bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4512: Super-enhanced permeability and retention (SUPR) effect induced by photo-immunotherapy (PIT) can accommodate massive nano-sized reagents deep into tumors.
Authors: Kobayashi Hisataka , Sano Kohei , Nakajima Takahito , Choyke Peter L. 
Published: August 2014

Abstract
A major barrier to cancer treatment is the inability to deliver sufficient concentrations of drug to the interior of tumors without incurring systemic toxicities. Nanomaterials are appealing because they can carry a large drug payload, however, tumor delivery is limited by modest leakage and retention in most tumors. Photo-immunotherapy (PIT) is a newly developed therapy involving the injection of a conjugate composed of an armed monoclonal antibody (mAb) and a near infrared phthalocyanine dye, IR700 [Mitsunaga M. Nature Med 2011;17:1685]. When exposed to NIR light, the conjugate induces a highly-selective necrotic cell death only in mAb-IR700 bound cancer cells. This target-specific necrotic cell death occurs within 10 minutes of exposure to NIR light and results in rapid morphologic changes including cellular swelling, bleb formation, and rupture of vesicles indicating necrotic cell death. Meanwhile, immediately adjacent receptor-negative cells are unharmed. Because it damages cells immediately adjacent to the tumor vasculature, PIT results in marked increases in vascular permeability leading to 12- to 25-fold enhanced nano-particle delivery into cancer tissue, an effect termed “super-enhanced permeability and retention (SUPR)” to differentiate it from inherent enhanced permeability and retention (EPR). Of particular interest is that nano-sized reagents including macromolecules (dendrimers), particles (quantum dots, iron oxide nano-particles), and liposomes up to 300 nm in diameter rapidly enter and are retained within the tumor space following PIT. Therefore, although PIT might not be able to eliminate all cancer cells due to heterogeneity of tumor antigen expression, SUPR allows the delivery of extremely high concentrations of nano-sized anti-cancer reagents such as daunorubicin containing liposome (Daunoxome), resulted in significantly synergic therapeutic effects of PIT and nano-sized agents. In conclusion, target-selective PIT can induce a SUPR effect leading to the accumulation of relatively high concentrations of nano-sized reagents into the tumor bedthus improving effectiveness of PIT..
Citation Format: Hisataka Kobayashi, Kohei Sano, Takahito Nakajima, Peter L. Choyke. Super-enhanced permeability and retention (SUPR) effect induced by photo-immunotherapy (PIT) can accommodate massive nano-sized reagents deep into tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4512. doi:10.1158/1538-7445.AM2013-4512
Abstract 4514: Targeted liposomes to pancreatic cancer are effective in controlling the tumor load in mice.
Authors: Kondapalli Lavanya , Lambros Maria P. , Huang Ying 
Published: August 2014

Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths. Targeted drug delivery to pancreas will increase the drug efficacy especially in inoperable tumors and reduce its toxicity. In this study we prepared targeted liposomes to SLC7A11 transporter which is upregulated in pancreatic cancers as our previous work has shown. The objective of our work was to evaluate the antitumor effect of targeted liposomes loaded with daunorubicin (DNR) in a mouse model of pancreatic cancer. Mice C57BL/6 were injected subcutaneously with 1x 106 PanO2 cells. When the tumors became palpable the mice were injected with different targeted or non targeted liposomal formulations of DNR. There were 5 groups: group A, saline; group B, free DNR; group C,DNR encapsulated in non-targeted liposomes; group D, DNR encapsulated in targeted liposomes; group E; DNR encapsulated in targeted liposomes with PEG. DNR dose was 5mg/kg once a week for the first two weeks. Another set of group of mice received a single dose. We measured the tumor size from the day of treatment until the animals were euthanized. On the day of autopsy, tumors were removed, sectioned and placed in a microscope to observe the DNR accumulation. Animals treated with targeted liposomes containing DNR had a significantly lower tumor load compared to those received DNR in nontargeted liposomes. The average body weight of animals that received free DNR shows a decrease which may be due to drug toxicity. Fluorescent images of tumor sections showed that the tumors treated with DNR in targeted liposomes had more fluorescence than tumors treated with free DNR or DNR encapsulated in nontargeted liposomes.The results indicate that DNR encapsulated in the targeted liposomes was more effective in reducing the tumor load compared to free DNR or DNR encapsulated in nontargeted liposomes.
Citation Format: Lavanya Kondapalli, Maria P. Lambros, Ying Huang. Targeted liposomes to pancreatic cancer are effective in controlling the tumor load in mice. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4514. doi:10.1158/1538-7445.AM2013-4514
Abstract 4516: Targeted delivery of resveratrol to improve therapeutic outcome in prostate cancer.
Authors: Singh Rajesh , Gupta Pranav , Singh Shailesh , Lillard James W. 
Published: August 2014

