Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

Hardeep S Oberoi,1 Natalia V Nukolova,1,2 Frederic C Laquer,3 Larisa Y Poluektova,4 Jiangeng Huang,1 Yazen Alnouti,1 Masanao Yokohira,5 Lora L Arnold,5 Alexander V Kabanov,1,2 Samuel M Cohen,5 Tatiana K Bronich,1,21Department of Pharmaceutical Sciences and Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA; 2Department of Chemistry, MV Lomonosov Moscow State University, Leninskie Gory, Moscow, Russia; 3Department of Chemistry, University of Nebraska at Omaha, 4Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 5Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USAAbstract: Polymer micelles with cross-linked ionic cores are shown here to improve the therapeutic performance of the platinum-containing anticancer compound cisplatin. Biodistribution, antitumor efficacy, and toxicity of cisplatin-loaded core cross-linked micelles of poly(ethylene glycol)-b-poly(methacrylic acid) were evaluated in a mouse ovarian cancer xenograft model. Cisplatin-loaded micelles demonstrated prolonged blood circulation, increased tumor accumulation, and reduced renal exposure. Improved antitumor response relative to free drug was seen in a mouse model. Toxicity studies with cisplatin-loaded micelles indicate a significantly improved safety profile and lack of renal abnormalities typical of free cisplatin treatment. Overall, the study supports the fundamental possibility of improving the potential of platinum therapy using polymer micelle-based drug delivery.Keywords: cross-linked micelle, cisplatin, ovarian cancer, block ionomer complex, drug delivery