Paclitaxel-2'-o-pentadecylhemiglutarate: a prodrug strategy for albumin based drug delivery Public Deposited

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  • March 21, 2019
  • Hackett, Michael J.
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacoengineering and Molecular Pharmaceutics
  • Delivery of antineoplastic agents to solid tumors remains a great challenge in formulation development. Preclinical successes often do not translate into clinical therapies due to the intrinsic imperfections of current models. The presented formulation begins with clinical observations indicating the ubiquitous protein, serum albumin, naturally accumulates selectively in spontaneously developed tumors. Albumin then provides a natural shuttle for therapeutic agents to solid tumors. To test this, a fatty diacid, 3-pentadecylglutaric acid (PDG), was synthesized. This fatty acid has the capacity to bind albumin tightly while concomitantly binding a therapeutic moiety, in this case paclitaxel. The paclitaxel-2'-O-pentadecylhemiglutarate conjugate binds albumin tightly but the extreme hydrophobicity led to poor loading efficiency and the formation of 120 nm albumin aggregates; a similar phenomenon observed in the clinically approved ABRAXANE. This aggregation was found to be the result of a specific interaction between paclitaxel and albumin. Dissociation of the conjugate from albumin is exceedingly slow with less than 3% released over 48 h under sink conditions. When administered to tumor bearing mice, the formulation behaved similarly to covalently attached albumin conjugates. Rapid and uniform organ distribution was observed followed by a slow re-emergence of complex into the vasculature giving rise to a half-life of 23 h. This is comparable to the half-life of the protein itself in mice. Tumor accumulation was moderate (~1%) and biochemical stability analysis of the conjugate suggests little conversion (<6% over 72 h) to free drug would occur. Despite decreased cytotoxicity, lower doses of the conjugate demonstrated comparable efficacy to TAXOL without the need for surfactants. Modification of paclitaxel was accomplished in a single step using PDG anhydride presenting a cost-effective method for improving the pharmacokinetics of a drug. Conceptually, this study lays the foundation for using the PDG technology for modifying other therapeutic agents. The success of the formulation is highly dependent on the selected therapeutic modality which can be broadly limited to any therapeutic agent bearing a nucleophilic moiety. It is expected a more hydrophilic drug that does not exhibit albumin binding may lead to increased efficacy in addition to improved pharmacokinetics.
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  • In Copyright
  • " ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the School of Pharmacy (Molecular Pharmaceutics)."
  • Cho, Moo J.
Degree granting institution
  • University of North Carolina at Chapel Hill
Place of publication
  • Chapel Hill, NC
  • Open access

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