title: Modulating paclitaxel bioavailability for targeting prostate cancer.
abstract: Four novel water-soluble peptide-paclitaxel conjugates were designed and synthesized as prostate-specific antigen (PSA)-activated prodrugs for prostate cancer therapy. These prodrugs were composed of a peptide, HSSKLQ or SSKYQ, each of which is selectively cleavable by PSA; a self-immolative linker, either para-aminobenzyl alcohol (PABS) or ethylene diamine (EDA); and the parent drug, paclitaxel. Introduction of a PABA or EDA linker between the peptide and paclitaxel in prodrugs 2-5 resulted in products with an increased rate of hydrolysis by PSA. The stability of prodrugs 2 and 3, with the PABA linker, was poor in the serum-containing medium because of the weak carbonate bond between the PABA and paclitaxel; however, this disadvantage was overcome by introducing a carbamate bond using an EDA linker in prodrugs 4 and 5. Thus, the incorporation of an EDA linker increased both the stability and PSA-mediated activation of these prodrugs. The cytotoxicity of each prodrug, as compared to paclitaxel, was determined against a variety of cell lines, including the PSA-secreting CWR22Rv1 prostate cancer cell line. The EDA-derived prodrug of paclitaxel 5 was stable and capable of being efficiently converted to an active drug that killed cells specifically in the presence of PSA, suggesting that this prodrug and similarly designed PSA-cleavable prodrugs may have potential as prostate cancer-specific therapeutic agents.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Kumar
authors.forename: Simon A
authors.initials: SA
authors.lastname: Williams
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: Samuel R
authors.initials: SR
authors.lastname: Denmeade
authors.forename: Saeed R
authors.initials: SR
authors.lastname: Khan
mesh_terms: D002021:Buffers; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016895:Culture Media, Serum-Free; D006801:Humans; D008297:Male; D015394:Molecular Structure; D017239:Paclitaxel / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000473:pathology*; D012996:Solutions; D013329:Structure-Activity Relationship
chemical_list: D002021:Buffers; D016895:Culture Media, Serum-Free; D011355:Prodrugs; D012996:Solutions; D017239:Paclitaxel