A Drug-Loaded Nanoparticle to Target Bone-Metastatic Prostate Cancer

Treatment for localized prostate cancer (PCa) has a tremendous success rate. However, the fact that the five-year overall survival rate drops from 100% to 30.2% when tumor cells metastasize to distant sites, represents an unmet medical need. In 90% of metastatic cases, bone is the primary metastatic site. Our objective is to co-load a poly(lactic-co-glycolic) (PLGA) nanoparticle (NP) with Cabazitaxel (CBZ) and Bortezomib (BTZ) and to conjugate a bone-targeting moiety, Alendronate (ALN), to the outside of the nanoparticle to facilitate targeting to bone tumors and to ameliorate the resulting bone damage. We hypothesize that this targeted nanomedicine will affect genes and proteins that contribute to invasion and migration, anti-apoptotic signaling, and ultimately lead to tumor-cell apoptosis. Furthermore, we predict that the nano-delivery system will help ameliorate bone lesions inflicted by the tumors. Methods: Nanoparticles were engineered using an Emulsion-Diffusion-Evaporation Technique in which PLGA is dissolved in dichloromethane, 5% polyvinyl alcohol, and Bis(sulfosuccinimydyl)suberate (BS3) crosslinker. For targeting, Alendronate (ALN) is later conjugated to the outside of the nanoparticle via this crosslinker. Results: Our average NP size was around 240 nm in diameter, a PDI of < 0.2, with a Zeta Potential (ZP) of -28 mV. Our drug loading capacity (DL) for CBZ was 11.97% and for BTZ 0.9%. Encapsulation efficiency (EE) for CBZ was 25.26% and 8.9% for BTZ. The IC50 for the CBZ NPs is 5.6 nM and BTZ NPs is 15.6 nM. We have successfully shown that the gene expression for various migration and invasion markers as well as cell signaling proteins have been affected by the nanoparticles. Conclusions: Our nanoparticles have a desirable size, PDI, ZP, DL, and EE for our intended therapeutic purpose. Furthermore, we have shown alterations in the cell signaling and gene expression responsible for Epithelial-to-Mesenchymal Transition-Transcription Factors (EMT-TFs), indicating that our nanotherapeutic has significant potential to treat metastatic PCa and to mitigate the damage done by metastatic tumors.