due to the pH-induced deprotonation with increasing pH to 7.4 in the mucus layer of the small intestine, the inner NPs would be released and effectively absorbed into blood circulation via opening the tight junctions by CS. PG-g-PEG-hyd-DOX NPs with demonstrated long-circulating properties can be accumulated in the tumor via EPR effect and dump the drug within tumor cells by acid-cleavage of hydrazone bonds between PG-g-PEG and DOX, achieving high therapeutic efficacy and low systemic toxicity. These results suggest that the design presented here, combining the functions of the gastrointestinal pH-sensitive electrostatic complex and intracellular acid-sensitive macromolecular prodrugs NPs, can sequentially overcome the biological barriers of oral anticancer drug delivery, which thus provides a promising nanomedicine platform for oral chemotherapy.

title: Polymer conjugates as anticancer nanomedicines
abstract: The transfer of polymer–protein conjugates into routine clinical use, and the clinical development of polymer–anticancer-drug conjugates, both as single agents and as components of combination therapy, is establishing polymer therapeutics as one of the first classes of anticancer nanomedicines. There is growing optimism that ever more sophisticated polymer-based vectors will be a signficant addition to the armoury currently used for cancer therapy.

title: PEG-b-PCL copolymer micelles with the ability of pH-controlled negative-to-positive charge reversal for intracellular delivery of doxorubicin.
abstract: The application of PEG-b-PCL micelles was dampened by their inherent low drug-loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-dimethyl maleamidic acid -ε-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile β-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2-6.3 μg/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The β-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of β-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile β-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release.

title: Recent developments in micellar drug carriers featuring substituted poly(ε-caprolactone)s
abstract: In the field of drug delivery, synthetic polymers have been widely explored due to their range of properties and functions achievable by tuning their structures. Poly(e-caprolactone)s in particular have established themselves as excellent candidates for biomedical applications because of their biocompatibility, biodegradability, and synthetic versatility. In this review, applications of functional poly(e-caprolactone)s in drug delivery systems are highlighted. Recent studies regarding the encapsulation or direct conjugation of drugs, bioactive molecules and moieties for targeting are discussed. Also considered are advances in amphiphilic polymers with functional poly(e-caprolactone)s that exhibit stimuli-responsive behavior: pH-, thermo-, photo-, and reduction-sensitive. Ongoing research and development of functional poly(e-caprolactone)s continues to expand their potential for use in micellar drug delivery systems.

title: Biodegradable block copolymer-doxorubicin conjugates via different linkages: preparation, characterization, and in vitro evaluation.
abstract: Doxorubicin (Dox) was conjugated onto a biodegradable block copolymer methoxy-poly(ethylene glycol)-block-poly(lactide-co-2,2-dihydroxymethylpropylene carbonate (mPEG-b-P(LA-co-DHP)) via a carbamate linkage and an acid-labile hydrazone linkage, respectively. Mutifunctional mixed micelles consisting of Dox-containing copolymer mPEG-b-P(LA-co-DHP/Dox) and folic acid-containing copolymer mPEG-b-P(LA-co-DHP/FA) were successfully prepared by coassembling the two component copolymers. The mixed micelles had well-defined core shell structure and their diameters were in the range of 70-100 nm. Both Dox-conjugates (via carbamate or hydrazone linkage) showed pH-dependent release behavior, and the micelles with hydrazone linkage showed more pH-sensitivity compared to those with carbamate linkage. The in vitro cell uptake experiment by CLSM and flow cytometry showed preferential internalization of FA-containing micelles by human ovarian cancer cell line SKOV-3 than that without FA. Flow cytometric analysis was conducted to reveal the enhanced cell apoptosis caused by the FA-containing micelles. These results suggested that these micelles containing both chemotherapeutic and targeting ligand could be a promising nanocarrier for targeting the drugs to cancer cells and releasing the drug molecules inside the cancer cells.

title: Micellar nanocarriers assembled from doxorubicin-conjugated amphiphilic macromolecules (DOX-AM).
abstract: Amphiphilic macromolecules (AMs) have unique branched hydrophobic domains attached to linear PEG chains. AMs self-assemble in aqueous solution to form micelles that are hydrolytically stable in physiological conditions (37 degrees C, pH 7.4) over 4 weeks. Evidence of AM biodegradability was demonstrated by complete AM degradation after 6 d in the presence of lipase. Doxorubicin (DOX) was chemically conjugated to AMs via a hydrazone linker to form DOX-AM conjugates that self-assembled into micelles in aqueous solution. The conjugates were compared with DOX-loaded AM micelles (i.e., physically loaded DOX) on DOX content, micellar sizes and in vitro cytotoxicity. Physically encapsulated DOX loading was higher (12 wt.-%) than chemically bound DOX (6 wt.-%), and micellar sizes of DOX-loaded AMs (approximately 16 nm) were smaller than DOX-AMs (approximately 30 nm). In vitro DOX release from DOX-AM conjugates was faster at pH 5.0 (100%) compared to pH 7.4 (78%) after 48 h, 37 degrees C. Compared to free DOX and physically encapsulated DOX, chemically bound DOX had significantly higher cytotoxicity at 10(-7) M DOX dose against human hepatocellular carcinoma cells after 72 h. Overall, DOX-AM micelles showed promising characteristics as stable, biodegradable DOX nanocarriers.

