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Prodrug strategy for PSMA-targeted delivery of TGX-221 to prostate cancer cells.

Abstract
TGX-221 is a potent, selective, and cell membrane permeable inhibitor of the PI3K p110β catalytic subunit. Recent studies showed that TGX-221 has antiproliferative activity against PTEN-deficient tumor cell lines including prostate cancers. The objective of this study was to develop an encapsulation system for parenterally delivering TGX-221 to the target tissue through a prostate-specific membrane aptamer (PSMAa10) with little or no side effects. In this study, PEG-PCL micelles were formulated to encapsulate the drug, and a prodrug strategy was pursued to improve the stability of the carrier system. Fluorescence imaging studies demonstrated that the cellular uptake of both drug and nanoparticles was significantly improved by targeted micelles in a PSMA positive cell line. The area under the plasma concentration time curve of the micelle formulation in nude mice was 2.27-fold greater than that of the naked drug, and the drug clearance rate was 6.16-fold slower. These findings suggest a novel formulation approach for improving site-specific drug delivery of a molecular-targeted prostate cancer treatment.
AuthorsYunqi Zhao, Shaofeng Duan, Xing Zeng, Chunjing Liu, Neal M Davies, Benyi Li, M Laird Forrest
JournalMolecular pharmaceutics (Mol Pharm) Vol. 9 Issue 6 Pg. 1705-16 (Jun 04 2012) ISSN: 1543-8392 [Electronic] United States
PMID22494444 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Micelles
  • Morpholines
  • Polyesters
  • Prodrugs
  • Pyrimidinones
  • TGX 221
  • polycaprolactone
  • Polyethylene Glycols
Topics
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Drug Delivery Systems (methods)
  • Humans
  • Male
  • Mice
  • Mice, Nude
  • Micelles
  • Morpholines (chemistry, pharmacokinetics, therapeutic use)
  • Polyesters
  • Polyethylene Glycols (chemistry)
  • Prodrugs (chemical synthesis, chemistry, pharmacokinetics)
  • Prostatic Neoplasms (drug therapy)
  • Pyrimidinones (chemistry, pharmacokinetics, therapeutic use)

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