Back to Search
Start Over
Modulating paclitaxel bioavailability for targeting prostate cancer
- Source :
-
Bioorganic & Medicinal Chemistry . Jul2007, Vol. 15 Issue 14, p4973-4984. 12p. - Publication Year :
- 2007
-
Abstract
- 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. [Copyright &y& Elsevier]
- Subjects :
- *PHYSICAL sciences
*BIOORGANIC chemistry
*PHARMACEUTICAL chemistry
*SCIENCE
Subjects
Details
- Language :
- English
- ISSN :
- 09680896
- Volume :
- 15
- Issue :
- 14
- Database :
- Academic Search Index
- Journal :
- Bioorganic & Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25342190
- Full Text :
- https://doi.org/10.1016/j.bmc.2007.04.029