Translating Novel Nanotherapeutics into Treatment for Hepatocellular Carcinoma from Bench to Bedside: A Case Study of the LDL-DHA Nanoparticle

Introduction To examine an investigational nanomedicine and discuss the steps needed for clinical translation.

For hepatocellular carcinoma (HCC), translating investigational therapies from the laboratory to the interventional radiology (IR) suite is complicated and expensive. We will examine the steps involved in obtaining approval of a novel drug with the low-density lipoprotein docosahexaenoic acid (LDL-DHA) nanoparticle as a case study for promising preclinical results in treating a rodent model of HCC. The agent has selective cytotoxicity toward HCC cells using redox-mediated processes, showing three-fold regression of tumor mass with no adverse effects on normal liver tissue.

Content organization

Preclinical

• Nanotherapeutic created from well-known delivery systems easily tailored for desired target, size, charge, and hydrophobicity.

• Cellular mechanism must be shown along with efficacy and off-target effects in animal models, with comparison to nanoparticles devoid of the drug.

• In our case, biological effects were compared with controls in healthy rats with orthotopic tumors using both open surgical and transarterial approaches.

• Investigational New Drug (IND) application must be submitted to the Food and Drug Administration (FDA), describing pharmacology, manufacturing information, and clinical protocols (supplemented by an institutional review board [IRB]).

Clinical

• Initial phases assess the safety/efficacy of the drug in increasing numbers of patients, first in healthy volunteers and then in those with the disease.

• Phase III verifies long-term effects in randomized controlled trials.

• New Drug Application (NDA) must be filed to allow marketing according to specific labeling.

Postmarket

• Surveillance after drug is on the market.

• The FDA may request studies on specialized populations, and clinicians may compare the drug to other treatments.

Learning Points With the success of transarterial therapies, we can expect to see newer agents for treating HCC. At a cost of roughly $1 billion over 10 to 15 years for the development of new drugs, investigators involved in creating embolics should understand the process and special considerations in translating nanotherapeutics into clinical use.

No conflict of interest has been declared by the author(s).