Biological evaluation of paclitaxel-peptide conjugates as a model for MMP2-targeted drug delivery.
Paclitaxel (PTX) is a highly effective cytotoxic agent widely used for the treatment of several solid tumors. However, PTX shows dose-limiting cytotoxicity and in most cases induces drug resistance followed by failure in treatment. To enhance the therapeutic index of a given drug, various drug delivery methods have been explored to systemically deliver sufficient amount of the drug to the desired site. In the present study, we designed and synthesized two PTX prodrugs by conjugating PTX at different sites with an octapeptide (AcGPLGIAGQ) that can be cleaved by MMP2 at tumor sites. As a result, PTX is expected to be released at the tumor sites, absorbed by the tumor cells, and thereby inhibit the tumor growth. We evaluated the in vitro activities of the two drugs in a panel of drug-sensitive and -resistant cancer cell lines and their in vivo efficacies in a HT1080 fibrosarcoma mouse xenograft model that overexpresses MMP2. Our in vitro results showed that the PTX-AcGPLGIAGQ conjugates inhibited cancer cell proliferation with higher activity compared to that observed for free PTX, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle. Consistent with the in vitro results, treatment with PTX-octapeptide conjugate resulted in extensive areas of necrosis and a lower percentage of proliferating cells in xenograft tumor sections. Together, our results indicate the potential of the tumor-targeted delivery of PTX to exploit the specific recognition of MMP2, reduce toxicity, and selectively kill tumor cells.
Yamada
Roppei
R
Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, School of Pharmacy, Los Angeles, CA, USA.
Kostova
Maya B
MB
Anchoori
Ravi Kumar
RK
Xu
Shili
S
Neamati
Nouri
N
Khan
Saeed R
SR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003114:Colony-Forming Units Assay; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D009842:Oligopeptides; D011355:Prodrugs; D020778:Matrix Metalloproteinase 2; D017239:Paclitaxel