Preclinical evaluation of a hypotonic docetaxel nanosuspension formulation for intravesical treatment of non-muscle-invasive bladder cancer.

Intravesical chemotherapy is a key approach for treating refractory non-muscle-invasive bladder cancer (NMIBC). However, the effectiveness of intravesical chemotherapy is limited by bladder tissue penetration and retention. Here, we describe the development of a docetaxel nanosuspension that, when paired with a low osmolality (hypotonic) vehicle, demonstrates increased uptake by the bladder urothelium with minimal systemic exposure. We compare the bladder residence time and efficacy in an immune-competent rat model of NMIBC to the clinical comparator, solubilized docetaxel (generic Taxotere) diluted for intravesical administration. We found that only the intravesical docetaxel nanosuspension significantly decreased cell proliferation compared to untreated tumor tissues. The results presented here suggest that the combination of nanoparticle-based chemotherapy and a hypotonic vehicle can provide more efficacious local drug delivery to bladder tissue for improved treatment of refractory NMIBC.

Preclinical 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 NPs) 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 NPs and CDDP solution against a papillary bladder cancer cell line. Local toxicity was assessed by three weekly intravesical administrations of CDDP formulations. CDDP NPs and CDDP solution were evaluated for bladder absorption in murine models 1 and 4 hours after intravesical administration. In vivo efficacy was evaluated in an immunocompetent carcinogen model of NMIBC.Results: CDDP NPs showed decreased local toxicity, as assessed by bladder weight, compared with CDDP solution. Furthermore, >2 µg/mL of platinum was observed in mouse serum after intravesical administration of CDDP solution, whereas serum platinum was below the limit of quantification after intravesical administration of CDDP NPs. CDDP NPs provided significantly increased (P < 0.05) drug levels in murine bladders compared with CDDP solution for at least 4 hours after intravesical administration. In vivo, CDDP NPs reduced cancer cell proliferation compared with untreated controls, and was the only treatment group without evidence of invasive carcinoma.Conclusions: Cisplatin-loaded PAA NPs have the potential to improve intravesical treatment of NMIBC while reducing local and systemic side effects. Clin Cancer Res; 23(21); 6592-601. ©2017 AACR.

Self-assembly of amphiphilic plasmonic micelle-like nanoparticles in selective solvents.

Amphiphilic plasmonic micelle-like nanoparticles (APMNs) composed of gold nanoparticles (AuNPs) and amphiphilic block copolymers (BCPs) structurally resemble polymer micelles with well-defined architectures and chemistry. The APMNs can be potentially considered as a prototype for modeling a higher-level self-assembly of micelles. The understanding of such secondary self-assembly is of particular importance for the bottom-up design of new hierarchical nanostructures. This article describes the self-assembly, modeling, and applications of APMN assemblies in selective solvents. In a mixture of water/tetrahydrofuran, APMNs assembled into various superstructures, including unimolecular micelles, clusters with controlled number of APMNs, and vesicles, depending on the lengths of polymer tethers and the sizes of AuNP cores. The delicate interplay of entropy and enthalpy contributions to the overall free energy associated with the assembly process, which is strongly dependent on the spherical architecture of APMNs, yields an assembly diagram that is different from the assembly of linear BCPs. Our experimental and computational studies suggested that the morphologies of assemblies were largely determined by the deformability of the effective nanoparticles (that is, nanoparticles together with tethered chains as a whole). The assemblies of APMNs resulted in strong absorption in near-infrared range due to the remarkable plasmonic coupling of Au cores, thus facilitating their biomedical applications in bioimaging and photothermal therapy of cancer.