Treatment of patients with primary and metastatic liver tumors is a challenging unsolved problem. Only 5-20% of patients with tumors in the liver are surgical candidates, and systemic chemotherapy alone has been demonstrated to be of limited efficacy in treating hepatocellular carcinoma and liver metastases. Minimally invasive image-guided interventional techniques, including transarterial interventions and percutaneous interventions (e.g., radiofrequency ablation, laser ablation), have been introduced into the clinic for the treatment of patients with liver tumors. However, these techniques are limited by incomplete elimination of cancer cells, which can lead to local tumor recurrence. Therefore, there is an urgent need to develop innovative local treatment approaches for liver tumors. We believe that intraarterially delivered nanoparticles offers a unique opportunity for highly concentrated local delivery of heat and chemotherapeutic agents and thus may significantly improve the efficacy of treatment for liver tumors. We have developed an innovative proprietary technology that is capable of mediating simultaneous near-infrared laser-triggered photothermal ablation (PTA) and local release of doxorubicin (DOX). Our DOX-loaded, polyethylene glycol-coated hollow gold nanospheres (DOX@PEG-HAuNS) have demonstrated low systemic toxicity under normal body temperatures and significantly enhanced antitumor efficacy when combined with laser exposure under hyperthermia and ablative temperatures. In this SBIR program, we have assembled a multidisciplinary team to implement a coherent strategy to address developmental and translational challenges. Our specific aims are: 1) To synthesize and characterize high-quality DOX@PEG-HAuNS in large scale and under Good laboratory Practice (GLP) production conditions, 2) To determine the pharmacokinetics (PK) and biodistribution of DOX@PEG-HAuNS after IA injection in rats, and to demonstrate the feasibility of concurrent PTA and DOX chemotherapy in an orthotopic rat liver cancer model and a clinically relevant large animal liver cancer model (rabbit VX2 model). We believe that the proposed dual-modality treatment strategy will offer superior local tumor control while reducing the likelihood of adverse events. Success of the proposed work will pave the way for future clinical trials of DOX@PEG-HAuNS.
Public Health Relevance Statement: Public Health Relevance: The mortality associated with primary and metastatic liver tumors remains high, and novel treatments for liver tumors are urgently needed. The current project offers a minimally invasive treatment strategy that combines image-guided photothermal ablation with chemotherapy. This strategy, when successfully introduced into the clinic, will fulfil the unmet clinical need for better treatment for unresectable primary and metastatic liver tumors.
Project Terms: Ablation; Address; Adverse effects; Adverse event; Animals; assault; Award; Biodistribution; Body Temperature; cancer cell; Cancer Etiology; cancer imaging; Cancer Model; cancer therapy; Cessation of life; chemotherapeutic agent; chemotherapy; Clinic; Clinical; Clinical Trials; clinically relevant; Colorectal Cancer; cytotoxic; Development; Doxorubicin; Drug Kinetics; Ethanol; Future; Gold; good laboratory practice; Heating; Hyperthermia; Image; improved; Individual; individualized medicine; Injection of therapeutic agent; innovation; Intervention; irradiation; Label; Laboratories; Lasers; Lead; Light; Liver; Liver neoplasms; liver transplantation; Magnetic Resonance; malignant breast neoplasm; Malignant neoplasm of liver; Malignant Neoplasms; Mediating; melanoma; Metastatic Neoplasm to the Liver; minimally invasive; Modality; Modeling; Monitor; Mortality Vital Statistics; multidisciplinary; nanoparticle; Nanosphere; Nanotechnology; nanotherapeutic; National Cancer Institute; Neoplasm Metastasis; novel; Oceans; Operative Surgical Procedures; Oryctolagus cuniculus; outcome forecast; Patients; Phase; Polyethylene Glycols; Positron-Emission Tomography; preclinical study; Primary carcinoma of the liver cells; Production; programs; public health relevance; Radiofrequency Interstitial Ablation; Rattus; Recurrence; Reproducibility; Small Business Innovation Research Grant; Solid Neoplasm; Sterilization; success; Techniques; Technology; Temperature; Therapeutic Embolization; Time; Toxic effect; Toxicology; Translating; Treatment Efficacy; Treatment outcome; treatment strategy; tumor; Tumor Tissue; University of Texas M D Anderson Cancer Center; Unresectable; uptake; Work; X-Ray Computed Tomography
