Extremely long tumor retention, on-demand releasing Nano-Taxel for eradicating ovarian cancers

TitleExtremely long tumor retentionon demand releasing Nano Taxel for eradicating ovarian cancers Project Summary Treatment of late stage ovarian cancer remains one of the greatest challenges for gynecologic oncologistsThe clinical efficacy of paclitaxelPTXa first line chemotherapyis limited due to its severe adverse effect and poor drug exposure and delivery to target tissuesAbraxaneAlbumin bound paclitaxelparticle sizenmwas designed to overcome the dose limiting toxicity of standard PTXHoweverAbraxanedoes not function as a true nanoparticlebecause the control over drug propertiessuch as release ratesis not possible with this formulationThe safety and effectiveness of Abraxanein ovarian cancer patients have not been establishedNew 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 drugsIt has also been reported that smaller nanoparticles such asnm micelles could penetrate poorly permeable tumors for a better anti tumor effectThe smart PTX loaded micellar nanoparticlesNano Taxelwith smaller sizenmextremely long tumor retentionat leastdaysand on demand drug releasing properties to be developed in this proposal may offer better efficacy and toxicity profile against ovarian cancertherefore have great commercial potentials to lead to a marketable PTX nanoformulation for the treatment of ovarian cancerThe overall goal of this proposal is to develop highly effective and less toxic micellar formulation of PTXNano Taxelagainst ovarian cancer in preclinical animal models in Phase I studiesand perform current good manufacturing practicecGMPproduction andampIND enabling pharmacology and toxicology studies in Phase II studies that will eventually lead to an IND filing to the FDA for a first inhuman phase I clinical trialOur hypotheses areiThe smaller and extremely long tumor retention micelle formulation of PTXcompared to its free form are more efficacious and less toxic against ovarian canceriiThe 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 cellstherefore will greatly improve the efficacy and toxicity profileandiiiOAa highly potent targeting ligandwhen decorated on the surface of Nano Taxel to facilitate the in vivo delivery to ovarian cancerwill further improve its therapeutic indexState of the art design of nanocarriers via engineering telodendrimers with well defined structures represents the frontier development of the nanomedicinein terms of ease of largescale productionfine tunable and highly reproducible structure and propertiesIt will address many translational barriers of nanotherapeutic agentsThe use of boronate crosslinked micelles with extremely long tumor retention and on demand drug releasing properties to delivery PTX to ovarian cancer is highly innovativeItandapos s an excellent approach to prevent pre mature drug release during circulation and deliver high concentrations of drug to tumorsIt is expected that this research will lead to new approach for ovarian cancer therapy Project Narrative The proposed research will lead to the development of highly efficacious and less toxic nanoformulations of PTXNano Taxelfor ovarian cancer therapyUnique features of Nano Taxel areithe size of the micelle formulation of PTX is undernmwhich is more suitable for penetrating poorly permeable tumors including metastatic ovarian canceriithere is minimal premature drug release from the cross linked nanoparticles in blood circulationiiithe extremely long retentionat leastdaysat tumor site will greatly enhanced the antitumor activity of PTXand reduce the dose and cost for patientsiva highly potentintegrin targeting ligand will be used to facilitate in vivo delivery of PTXNano Taxelto ovarian cancervPTX resistance may be overcome by using these nanoparticles that are not recognized by P glycoproteinone of the main mediators of multidrug resistancethereby resulting in an increased intracellular concentration of drugsvithe stability and drug release of PTXNano Taxelcan be fine tuned via different level of boronate crosslinkingwhich will greatly improve the pharmacokineticsefficacy and toxicity profileandviiMannitol will be used as an on demand drug release triggering agent to enhance the therapeutic efficacy of the nanoparticle drugsWe expect these smart nanoparticle drugs to be much more efficacious and less toxic than the conventional and albumin bound PTX formulationsThis project will have a tremendous impact on the improvement of survival rate and quality of life of patients with ovarian cancer