Development of Bortezomib-Loaded Nanoparticles for Locoregional Treatment of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the 6th most common cancer and the 4th leading cause of carcinoma-related death worldwide; yet there no curative chemotherapy strategy available for unresectable HCC. Bortezomib (BTZ) is a proteasome inhibitor that is FDA-approved for multiple myeloma and certain subtypes of chronic myelogenous leukemia; and in drug screening tests it shows promising potency in HCC cells. Systemic administration at required doses proves to be toxic in mice, however, repeated intra-tumoral injections results in tumor regression. The objective of this study is to develop a BTZ-loaded nanoparticle that can lower the systemic toxicity through local release of BTZ over several days. The BTZ-loaded nanoparticles were prepared by a facile assembly technique combining flash nanocomplexation (FNC) and flash nanoprecipitation (FNP), achieving high uniformity, stability, and adjustability by controlling the input parameters during preparation process. In the pilot in vivo study, the BTZ-loaded nanoparticles demonstrated local retention for more than 10 days in tumor tissue following intratumoral injection and exerted similar tumor-killing effect with same dose, yet less injection frequency as compared to free BTZ. The BTZ-loaded nanoparticles exhibited potential as a locoregional delivery system to provide a new therapeutic modality for future HCC treatment.