Antitumor Activity of 1,18-Octadecanedioic Acid-Paclitaxel Complexed with Human Serum Albumin

We describe the design,
synthesis, and antitumor activity of an
18 carbon α,ω-dicarboxylic acid monoconjugated via an
ester linkage to paclitaxel (PTX). This 1,18-octadecanedioic acid-PTX
(ODDA-PTX) prodrug readily forms a noncovalent complex
with human serum albumin (HSA). Preservation of the terminal carboxylic
acid moiety on ODDA-PTX enables binding to HSA in the
same manner as native long-chain fatty acids (LCFAs), within hydrophobic
pockets, maintaining favorable electrostatic contacts between the
ω-carboxylate of ODDA-PTX and positively charged
amino acid residues of the protein. This carrier strategy for small
molecule drugs is based on naturally evolved interactions between
LCFAs and HSA, demonstrated here for PTX. ODDA-PTX shows
differentiated pharmacokinetics, higher maximum tolerated doses and
increased efficacy in vivo in multiple subcutaneous
murine xenograft models of human cancer, as compared to two FDA-approved
clinical formulations, Cremophor EL-formulated paclitaxel (crPTX)
and Abraxane (nanoparticle albumin-bound (nab)-paclitaxel).