A dicarboxylic fatty acid derivative of paclitaxel for albumin-assisted drug delivery.
Paclitaxel (PTX) is a potent chemotherapy for many cancers but it suffers from very poor solubility. Consequently, the TAXOL formulation uses copious amounts of the surfactant Cremophor EL to solubilize the drug for injection, resulting in severe hypersensitivity and neutropenia. In contrast to Cremophor EL, presented is a way to solubilize PTX by conjugation of a dicarboxylic fatty acid for specific binding to the ubiquitous protein, serum albumin. The conjugation chemistry was simplified to a single step using the activated anhydride form of 3-pentadecylglutaric (PDG) acid, which is reactive to a variety of nucleophiles. The PDG derivative is less cytotoxic than the parent compound and was found to slowly hydrolyze to PTX (≈ 5% over 72 h) in serum, tumor cytosol, and tumor tissue homogenate. When injected intravenously to tumor-bearing mice, [(3) H]-PTX in the TAXOL formulation was cleared rapidly with a half-life of 7 h. In the case of the PDG derivative of PTX, the drug is quickly distributed and approximately 20% of the injected dose remained in the vasculature experiencing a 23 h half-life. These improvements from modifying PTX with the PDG fatty acid present the opportunity for PDG to become a generic modification for the improvement of many therapeutics.
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7571, USA.
Michael J
MJ
Hackett
Shyamsunder
S
Joolakanti
Megan E
ME
Hartranft
Patrick C
PC
Guley
Moo J
MJ
Cho
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D001711:Biotransformation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004337:Drug Carriers; D004355:Drug Stability; D005227:Fatty Acids / Q000737:chemistry* / Q000633:toxicity; D005260:Female; D005977:Glutarates / Q000737:chemistry* / Q000633:toxicity; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D007275:Injections, Intravenous; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000075462:Serum Albumin, Human; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution
C422455:ALB protein, human; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D005227:Fatty Acids; D005977:Glutarates; D012709:Serum Albumin; D017239:Paclitaxel; D000075462:Serum Albumin, Human