The goal of this proposed project is to develop a new technique that allows controlled formulation of docetaxel- polylactide nanoparticles containing aptamer targeting ligands that can be used for in vivo targeting of Prostate Specific Membrane Antigen for improved prostate cancer therapy. Targeted prostate cancer therapy mediated by chemotherapeutics-incorporated polymeric nanoparticles has limited success in clinic. Various formulation challenges still exist, such as increasing drug loading and loading efficiency, controlling NP size and surface characteristics, and eliminating drug burst release effect. Without proper control of these formulation parameters, incorporating cancer targeting ligand to nanoparticles will only increase the complexity of nanoparticle and provide limited benefit for the desired targeted cancer therapy. In current polymeric nanoparticles developed for cancer drug delivery, drug molecules are either covalently linked to a hydrophilic polymer via coupling chemistry to create a unimolecular polymer-drug conjugate or non-covalently encapsulated into the hydrophobic polymeric nanoparticles. Polymer-drug conjugates usually have controlled drug release. However, their relatively small sizes, typically in a range of 1-5 nm, may render relatively fast renal clearance compared to larger nanoparticles. Polymeric nanoparticles, on the other hand, are typically in a range of 30-300 nm, and therefore have reduced renal clearance compared to polymer-drug conjugates. However, low drug loading, low loading efficiency, and burst drug release kinetics are typical formulation challenges of polymer/drug nanoparticles prepared via encapsulation approaches. These formulation challenges significantly prohibit the clinic translation of polymeric nanoparticles for cancer therapy.
We aim to develop docetaxel-polylactide conjugated nanoparticles, or called nanoconjugates, through docetaxel-initiated ring-opening polymerization of lactide followed by nanoprecipitation. Compared to nanoparticles prepared via conventional encapsulation approach, docetaxel-polylactide nanoconjugates can be prepared with 100% drug loading efficiency and drug loading up to 30-40 wt% controlled by monomer/initiator ratio. Drug burst release are eliminated or substantially reduced. Aptamer targeting ligand will be incorporated to docetaxel-polylactid nanoconjugates for enhanced antitumor efficacy and reduced systemic toxicity.
Current polymeric nanoparticles have undesirable formulation challenges such as low drug loading, low loading efficiency and drug burst release. These drawbacks prohibit them from being used for targeted cancer drug delivery. To address these formulation challenges, we aim to develop high loading polylactide-docetaxel nanoparticles via site-specific ring-opening polymerization for in vitro and in vivo prostate cancer targeting.
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