title: Fabrication and characterization of biocompatible hybrid nanoparticles from spontaneous co-assembly of casein/gliadin and proanthocyanidin
abstract: Proanthocyanidins (PACs), a group of polyphenolic secondary metabolites in plants, have drawn great interest because of their enormous potential in reducing the incidence of myocardial infarction and death from cardiovascular disease. However, their activities are sensitive to pH, temperature, and light, which limit their applications. For the first time, we developed an easy method to fabricate protein-PAC hybrid nanoparticles via the simple affinity binding between casein or gliadin and PAC. The effects of variable processing parameters (such as ratios of protein and PAC, protein concentration, sodium chloride content, pH, and time) on the characterization of the nanocomplexes were probed. Under optimal conditions, the nanocomplexes were regular shapes approximately 30 nm in size, as observed by transmission electron microscopy. The antioxidant capacity of nanocomplexes improved 12%, 26%, and 14% over that of pure PAC with sodium chloride (0.8 M), ultraviolet radiation (10 w), and heating treatment (80 °C, 30 min), respectively. No cytotoxicity for normal liver cells was found in any of the nanocomplexes measured by methyl thiazolyl tetrazolium assay. Conversely, protein-PAC hybrid nanoparticles exhibited clear cytotoxicity against liver hepatocellular carcinoma (HepG2 cells). This simple approach to fabricating nanocomplexes by co-assembling natural protein with bioactive compounds may open a new avenue to encapsulating and delivering sensible pharmaceuticals and drugs, with potential applications in functional foods, drugs, and personal care products.

title: Nanoparticle-based combination therapy toward overcoming drug resistance in cancer.
abstract: The use of multiple therapeutic agents in combination has become the primary strategy to treat drug resistant cancers. However, administration of combinatorial regimens is limited by the varying pharmacokinetics of different drugs, which results in inconsistent drug uptake and suboptimal drug combination at the tumor sites. Conventional combination strategies in aim to maximize therapeutic efficacy based on maximum tolerated dose does not account for the therapeutic synergism that is sensitive to both dosing and scheduling of multiple drugs. In the present review, we will discuss the development of multidrug-loaded nanoparticles against drug resistant cancers. Nanoparticle-based combination therapy against experimental multidrug resistant (MDR) cancer models will be summarized. In addition, we will highlight the recent advances in nanoparticle-based combination strategies against clinical cancer drug resistance, including co-encapsulation of drugs with different physicochemical properties, ratiometric control over drug loading, and temporal sequencing on drug release. These emerging strategies promise novel and better tailored combinatorial regimens for clinical cancer treatment.

title: Polymeric nanoparticles with precise ratiometric control over drug loading for combination therapy.
abstract: We report a novel approach for nanoparticle-based combination chemotherapy by concurrently incorporating two different types of drugs into a single polymeric nanoparticle with ratiometric control over the loading of the two drugs. By adapting metal alkoxide chemistry, we synthesize highly hydrophobic drug-poly-L-lactide (drug-PLA) conjugates, of which the polymer has the same chain length while the drug may differ. These drug-polymer conjugates are then encapsulated into lipid-coated polymeric nanoparticles through a single-step nanoprecipitation method. Using doxorubicin (DOX) and camptothecin (CPT) as two model chemotherapy drugs, various ratios of DOX-PLA and CPT-PLA conjugates are loaded into the nanoparticles with over 90% loading efficiency. The resulting nanoparticles are uniform in size, size distribution and surface charge. The loading yield of DOX and CPT in the particles can be precisely controlled by simply adjusting the DOX-PLA:CPT-PLA molar ratio. Cellular cytotoxicity results show that the dual-drug loaded nanoparticles are superior to the corresponding cocktail mixtures of single-drug loaded nanoparticles. This dual-drug delivery approach offers a solution to the long-standing challenge in ratiometric control over the loading of different types of drugs onto the same drug delivery vehicle. We expect that this approach can be exploited for many types of chemotherapeutic agents containing hydroxyl groups and thus enable codelivery of various drug combinations for combinatorial treatments of diseases.