Abstract
Conventional chemotherapeutics offered to treat prostate cancer (PCa) are not selectively targeted and due to this fact they are toxic to the normal cells. Thus, it is imperative to identify new anti-cancer agents and/or methods to selectively target PCa cells without affecting normal cells. In this regard, resveratrol (trans-3, 5, 4’-trihydroxystilbene), a plant polyphenol, has shown very promising results. Despite the proven anti-tumor effects of resveratrol, clinical use of this compound is restricted due to its poor bioavailability. To surmount these problems, we developed nanoparticles, loaded with resveratrol, using a planetary-balled milling (PBM) technique and tagged them with folate for targeted delivery to PCa cells, which express high affinity folate receptors. Image Stream multispectral imaging was used to measure the response of resveratrol-loaded PBM nanoparticles, and free resveratrol on various PCa cell lines. Resveratrol-loaded folic acid-coated PBM nanoparticles selectively targeted PCa cells and induced apoptosis. Furthermore, our results indicate that targeted delivery of resveratrol using PBM nanoparticles was 70-85% more effective in killing PCa cells at concentrations lower than the IC50 of free resveratrol.
Citation Format: Rajesh Singh, Pranav Gupta, Shailesh Singh, James W. Lillard. Targeted delivery of resveratrol to improve therapeutic outcome in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4516. doi:10.1158/1538-7445.AM2013-4516
Abstract 4522: Nanoparticle chemosensitization.
Authors: Sethi Manish , Kowalczyk Sonya R. , Kapadia Chintan H. , Werner Michael E. , Sukumar Rohit , Wang Edina , Wang Andrew Z. 
Published: August 2014

Abstract
Systemic drug toxicity and multi-drug resistance are the two major obstacles in the treatment of cancer. While multi-drug resistance can be easily overcome by the use of chemosensitizers, the process of chemosensitization itself has been shown to be highly toxic to the normal cells. This is because chemosensitizers not only sensitize the tumor tissue but also the normal tissue to the effect of the drug leading to a substantial increase in the systemic toxicity of the drug. On the other hand, nanoparticles (NPs) can decrease systemic toxicity by virtue of their property of preferential accumulation at the site of tumor, making them an ideal candidate for the delivery of the chemosensitizers. We developed a novel method to overcome both of the major obstacles in cancer treatment by synthesizing NP formulations of two potent chemosensitizers, wortmannin (Wtmn) and olaparib. Wtmn is a highly effective PI3 kinase and DNA-PK inhibitor while olaparib is highly potent Poly ADP ribose polymerase (PARP) inhibitor.
NP Wtmn and NP olaparib were synthesized using a biodegradable core-shell NP platform. We studied the chemosensitization effects of NP Wtmn and NP olaparib in vitro using the lung cancer cell lines H23 and H460, and a multi-drug resistant lung cancer cell line H69AR followed by the drug treatment. We used different chemotherapeutic drugs such as etoposide, gemcitabine and docetaxel to demonstrate the effect of NP chemosensitizers. The biodistribution of the NPs was determined using the mouse xenograft model of H460. Normal tissue toxicity was evaluated by using NP chemosensitizers and compared with their small molecule counterparts. Finally, we evaluated NP Wtmn and NP olaparib as a chemosensitizers in vivo using murine xenograft models of H69AR and H460 and compared them to that of free chemosensitizers.
NP chemosensitizers, similar to their small molecule counterparts, are highly potent in vitro in all three cell lines. The biodistribution study showed that NP formulation leads to a higher tumor accumulation when compared to the free molecules. Toxicity study showed significantly less hepatic and hematologic toxicity with NP formulation than the free molecules. In vivo efficacy study demonstrated that NP Wtmn and NP olaparib are potent chemosensitizers and are more effective than their small molecule counterparts. Further, we demonstrated that NP Wtmn can overcome drug resistance in H69AR cell line. Our work demonstrates the proof of principle in utilizing nanomedicine for the improving chemosensitization.
Citation Format: Manish Sethi, Sonya R. Kowalczyk, Chintan H. Kapadia, Michael E. Werner, Rohit Sukumar, Edina Wang, Andrew Z. Wang. Nanoparticle chemosensitization. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4522. doi:10.1158/1538-7445.AM2013-4522
Abstract 4524: Designer nanoparticles for selective targeting of multiple myeloma and overcoming CAM-DR.
Authors: Kiziltepe Tanyel , Ashley Jonathan , Stefanick Jared , Bilgicer Basar 
Published: August 2014

