Abstract 1342: A production-scalable cabazitaxel cellulose nanoparticle exhibits significant efficacy in a bone model of docetaxel-resistant prostate cancer

Abstract

Abstract Purpose: This study aimed to: (1) evaluate the antitumor efficacy of a controlled release cabazitaxel cellulose nanoparticle (CBZed-Nano) in an orthotopic bone model of docetaxel-resistant LNCaP C4-2B prostate cancer, and (2) confirm the efficacy of dose preparation by scalable instrumentation (NanoAssemblr), in a subcutaneous PC3 prostate xenograft model. Methods: mPEG-OH and cabazitaxel (CBZ) were coupled to a carboxymethylcellulose acetate polymer to yield CBZed-Nano, according to established coupling and purification methods (1). Particles were prepared by nanoprecipitation of polymer into saline by either a manual vortex technique (1) or a NanoAssemblr™ (NA) microfluidic-based instrument. Particles were purified by dialysis and sterile filtration (1). Particle size was measured by a DLS Malvern Zetasizer, morphology was screened by TEM, and residual substances were measured by LC. Male NOD-SCID mice were inoculated via intrafemoral injection with docetaxel-resistant LNCaP C42B prostate cancer. One day after inoculation, mice were treated with vortex prep CBZed-Nano (55 mg/kg) or CBZ (2 mg/kg) on a q1,5,9d schedule. Survival curves were generated (n = 10 mice per group). To directly compare preparation technique, nude mice bearing s.c. PC3 prostate cancer xenografts were treated at Bolder BioPath (Boulder, US) with CBZed-Nano (NA and vortex prep, 85 to 142 mg/kg) and CBZ (15-25 mg/kg) on a q1,5,9d schedule. Results: The CBZed-Nano polymer conjugate contained 36 wt% CBZ and 11 wt% PEG, with residual free CBZ < 0.01 wt% of CBZ content. Particles prepared by vortex and NA were 94 and 70 nm respectively (by DLS). By TEM analysis, NA particles exhibit a more uniform spherical morphology. Mice bearing docetaxel resistant LNCaP C42B tumors exhibited a partial response to CBZ treatment, with a median survival of 61 days, compared to 34 days for vehicle controls. In contrast, mice treated with CBZed-Nano exhibited a significantly improved response, with 70% durable cure. Efficacy was observed regardless of CBZed-Nano preparation technique. Mice treated with CBZ exhibited a 38-63% durable cure in the 60, 75, and 100% MTD groups. In comparison, mice treated with CBZed-Nano exhibited a 92-100% durable cure, confirming both the superior activity of CBZed-Nano relative to free CBZ, and confirming antitumor activity of the scalable NanoAssemblr production. Conclusion: The CBZed-Nano preparation technique is scalable, with manual and NanoAssemblr™ produced dose being equally efficacious in a PC3 prostate cancer model. Significant efficacy (70% durable cure) in a docetaxel-resistant prostate cancer of the bone model was also observed. The data suggests that CBZed-Nano is more tolerable than CBZ, and that it may overcome taxane-resistant solid tumor indications. (1) Bioconjugate Chem 22 2011, 2474-2486 (2) Biomaterials 33 2012, 3931-3941 Citation Format: Joseph Bteich, Bryan Hoang, Elijus Undzys, Mohammed Mohammed, Ai Lin Su, Kevin Ou, David Emerson, Kenneth Sokoll, Shyh-Dar Li, Mohit Trikha, Henry Lowman, Mark J. Ernsting. A production-scalable cabazitaxel cellulose nanoparticle exhibits significant efficacy in a bone model of docetaxel-resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1342.