Bone Microenvironment Targeted Nanoparticles for Metastatic Prostate Cancer Treatment

Introduction The most common site of metastatic prostate cancer is the bone. These metastatic lesions are difficult to treat and often result in off target cytotoxicity from current chemotherapeutics. We hypothesize that targeted nanoparticles (NPs) designed to deliver chemotherapeutics to cancer lesions in the bone microenvironment could improve the side effect profile that results from non-discriminate action of cytotoxic agents. We have designed a novel targeted nanotherapeutic system to target the bone microenvironment in an effort to more efficiently delivery chemotherapeutics to the site of metastasis. The core of the NPs are composed of poly (D,L-lactic-co-glycolic acid) (PLGA) biodegradable polymer. The PLGA NPs have been loaded with the microtubule inhibitor, cabazitaxel. The surface of the NP has been conjugated with an amino-bisphosphonate, which has high affinity for the hydroxyapatite structure of the bone. Methods NPs were formulated using a modified water in oil in water double emulsion solvent evaporation technique. The physiochemical properties of the NPs were characterized.Ex vivo bone binding studies were performed. Cell viability studies were performed on C4-2B and PC3 cell lines. NPs were also tested on 3D tumor spheroids. Finally, NPs were tested for efficacy in an intraosseous tumor model of metastatic prostate cancer in athymic nude male mice. Results NPs were made with favorable physiochemical characteristics: mean hydrodynamic diameter of 236.8 nm ± S.D. 1.19, mean polydispersity of 0.121 ± SEM 0.003, encapsulation efficiency of 57%, and drug loading of 3.74. Cellular cytoxicity assay showed that C4-2B cells were more sensitive to the free cabazitaxel, the non-targeted NPs, and the targeted- NPs compared to PC-3 cells. We did not see an appreciable difference between the targeted-NPs and equivalent treatment of free cabazitaxel in 3D assays. In vivo analysis showed that both the non-targeted and targeted-NPs were more effective than free cabazitaxel at reducing tumor burden. Additionally, targeted-NPs improved bone morphology at tumor lesions. Conclusion In this project we have engineered a bone targeted NP formulation for metastatic prostate cancer. We have determined the chemical and physical characteristics of this system and tested the in vitro cytotoxicity. Finally, we have shown the efficacy of these targeted-NPs in an intraosseous model of bone metastatic prostate cancer.