This Phase I proposal details the rationale and the research plan for the synthesis and characterization of targeted, backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The polymeric carrier will be composed of alternating N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of two anticancer drugs (paclitaxel and gemcitabine) and of Fab'fragment of the OV-TL16 antibody (complementary to OA-3 antigen expressed on the majority of human ovarian carcinomas). The combination of FDA approved anticancer drugs, paclitaxel and gemcitabine, is one of novel combinations evaluated in the clinics. Attachment of both drugs to the Fab'fragment-targeted, long-circulating (high molecular weight) backbone degradable HPMA copolymer carrier will result in enhanced and simultaneous delivery of both drugs to cancer cells. The combination of active targeting, due to biorecognition of the Fab'fragments, and of passive targeting, due to the EPR (enhanced permeability and retention) effect, will result in augmented efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.
The specific aims of the proposal are three-fold: A) Design, synthesis, and characterization of Fab'fragment- targeted HPMA copolymer-paclitaxel/gemcitabine conjugates;optimization of the structure based on feedback from biological evaluation. B) Evaluation of the conjugates on human ovarian cancer cells in vitro: internalization and subcellular fate, stability and enzymatically catalyzed drug release, and cytotoxicity. C) Therapeutic efficacy of polymer-drug conjugates on a human ovarian carcinoma xenograft model in nude mice. By completion of the Phase I studies TheraTarget will have established the feasibility of synthesis and characterization of the HPMA copolymer-drug conjugates, evaluated their activity in vitro and in vivo, and selected the leading conjugate for Phase II evaluation. The ultimate goal of the project is the development of an effective and marketable polymer drug delivery system capable of significantly improving the survival time of ovarian cancer patients.
This Phase I proposal details the rationale and the research plan for the synthesis and characterization of backbone degradable, long-circulating polymer conjugates containing two anticancer drugs per macromolecule. The simultaneous delivery of two drugs to ovarian cancer cells will result in enhanced efficacy and minimal adverse effects, thus improving the usefulness of cancer therapy.
|Zhang, Libin; Zhang, Rui; Yang, Jiyuan et al. (2016) Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate. J Control Release 235:306-318|
|Yang, Jiyuan; Kope?ek, Jind?ich (2016) Design of smart HPMA copolymer-based nanomedicines. J Control Release 240:9-23|
|Yang, Jiyuan; Zhang, Rui; Radford, D Christopher et al. (2015) FRET-trackable biodegradable HPMA copolymer-epirubicin conjugates for ovarian carcinoma therapy. J Control Release 218:36-44|
|Yang, Jiyuan; Kope?ek, Jind?ich (2015) POLYMERIC BIOMATERIALS AND NANOMEDICINES. J Drug Deliv Sci Technol 30:318-330|
|Duangjai, Acharaporn; Luo, Kui; Zhou, Yan et al. (2014) Combination cytotoxicity of backbone degradable HPMA copolymer gemcitabine and platinum conjugates toward human ovarian carcinoma cells. Eur J Pharm Biopharm 87:187-96|
|Yang, Jiyuan; Kope?ek, Jind?ich (2014) Macromolecular therapeutics. J Control Release 190:288-303|
|Zhang, Rui; Yang, Jiyuan; Sima, Monika et al. (2014) Sequential combination therapy of ovarian cancer with degradable N-(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates. Proc Natl Acad Sci U S A 111:12181-6|
|Zhang, Rui; Luo, Kui; Yang, Jiyuan et al. (2013) Synthesis and evaluation of a backbone biodegradable multiblock HPMA copolymer nanocarrier for the systemic delivery of paclitaxel. J Control Release 166:66-74|
|Pan, Huaizhong; Sima, Monika; Yang, Jiyuan et al. (2013) Synthesis of long-circulating, backbone degradable HPMA copolymer-doxorubicin conjugates and evaluation of molecular-weight-dependent antitumor efficacy. Macromol Biosci 13:155-60|
|Larson, Nate; Yang, Jiyuan; Ray, Abhijit et al. (2013) Biodegradable multiblock poly(N-2-hydroxypropyl)methacrylamide gemcitabine and paclitaxel conjugates for ovarian cancer cell combination treatment. Int J Pharm 454:435-43|
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