Document Detail

A dicarboxylic fatty acid derivative of paclitaxel for albumin-assisted drug delivery.
MedLine Citation:
PMID:  22674061     Owner:  NLM     Status:  MEDLINE    
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.
Michael J Hackett; Shyamsunder Joolakanti; Megan E Hartranft; Patrick C Guley; Moo J Cho
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-06-06
Journal Detail:
Title:  Journal of pharmaceutical sciences     Volume:  101     ISSN:  1520-6017     ISO Abbreviation:  J Pharm Sci     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-07-20     Completed Date:  2012-12-07     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  2985195R     Medline TA:  J Pharm Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3292-304     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Wiley Periodicals, Inc.
Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7571, USA.
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MeSH Terms
Antineoplastic Agents, Phytogenic / administration & dosage,  blood,  chemistry,  pharmacokinetics*
Cell Line, Tumor
Cell Survival / drug effects
Chemistry, Pharmaceutical
Colorectal Neoplasms / metabolism*,  pathology
Drug Carriers*
Drug Stability
Fatty Acids / chemistry*,  toxicity
Glutarates / chemistry*,  toxicity
Injections, Intravenous
Mice, Inbred BALB C
Paclitaxel / administration & dosage,  analogs & derivatives,  blood,  chemistry,  pharmacokinetics*
Protein Binding
Serum Albumin / chemistry,  metabolism*,  toxicity
Technology, Pharmaceutical / methods
Tissue Distribution
Grant Support
R01 CA126825/CA/NCI NIH HHS; R01 CA126825/CA/NCI NIH HHS
Reg. No./Substance:
0/ALB protein, human; 0/Antineoplastic Agents, Phytogenic; 0/Drug Carriers; 0/Fatty Acids; 0/Glutarates; 0/Serum Albumin; 33069-62-4/Paclitaxel

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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