CD44-targeted microparticles for delivery of cisplatin to peritoneal metastases.
Intraperitoneal (ip) chemotherapy increases the survival of optimally debulked patients with ovarian cancer due to direct access of the drug to tumor nodules growing on the peritoneal surface. CD44 is overexpressed in many ovarian cancers. To further improve efficacy, we sought to develop a cisplatin-loaded microparticle that would target to CD44 on cancer cells when injected ip. Hyplat microparticles were produced by cross-linking hyaluronan via its carboxylate groups with cisplatin at a high temperature. Hyplat particles had an average diameter of 580 nm, and cisplatin was incorporated with an efficiency of approximately 50%. Drug release varied with chloride concentration but not pH. Flow cytometric analysis and confocal microscopy confirmed that CD44 positive cells (OV2008, A2780) internalized Hyplat more efficiently than CD44 negative cells (UCI101); uptake was compromised by knocking down CD44 expression. Clearance of Hyplat from the mouse peritoneum was reduced by 7-fold and tumor uptake was increased by 2- to 3-fold in CD44-positive but not CD44-negative tumor models compared to that attained with free cisplatin. Hyplat was more effective than cisplatin at slowing the growth of intraperitoneally inoculated A2780 ovarian cancer cells and improving survival thus demonstrating the potential of Hyplat to enhance the efficacy of ip chemotherapy.
Li
Shyh-Dar
SD
Moores Cancer Center, University of California, San Diego, La Jolla, California 92093-0819, USA.
Howell
Stephen B
SB
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010316:Particle Size; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D002945:Cisplatin