Cisplatin-loaded polymeric complex micelles with a modulated drug/copolymer ratio for improved in vivo performance.

This study aimed to evaluate the performance of cisplatin-loaded polymeric micelles (CDDP-PMs) with different drug/copolymer ratios of 1:1, 1:3 and 1:6 (w/w) prepared by coordinated complexation and self-assembly method. The mass ratio influenced the self-assembly behaviors and the complex degree, where both single- and double- complexation existed in CDDP-PMs. With the increase of CDDP/copolymer ratio, the particle size and drug loading increased, while encapsulation efficiency decreased. The PEG density of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 were 0.20, 0.61 and 0.38 PEG/nm2, respectively. CDDP-PM1-3 and CDDP-PM1-6 had similar sustained release behavior, while CDDP-PM1-1 showed burst release. Pharmacokinetics showed the AUC of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 27.2, 76.6 and 13.0 fold higher than CDDP solution. Tissue distribution presented the platinum concentration of CDDP-PM1-6, CDDP-PM1-3 and CDDP-PM1-1 was 1.03, 0.80 and 0.48 times of CDDP solution in kidney at 10 min, and 17.61, 28.63 and 16.6 times in tumor at 48 h respectively, indicating CDDP-PMs significantly reduced nephrotoxicity and increased tumor-targeting accumulation. In vivo antitumor test showed that CDDP-PMs exhibited an improved antitumor efficacy and lower systemic toxicity compared with CDDP solution. From CDDP-PM1-1 to CDDP-PM1-6, the toxicity decreased with the increase of copolymer ratio, but the tumor inhibition rate also decreased. CDDP-PM1-3 had relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot. This work provides an effective strategy by modulating drug/copolymer ratio of CDDP-PMs to balance the antitumor efficacy and toxicity for better payoff. STATEMENT OF SIGNIFICANCE: Cancer chemotherapy always exists a contradiction between antitumor efficacy and toxicity. Higher efficacy against tumor often associated with larger toxicity for normal tissues. This work provides an important strategy by modulating the drug/copolymer ratios to balance the antitumor efficacy and toxicity to obtain better payoff. The cisplatin-loaded polymeric micelles (CDDP-PMs) based on the complexation between CDDP and copolymer with different mass ratios make differences in vitro and in vivo because of the single- or double-complexation degree. Most importantly, we found the balance at CDDP/copolymer ratio of 1:3, which has relative high therapeutic effect and low toxicity compared with other formulations. CDDP-PM1-3 could improve the antitumor efficacy by increasing the dose within systemic tolerability, but CDDP solution cannot.