Abstract
In the continuing search for effective treatments for cancer, here we report the targeting and efficacy studies pursued with a designer multifunctional nanoparticle that combines traditional chemotherapy with cell targeting and anti-cellular-adhesion functionalities to selectively target multiple myeloma (MM) cells and overcome cell adhesion-mediated drug resistance (CAM-DR). Anti-cellular-adhesion evolves as a promising target in oncology. VLA-4-mediated adhesion to the bone marrow extracellular matrix and stromal cells confers MM cells with CAM-DR. In our design, we used micellar nanoparticles as dynamic self-assembling scaffolds to present VLA-4-antagonist peptides and doxorubicin conjugates simultaneously to selectively target MM cells and to overcome CAM-DR. Doxorubicin was conjugated to the nanoparticles through an pH-sensitive hydrazone bond to prevent premature release and thus non-specific toxicity. Peptides were conjugated via a multifaceted synthetic procedure for generating highly effective targeting. Each component of the nanoparticle was purified to &gt;98% purity prior to particle formation, and by controlling the stoichiometries of each component during particle formation, we were able to precisely control the number of targeting functionalities per nanoparticle. The nanoparticles, which exhibited a size of ∼20nm, were efficiently internalized by MM cells with an optimal peptide valency of 20 per micelle, and induced cytotoxicity to MM cells. Mechanistic studies revealed that nanoparticles induced DNA double strand breaks as evidenced by H2AX phosphorylation, and triggered apoptosis, which was associated with PARP and caspase-8 cleavage. Importantly, multifunctional nanoparticles were more efficacious than doxorubicin in the presence of fibronectin (IC50=0.15±0.04 μM and 0.42±0.09 μM, respectively), and overcame CAM-DR induced by adherence of MM cells to fibronectin. Finally, in a MM xenograft model, nanoparticles preferentially homed to MM tumors, with a ∼10 fold more drug accumulation when compared to doxorubicin, and demonstrated dramatic tumor growth inhibition with much reduced overall systemic toxicity. Taken together, we demonstrate the disease-driven engineering of a nanoparticle-based drug delivery system, enabling the model of an integrative approach in the treatment of MM.
Citation Format: Tanyel Kiziltepe, Jonathan Ashley, Jared Stefanick, Basar Bilgicer. Designer nanoparticles for selective targeting of multiple myeloma and overcoming CAM-DR. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4524. doi:10.1158/1538-7445.AM2013-4524
Abstract 4527: Sensitization of cancer cells to cisplatin by curcumin: mlecular mechanism and drug delivery.
Authors: Daurio Natalie , Tuttle Stephen , Sood Nimil , Hammer Daniel , Koumenis Constantinos 
Published: August 2014