title: Camptothecin-Polysaccharide Co-assembly and Its Controlled Release.
abstract: β-Cyclodextrin modified camptothecin (CPT-CD) was synthesized through esterification reaction and "click chemistry" to greatly improve the solubility of CPT in aqueous solution, and then, a supramolecular nanoparticle was constructed by strong noncovalent interaction between β-cyclodextrin and adamantane and amphiphilic interaction by simply mixing CPT-CD and adamantane modified hyaluronic acid (HA-ADA) together. The obtained nanoparticle had a hydrophilic HA shell, which could target and recognize HA receptors overexpressed on the surface of cancer cells, and a hydrophobic CPT core, which could protect CPT from hydrolyzation. The results of cytotoxicity experiments showed that the nanoparticle we have designed in this work exhibited similar anticancer activities to, but with much lower side effects than, the commercial chemotherapeutic drug CPT in vitro. We believe that this work might provide a strategy for improving the treatment performance of CPT in laboratory and clinical settings.

title: Comb-like amphiphilic copolymers bearing acetal-functionalized backbones with the ability of acid-triggered hydrophobic-to-hydrophilic transition as effective nanocarriers for intracellular release of curcumin.
abstract: The pH-responsive micelles have enormous potential as nanosized drug carriers for cancer therapy due to their physicochemical changes in response to the tumor intracellular acidic microenvironment. Herein, a series of comb-like amphiphilic copolymers bearing acetal-functionalized backbone were developed based on poly[(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl) ethane methacrylate-co-poly(ethylene glycol) methyl ether methacrylate] [P(TTMA-co-mPEGMA)] as effective nanocarriers for intracellular curcumin (CUR) release. P(TTMA-co-mPEGMA) copolymers with different hydrophobic-hydrophilic ratios were prepared by one-step reversible addition fragmentation chain transfer (RAFT) copolymerization of TTMA and mPEGMA. Their molecular structures and chemical compositions were confirmed by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR) and gel permeation chromatography (GPC). P(TTMA-co-mPEGMA) copolymers could self-assemble into nanosized micelles in aqueous solution and displayed low critical micelle concentration (CMC). All P(TTMA-co-mPEGMA) micelles displayed excellent drug loading capacity, due to the strong π-π conjugate action and hydrophobic interaction between the PTTMA and CUR. Moreover, the hydrophobic PTTMA chain could be selectively hydrolyzed into a hydrophilic backbone in the mildly acidic environment, leading to significant swelling and final disassembly of the micelles. These morphological changes of P(TTMA-co-mPEGMA) micelles with time at pH 5.0 were determined by DLS and TEM. The in vitro CUR release from the micelles exhibited a pH-dependent behavior. The release rate of CUR was significantly accelerated at mildly acidic pH of 4.0 and 5.0 compared to that at pH 7.4. Toxicity test revealed that the P(TTMA-co-mPEGMA) copolymers exhibited low cytotoxicity, whereas the CUR-loaded micelles maintained high cytotoxicity for HepG-2 and EC-109 cells. The results indicated that the novel P(TTMA-co-mPEGMA) micelles with low CMC, small and tunable sizes, high drug loading, pH-responsive drug release behavior, and good biocompatibility may have potential as hydrophobic drug delivery nanocarriers for cancer therapy with intelligent delivery.

title: Effective co-delivery of doxorubicin and curcumin using a glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer micelle for combination cancer chemotherapy.
abstract: A glycyrrhetinic acid-modified chitosan-cystamine-poly(ε-caprolactone) copolymer (PCL-SS-CTS-GA) micelle was developed for the co-delivery of doxorubicin (DOX) and curcumin (CCM) to hepatoma cells. Glycyrrhetinic acid (GA) was used as a targeting unit to ensure specific delivery. Co-encapsulation of DOX and CCM was facilitated by the incorporation of poly(ε-caprolactone) (PCL) groups. The highest drug loading content was 19.8% and 8.9% (w/w) for DOX and CCM, respectively. The PCL-SS-CTS-GA micelle presented a spherical or ellipsoidal geometry with a mean diameter of approximately 110nm. The surface charge of the micelle changed from negative to positive, when the pH value of the solution decreased from 7.4 to 6.8. Meanwhile, it also exhibited a character of redox-responsive drug release and GA/pH-mediated endocytosis in vitro. In simulated body fluid with 10mM glutathione, the release rate in 12h was 80.6% and 67.2% for DOX and CCM, respectively. The cell uptake of micelles was significantly higher at pH 6.8 than pH 7.4. The combined administration of DOX and CCM was facilitated by PCL-SS-CTS-GA micelle. Results showed that there was strong synergic effect between the two drugs. The PCL-SS-CTS-GA micelle might turn into a promising and effective carrier for improved combination chemotherapy.