Therapeutic Targeting Agents for Ovarian Cancer

点击翻译按钮获取中文摘要

 DESCRIPTION (provided by applicant): This is a competitive renewal proposal of the R01 CA115483 grant after 9 years. In our last competitive renewal 4 years ago, we proposed to develop a novel oligocholic acid/PEG based nanoplatform to load paclitaxel (PTX) and SN-38 for targeted delivery via i.v. and i.p. for OvCa therapy. We also proposed to use [14C]-labeled paclitaxel to determine the in vivo biodistribution and OvCa targeting properties of PTX-loaded nanocarriers, in both subcutaneous and intraperitoneal OvCa xenograft models. This last 4 year grant support resulted in 24 publications and 3 patent applications. In this second competitive renewal, we propose to further develop our oligocholic acid/PEG based nanoplatform by (i) incorporating novel strategies for efficient display of targeting ligands, and (ii) chemical tuningof the cholic acid core of the amphiphilic telodendrimer (monomer unit) for high capacity loading of a wide range of anti-cancer drugs. These novel concepts will be systematically applied to the basic nanoplatform one at a time and the resulting nanoparticles will be fully characterized for their physicochemical properties and their in vivo tumor targeting properties. Those superior features will then be combined and adopted to the development of a novel third generation targeting nanocarrier that is highly versatile, multifunctional, easy to formulate in the clinics, nd can function as an efficacious drug delivery system for cancer therapy. We will continue to use OvCa xenograft, subcutaneous and intraperitoneal models, to evaluate these novel nanoconstructs. We have previously demonstrated that therapeutic efficacy of telodendrimer-based micellar nanoparticles developed in our laboratory can be enhanced by (i) introducing inter- telodendrimer covalent but reversible crosslinkages to improve the in vivo stability of the nanocarrier, and (ii) by decorating the surface of the nanocarrier with tumor targeting ligands such as OA02 (a cyclic peptide) against 31 integrin. The next generation telodendrimer- based micellar nanoparticle will (i) enable improvement of targeting ligand display, and (ii) increase the range of therapeutic pay-loads suitable for the nanoplatform. We believe these improvements will greatly enhance the versatility and in vivo efficacy of these nanoparticle drugs, not only in xenograft or transgenic murine tumor models, but also in clinical OvCa. In this Competitive Renewal Proposal, we plan to pursue the following specific aims: 1. To improve the ligand display on our micellar nanocarrier 2. To develop new hybrid telodendrimers that can nanoformulate drugs that otherwise cannot be nanoformulated with our existing telodendrimers. 3. Promising nanocarriers from aim 1 and 2 will be selected and evaluated in subcutaneous and intraperitoneal OvCa xenograft models in nude mice for biodistribution and therapeutic efficacies.