Human Serum Albumin (HSA) is the most prevalent protein in human blood. Using this protein as a carrier for drug delivery is a commonly used strategy with utility in significant extension of half-life. In chemotherapeutic cytotoxin delivery, HSA has famously been used in a nanoparticle formulation of paclitaxel, Abraxane. Abraxane is a polydisperse amorphous paclitaxel formulation that consists of micro- and nanoscale particulates of the drug with HSA. This formulation was approved by the FDA in 2005 because it avoided the use of the toxic excipients found in the standard Taxol formulation of paclitaxel, namely the Cremaphor EL. In initial preclinical studies and over the years, Abraxane has been shown to have a modest therapeutic index, comparable to Taxol, and a maximum tolerated dose (MTD) in the range of 20-30 mg/kg in mice. With the advent of combination immunotherapeutics using Abraxane, it is evident that PTX formulations with a vastly, expanded therapeutic index would be highly beneficial.<br/>The Gianneschi group has capitalized on the power of preserving the carboxylic moiety at the terminus of the fatty acid ligands, as seen for semaglutide. The formulation involves a covalently linked Paclitaxel with ODDA, which is then complexed with HSA prior to intravenous injection. The complex takes advantage of 5 high affinity long chain, fatty acid (LCFA) binding sites present on native HSA. Allowing 5 ODDA-PTX molecules are bound to each albumin protein. Critical aspects include vastly improved therapeutic index owing to targeting to fatty acid transporters in cancer tissue and prolonged circulation half-life. Despite the success of ODDA-PTX in animal studies, a major issue is the need for pre-formulation with HSA prior to injection. This is needed because ODDA-PTX is not soluble in water alone, limiting further animal testing capabilities. Here we have formulated a b-CyD-ODDA-PTX complex that improves aqueous solubility of the drug via the b-CyD while minimizing off target effects through the ODDA-PTX drug.

Aqueous formulation of 1,18-octadecanedioic acid-paclitaxel with heptakis(2,6-di-O-methyl)-β-cyclodextrin

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.