Preclincial Evaluation of Intravesical Cisplatin Nanoparticles for Non-Muscle-Invasive Bladder Cancer

Purpose: Prior clinical trials evaluating cisplatin for non-muscle invasive bladder cancer (NMIBC) were stopped due to local and systemic toxicity. Currently, there is still a need for improved intravesical therapies, and nanoparticle-based CDDP may be efficacious without the toxicity of free cisplatin observed in the past. Experimental Design: Cisplatin nanoparticles (CDDP NP) were developed using biocompatible poly(L-aspartic acid sodium salt) (PAA), both with and without low and high grafting density of methoxy-polyethylene glycol (PEG). In vitro cytotoxicity studies confirmed activity of CDDP-NP and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP-NP and CDDP solution were evaluated for bladder absorption in murine models 1 h and 4 h after intravesical administration. In vivo efficacy was evaluated in an immune competent carcinogen model of NMIBC. Results: CDDP-NP showed decreased local toxicity, as assessed by bladder weight, compared to CDDP solution. Further, > 2 µg/ml of platinum was observed in mouse serum after intravesical administration of CDDP solution, while serum platinum was below the limit of quantification (BLQ) after intravesical administration of CDDP-NP. CDDP-NP provided significantly increased (P< 0.05) drug levels in murine bladders compared to CDDP solution for at least 4 h after intravesical administration. In vivo, CDDP NP reduced cancer cell proliferation compared to untreated controls, and was the only treatment group without evidence of invasive carcinoma. Conclusions: Cisplatin-loaded PAA nanoparticles have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects.

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