Abstract B51: Targeted nanoparticle approach to treating metastatic prostate cancer

Abstract

Abstract Introduction: Treatment outcomes of bone metastatic prostate cancer remain poor despite an increasing number of therapeutic options approved in recent years. Limitations exist in the drugs that are approved, such as no overall survival benefits or serious dose-limiting toxicities. We have engineered a targeted nanoparticle (NP) system to deliver cabazitaxel to bone lesions. The amino-bisphosphonate, alendronate, was used as the bone-targeting moiety on the surface of the NP. The objective of this approach is to increase therapeutic payload at the site of bone metastasis to achieve an improved therapeutic index. Methods: Poly(lactic-co-glycolic acid) NPs were synthesized using a modified water-in-oil-in-water double-emulsion solvent evaporation technique followed by binding of alendronate to the surface of the NP. We characterized NPs for size and zeta potential using dynamic light scattering. Cabazitaxel encapsulation efficiency, drug loading, and release kinetics were optimized by quantification with HPLC analysis. In vitro cell viability studies were performed on C4-2B and PC3 prostate cancer cell lines. 3D prostate cancer spheroids were utilized as well to test cell viability and NP penetration. Ex vivo bone binding studies were used to test nanoparticle affinity for hydroxyapatite structure. In vivo tumor efficacy studies were carried out with male athymic nude mice implanted with intraosseous tumors consisting of PC3-luciferase cells. After bone tumors were established for 1 week, mice were treated via tail vein injection with either saline, free cabazitaxel, non-targeted NPs, or targeted NPs for one month (starting n=6 per group). Response was measured with in vivo bioluminescence imaging, tumor limb weight at conclusion of experiment, and mouse x-ray monitoring. In addition, animal behavior experiments were performed on all treatment groups to assess functional status through gait analysis and pain through von Frey filament assay. Results: NPs were successfully synthesized to mean size of 236 nm with a PDI of .120. Highest encapsulation of cabazitaxel into nanoparticle was 55.8% with a drug loading of 3.7%. Release kinetics showed a strong burst phase release over the first 8 hours and subsequent sustained release up to 72 hours. In vitro cell viability and 3D spheroid experiments showed targeted and nontargeted NP to be equivalent to free drug. Ex vivo bone binding experiment showed targeted NP had a 4-fold increase in binding to bone at 6 hours and an 8-fold increase in bone binding at 72 hours compared to nontargeted NP. Tumor efficacy experiment showed targeted NP and nontargeted NP had a statistically significant overall reduction in tumor measured by bioluminescence (P value < 0.005). Interestingly, mice treated with targeted NP had no bone lesions on x-ray, whereas 100% of mice in saline group, 100% of mice in cabazitaxel group, and 33% of mice in nontargeted NP group had bone lesions. Gait analysis did not show a statistically significant difference between groups. However, von Frey assay showed a significant reduction in relative response in the targeted NP group (P value < 0.005). Conclusion: We have successfully synthesized a bone-targeted NP system. In this project, we have shown that targeted NPs help maintain bone structure in tumor-burdened limbs as well as decrease tumor size. We have also shown that these targeted NPs reduce the relative response to von Frey filament pain stimulation in the tumor limb. This bone-targeted NP system is a promising potential therapeutic in developing improved treatments for bone-metastatic prostate cancer patients. Note: This abstract was not presented at the conference. Citation Format: Andrew Gdowski, Amalendu Ranjan, Marjana Sarker, Jamboor Vishwanatha. Targeted nanoparticle approach to treating metastatic prostate cancer [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B51.