Quaternary nanoparticles enable sustained release of bortezomib for hepatocellular carcinoma

Background and Aims Hepatocellular carcinoma (HCC) represents the third leading cause of cancer‐related mortality in the world. Over the past two decades, there has been minimal improvement in therapies as well as clinical outcomes for patients with Barcelona Clinic Liver Cancer (BCLC)‐B. These patients are treated with local interventions, including transarterial chemoembolization. Current methodologies only allow sustained intratumoral release measured in hours. Methodologies to allow sustained local release of the drug cargo over days to weeks are acutely needed. We hypothesize that tumor response as well as outcomes of patients with BCLC‐B can be improved through utilization of a highly cytotoxic agent delivered with a sustained release platform. Approach and Results High‐throughput drug screening across 40 HCC patient‐derived organoids identified bortezomib (BTZ) as a highly cytotoxic small molecule for HCC. We designed and manufactured sustained release BTZ nanoparticles (BTZ‐NP) using a flash nanocomplexation/nanoprecipitation process. We quantified the release profile and tested the anti‐tumoral effects in vivo. The BTZ‐NP formulation demonstrated a sustained release of BTZ of 30 days. This BTZ‐NP formulation was highly effective in controlling tumor size and improved survival in vivo in three animal models of HCC, including when delivered via the hepatic artery, as we envision its delivery in patients. In addition, the BTZ‐NP formulation was superior to treatment with doxorubicin‐drug eluting beads. Conclusions The BTZ‐NP formulation provides a potent and safe treatment of HCC via a localized delivery approach. These results warrant additional preclinical studies to advance this technology to human clinical trials. Human HCC tissue was collected and patient derived organoids (PDO) were established. These PDOs were utilized for high throughput drug screening, which led to identifying bortezomib as a highly potent anti‐HCC drug. Bortezomib was then formulated with PLGA nanoparticles for sustained release (BTZ‐NP). Efficacy of BTZ‐NP was tested in 3 animal models. First, it was tested in a patient derived xenograft model (PDX) through direct intra‐tumoral injection. Next, BTZ‐NP was tested in an immunocompetent mouse model (Hepa 1‐6 cells injected into the liver of C57bl/6j mice) through a direct intra‐tumoral injection approach. Last, to simulate trans‐arterial delivery through the hepatic artery, a rat model of HCC was developed and utilized to tes