title: Development of a peptide-drug conjugate for prostate cancer therapy.
abstract: TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate to specifically deliver TGX-221 to HER2 overexpressing prostate cancer cells. Four TGX-221 derivatives with added hydroxyl groups were synthesized for peptide conjugation. Among them, TGX-D1 exhibited a similar bioactivity to TGX-221, and it was selected for conjugation with a peptide promoiety containing a HER2-targeting ligand and a prostate specific antigen (PSA) substrate linkage. From this selection, the peptide-drug conjugate was proven to be gradually cleaved by PSA to release TGX-D1. Cellular uptake of the peptide-drug conjugate was significantly higher in prostate cancer cells compared to the parent drug. Moreover, both the peptide-drug conjugate and its cleaved products demonstrated comparable activities as the parent drug TGX-D1. Our results suggest that this peptide-drug conjugate may provide a promising chemotherapy for prostate cancer patients.
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, 2464 Charlotte Street, Kansas City, Missouri 64108, USA.
authors.forename: Wanyi
authors.initials: W
authors.lastname: Tai
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Shukla
authors.forename: Bin
authors.initials: B
authors.lastname: Qin
authors.forename: Benyi
authors.initials: B
authors.lastname: Li
authors.forename: Kun
authors.initials: K
authors.lastname: Cheng
mesh_terms: D000728:Androgens / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002853:Chromatography, Liquid; D004355:Drug Stability; D006801:Humans; D008297:Male; D009025:Morpholines / Q000138:chemical synthesis / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D053719:Tandem Mass Spectrometry
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D009025:Morpholines; D010455:Peptides; D011355:Prodrugs; D017430:Prostate-Specific Antigen; D011744:Pyrimidinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C504718:TGX 221; C508053:ERBB2 protein, human