title: 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.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas , Simons Laboratories, 2095 Constant Ave. Rm. 136B, Lawrence, Kansas 66047, United States.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Duan
authors.forename: Xing
authors.initials: X
authors.lastname: Zeng
authors.forename: Chunjing
authors.initials: C
authors.lastname: Liu
authors.forename: Neal M
authors.initials: NM
authors.lastname: Davies
authors.forename: Benyi
authors.initials: B
authors.lastname: Li
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009025:Morpholines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011744:Pyrimidinones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D008823:Micelles; D009025:Morpholines; D011091:Polyesters; D011355:Prodrugs; D011744:Pyrimidinones; C504718:TGX 221; C016240:polycaprolactone; D011092:Polyethylene Glycols