Title: Extremely long tumor retention, on-demand releasing Nano-Taxel for eradicating ovarian cancers Project Summary Treatment of late-stage ovarian cancer remains one of the greatest challenges for gynecologic oncologists. The clinical efficacy of paclitaxel (PTX), a first-line chemotherapy, is limited due to its severe adverse effect and poor drug exposure and delivery to target tissues. Abraxane (Albumin-bound paclitaxel, particle size ~130 nm) was designed to overcome the dose-limiting toxicity of standard PTX. However, Abraxane does not function as a true nanoparticle, because the control over drug properties, such as release rates, is not possible with this formulation. The safety and effectiveness of Abraxane in ovarian cancer patients have not been established. New nanocarriers able to minimize the premature drug release in blood circulation while releasing drug on-demand at tumor site have profound impact on the improvement of the efficacy and toxicity profile of the chemotherapeutic drugs. It has also been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart PTX loaded micellar nanoparticles (Nano-Taxel) with smaller size (~20 nm), extremely long tumor retention (at least 12 days), and on-demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against ovarian cancer, therefore have great commercial potentials to lead to a marketable PTX-nanoformulation for the treatment of ovarian cancer. The overall goal of this proposal is to develop highly effective and less toxic micellar formulation of PTX (Nano-Taxel) against ovarian cancer in preclinical animal models in Phase I studies, and perform current good manufacturing practice (cGMP) production & IND-enabling pharmacology and toxicology studies in Phase II studies that will eventually lead to an IND filing to the FDA for a first-in- human phase I clinical trial. Our hypotheses are: (i) The smaller and extremely long tumor retention micelle formulation of PTX, compared to its free form are more efficacious and less toxic against ovarian cancer; (ii) The on-demand drug releasing properties of Nano-Taxel achieved by boronate crosslinking strategy will minimize the premature drug release during circulation but allow instant drug release at tumor sites or in tumor cells, therefore will greatly improve the efficacy and toxicity profile; and (iii) OA02, a highly potent targeting ligand, when decorated on the surface of Nano-Taxel to facilitate the in vivo delivery to ovarian cancer, will further improve its therapeutic index. State-of-the-art design of nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of ease of large- scale production, fine-tunable and highly reproducible structure and properties. It will address many translational barriers of nanotherapeutic agents. The use of boronate crosslinked micelles with extremely long tumor retention and on-demand drug releasing properties to delivery PTX to ovarian cancer is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumors. It is expected that this research will lead to new approach for ovarian cancer therapy.
The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of PTX (Nano-Taxel) for ovarian cancer therapy. Unique features of Nano-Taxel are: (i) the size of the micelle formulation of PTX is under 30 nm, which is more suitable for penetrating poorly permeable tumors including metastatic ovarian cancer; (ii) there is minimal premature drug release from the cross-linked nanoparticles in blood circulation; (iii) the extremely long retention (at least 12 days) at tumor site will greatly enhanced the antitumor activity of PTX, and reduce the dose and cost for patients (iv) a highly potent ?3?1 integrin targeting ligand will be used to facilitate in vivo delivery of PTX (Nano-Taxel) to ovarian cancer; (v) PTX resistance may be overcome by using these nanoparticles that are not recognized by P-glycoprotein, one of the main mediators of multidrug resistance, thereby resulting in an increased intracellular concentration of drugs; (vi) the stability and drug release of PTX (Nano-Taxel) can be fine-tuned via different level of boronate crosslinking, which will greatly improve the pharmacokinetics, efficacy and toxicity profile; and (vii) Mannitol will be used as an on-demand drug-release triggering agent to enhance the therapeutic efficacy of the nanoparticle drugs. We expect these smart nanoparticle drugs to be much more efficacious and less toxic than the conventional and albumin-bound PTX formulations. This project will have a tremendous impact on the improvement of survival rate and quality of life of patients with ovarian cancer.
