P-gp inhibitor polymeric micelle platform for enhanced drug solubilization and oral bioavailability

About This Grant

Abstract DelAQUA Pharmaceuticals is developing a non-PEG, stealth, hyper-loaded polymeric micelle (PM) approach for drug coadministration with P-glycoprotein (Pgp) inhibitors to address the barriers of poor solubility and low oral bioavailability due to Pgp efflux. Oral administration is the preferred drug delivery route based on convenience, safety, cost-effectiveness, improved access to care, and high patient compliance rates. However, physiological and biochemical challenges exist for effective oral drug administration. Poor aqueous solubility significantly contributes to low bioavailability, impacting about 40% of approved drugs and upwards of 90% of newly synthesized drug candidates in development. Oral bioavailability is also often limited by Pgp-mediated efflux in the gut. It significantly limits the oral bioavailability/uptake of many lipophilic drugs, mediates their direct excretion into the intestinal lumen, and results in drug resistance. This absorption barrier is estimated to impact >25% of lipophilic drugs, which comprise most small-molecule drugs in pre-clinical development. Paclitaxel (PTX), an important drug in treating many cancers, suffers from poor solubility and Pgp efflux. The PTX standard of care, Abraxane®, only addresses the solubility problem using an albumin-based nanoparticle, still requires intravenous administration, and the response rate remained relatively low (33%) in metastatic breast cancer patients. As such, an unmet need remains for innovative solutions for oral delivery of PTX and other Pgp substrate drugs with poor solubility. DelAQUA’s platform technology utilizes water-soluble and nontoxic polymers arranged in an amphiphilic triblock copolymer structure to incorporate poorly soluble drugs into biocompatible, chemically versatile, and tunable PMs. The molecular interactions between the poly(2-oxazoline) (POx) hydrophilic and hydrophobic repeat units of block copolymers drive the formation of a hydrophilic corona with a hydrophobic core to support improved solubilization and superior loading. The POx platform has been used to package a variety of drug combinations and has co-delivered two drugs in a single micelle with increased tumor distribution of both drugs. This Phase I project seeks to establish the feasibility of the PM platform for co- formulating poorly soluble Pgp substrate drugs like PTX with Pgp inhibitors like elacridar to enhance oral bioavailability through the following Specific Aims: 1) develop an optimized oral micelle formulation for the co- administration of PTX and Pgp inhibitors, 2) assess the oral bioavailability and tumor accumulation of PTX with Pgp inhibitor micelle formulation in tumor-bearing mice, and 3) validate the therapeutic efficacy of an oral micelle PTX:elacridar formulation in a mouse model of breast cancer. This work will equip DelAQUA with a well- characterized PM product for oral delivery of PTX with superior bioavailability and inform future work optimizing the formulation and expanding the platform for the solubilization of other Pgp substrate active pharmaceutical ingredients (APIs) for much-needed orally delivered therapeutics, yielding improved treatment outcomes and improved adherence and access to care.