Abstract
Curcumin, the major active component of the spice Turmeric, is known to sensitize cancer cells to treatment with cisplatin. However, the exact mechanism by which this occurs is unresolved. We hypothesize that sensitization is dependent on curcumin-mediated inhibition of thioredoxin reductase 1, a major antioxidant enzyme. We have shown that a knock down of TxnRd1 expression ameliorates sensitization by curcumin and that over-expression of TxnRd1 in cells with low endogenous levels enhances cisplatin sensitivity. The use of curcumin clinically has been limited by is its low bioavailability outside the GI tract. Therefore, we have also encapsulated curcumin into polymersome nanoparticles composed of poly(ethylene oxide)-block-polycaprolactone co-polymer to improve drug delivery. These vesicles have the unique advantage of being completely biodegradable and can be dual loaded with individual drugs in the membrane and aqueous core allowing for simultaneous delivery of curcumin and cisplatin. Preliminary studies have demonstrated that these polymersomes encapsulate both curcumin in the hydrophobic membrane and cisplatin in the aqueous core and can deliver them to tumor cells. Future studies will determine whether these bifunctional polymersomes demonstrate enhanced cytotoxicity to animal models of solid tumors.
Citation Format: Natalie Daurio, Stephen Tuttle, Nimil Sood, Daniel Hammer, Constantinos Koumenis. Sensitization of cancer cells to cisplatin by curcumin: mlecular mechanism and drug delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4527. doi:10.1158/1538-7445.AM2013-4527
Abstract 4530: Nanoparticle formulation of KU55933 as a potent radiosensitizer.
Authors: Lara Haydee , Foote Michael B. , Wang Edina C. , Sethi Manish , Casbas-Hernandez Patricia , Wang Andrew Z. 
Published: August 2014

Abstract
KU55933 is a potent and specific inhibitor of the Ataxia Telangiectasia Mutated (ATM) protein. Given ATM's critical role in DNA damage repair, specifically double-strand break repair, KU55933 holds high potential as a radiosensitizer. Indeed, previous preclinical studies have demonstrated the radiosentization effect of KU55933. However, clinical translation of KU55933 as a radiosensitizer has been prevented due to concerns of its potential toxicity. Systemic administration of KU55933 would sensitize normal cells as well as cancer cells to the effects of radiotherapy. Such sensitization would not improve the therapeutic index of radiotherapy. Therefore, the key challenge in the translation of KU55933 is to identify methods that can selectively deliver KU55933 to tumors while minimizing normal tissue dose. While traditional drug delivery methods cannot overcome this challenge, the development of nanoparticle (NP) drug delivery vehicles offers a unique opportunity. NPs are known to preferentially accumulate in tumors while provide low drug dose to nearby normal tissues. We hypothesize that NP delivery of KU55933 can not only improve the therapeutic efficacy of KU55933, but also lower its toxicity. In this study, we engineered a NP formulation of KU55933 using a biodegradable lipid-polymer NP. We then compared the radiosensitization effect of NP KU55933 to that of KU55933 in vitro using the non-small cell lung cancer (NSCLC) cell lines H23, A549 and H460. Clonogenic survival assays showed that NP KU55933 is a more potent radiosensitizer than KU55933. The differential radiosensitization effect of both KU55933 formulations was also evaluated in a xenograft mouse model of NSCLC. We validated our in vitro results by demonstrating that NP KU55933 is more effective than KU55933 as radiosensitizer in flank xenograft models of NSCLC. To compare the toxicity of NP KU55933 and KU55933, we determined the skin toxicity after radiotherapy with the two drug formulations. We found lower skin toxicity in mice treated with the NP KU55933 than that for KU55933. In conclusion, our studies demonstrate that NP formulation of KU55933 can enhance the radiosensitization effect and decreases the toxicity in vitro and in vivo. Our results suggest that NP KU55933 holds potential for clinical translation.
Citation Format: Haydee Lara, Michael B. Foote, Edina C. Wang, Manish Sethi, Patricia Casbas-Hernandez, Andrew Z. Wang. Nanoparticle formulation of KU55933 as a potent radiosensitizer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4530. doi:10.1158/1538-7445.AM2013-4530
Abstract 4535: Molecular-genetic imaging of prostate cancer.
Authors: Bhatnager Akrita , Gabrielson Kathleen , Fisher Paul B. , Pomper Martin G. 
Published: August 2014

Abstract
Cancer-specific promoters, such as the progression elevated gene-3 or the astrocyte elevated gene promoters, PEG-Prom and AEG-Prom, respectively, can be used as molecular genetic imaging instruments for tumor-selective imaging of cancer. We have previously shown this in experimental models of metastatic breast cancer and melanoma using bioluminescence imaging (BLI) and single photon emission computed tomography with computed tomography (SPECT/CT). Here we show that we can express PEG-Prom and AEG-Prom selectively in PC3-ML (human bone metastatic derived prostate cancer) cells and use these constructs for imaging prostate cancer in vivo. PC3-ML cells were transfected with firefly luciferase (FLuc) or the herpes simplex type I thymidine kinase (HSV1-tk), and validated for suitable transfection through bioluminescence and [125I]FIAU cell uptake assays, respectively. PC3-ML cells were administered through intra-cardiac injection to allow widespread metastases. A linear polyethyleneimine (l-PEI) nanoparticle was used for intravenous (IV) delivery of the promoter constructs to animals bearing metastases. PEG-Prom- and AEG-Prom-driven imaging reporter gene expression was monitored by small animal BLI and by SPECT/CT after IV administration of D-luciferin or [125I]FIAU, respectively. Both BLI and SPECT/CT imaging demonstrated tumor-specific PEG-Prom and AEG-Prom activity in the model of metastatic prostate cancer but not in control. Using the thoracic cavity and tibia as the regions of interest (ROI), quantification of the BLI data (n=6) at the 48 h time point after reporter gene delivery showed a range of 16- to 19-fold higher accumulation of FLuc in the metastasis group compared to control for PEG-Prom and AEG-Prom, respectively. BLI results were confirmed by histopathology, immunohistochemistry and western blot. Quantification of the SPECT/CT data (n=5) at the 56 h time point after reporter gene and 8 h after [125I]FIAU delivery showed a 3- to 11-fold higher accumulation of [125I]FIAU, depending on the tumor burden, in the group bearing metastases compared to control for AEG-Prom. Metastatic nodules detected by the SPECT/CT imaging were confirmed by pathology. The results demonstrate the potential of systemically delivered, PEG-Prom- and AEG-Prom-driven constructs for enabling the imaging of metastatic prostate cancer in vivo.
Citation Format: Akrita Bhatnager, Kathleen Gabrielson, Paul B. Fisher, Martin G. Pomper. Molecular-genetic imaging of prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4535. doi:10.1158/1538-7445.AM2013-4535
Abstract 4539: Selection of non-phophorylated peptide inhibitors of BRCA1.
Authors: White E. Railey , Ma Zhong , Hacker David E. , Beckta Jason M. , Huie Melissa B. , Williams David C. , Valerie Kristoffer , Hartman Matthew C. 
Published: August 2014

Abstract
A growing body of literature suggests Breast Cancer-Associated Protein 1 (BRCA1) is important not only as a cause, but also as a target in the quest for cancer treatment. BRCA1 deficient cells treated with radiation as well as PARP inhibitors and other chemotherapeutics demonstrate a greater sensitivity than cells with wild type BRCA1. Inhibitors of BRCA1 would take advantage of this synthetic lethality and represent a significant advance in cancer treatment as well as an understanding of the biology of DNA repair. Despite significant study of BRCA1 protein and function, it is a large protein (208 KDa) that is still largely uncharacterized, but its N- and C-terminal domains have been described by significant structural data. The BRCT (BRCA1 C-Terminal) Domain is a phosphoprotein binding domain that is commonly mutated or lost in cancers and has a binding cleft seemingly very suitable for drug design. Small molecule screens have been conducted against this domain, but the resulting hits with moderate affinity have not been shown to induce BRCA1 deficient phenotypes. Phosphopeptides have also been studied as potential BRCA1 inhibitors, yet despite some having affinities in the mid-nanomolar range the presence of a phosphate is not without its pharmacologic challenges. We generated an mRNA display library with 1.3 x 10ˆ13 cyclized peptides covalently attached to the mRNA that encoded them. Eight rounds of selection exposing the library to a GST-BRCT fusion resulted in non-phosphorylated peptides that bind to a BRCT domain of BRCA1. The sequences resulting from the selection have common homologies and initial characterization has shown that these peptides may be the first viable non-phosphoserine containing inhibitors of BRCA1.
Citation Format: E. Railey White, Zhong Ma, David E. Hacker, Jason M. Beckta, Melissa B. Huie, David C. Williams, Kristoffer Valerie, Matthew C. Hartman. Selection of non-phophorylated peptide inhibitors of BRCA1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4539. doi:10.1158/1538-7445.AM2013-4539