Novel DZ-Artemisinin for Treatment of Pancreatic Cancer
Abstract
The objective of this translational research project is to develop and validate a conjugate of heptamethine carbocyanine dye (HMCD) with an artemisinin (ART) analog as a highly effective therapeutic agent for targeted treatment of pancreatic cancer. Pancreatic cancer is the third leading cause of cancer mortality in the United States. Though surgical resection is the gold standard, this option is available only for patients with primary pancreatic cancer making about 20% of all pancreatic cancer patients. Metastatic pancreatic cancer is a condition with poor therapeutic outcomes and can be treated with chemotherapy regimens including the combination therapies Gemcitabine/Abraxane or FOLFIRINOX. However, most patients have a very limited response and eventually develop resistance, which is the main cause of treatment failure. In addition, these therapeutics exhibited undesirable side effects and in severe cases can be life-threatening due to non-specific systemic distribution. The poor survival rate and lack of effective therapy for pancreatic cancer are a critical unmet medical need. In the proposed project, we will take an alternative approach, subcellular targeted therapy, to develop an innovative treatment strategy for pancreatic cancer. Our preliminary results demonstrate that subcellular targeted therapy is an ideal strategy for pancreatic cancer treatment, as it can circumvent the therapeutic resistance to kill pancreatic cancer tumor cells by selectively entering cancer cells and effectively destroying cancer cell subcellular organelles including mitochondria to activate the cell death program. Artemisinin (ART) is the prototype of a group of naturally occurring small molecule drugs used to treat malaria and parasitic worm infections. ART analogs have been widely used in the clinic as antimalarials on vast populations without significant side effects. In recent years, research investigations have shown that ART and its derivatives, such as artesunate, artemether, and their active metabolite dihydroartemisinin possess antitumor properties. The anti-cancer action of these compounds is mediated by reactive oxygen species (ROS) that damage macromolecules and impair mitochondrial function. On the other hand, the efficacy of these molecules for cancer treatment, especially in the case of metastatic tumors, is limited by poor tumor targeting capability and unfavorable pharmacokinetic properties. In the proposed project, we use an innovative strategy to make ART and its analogs specifically target cancer cells, but not normal cells, so these drugs can be enriched for the effect of tumor cell killing. We have patented this innovative drug delivery strategy. This novel tumor cell targeting strategy is based on tumor cell-specific uptake and retention of the near-infrared (NIR) heptamethine carbocyanine dyes (HMCDs), which offer an unparalleled therapeutic option for pancreatic cancer. Since HMCDs automatically target a broad spectrum of cancer cells, without affecting normal cells, these compounds can be used as vehicles to deliver antitumor drug payloads. We pioneered the use of HMCDs for targeting both primary and metastatic tumors. We have successfully synthesized a series of HMCD-ART analog conjugates we called DZ-ART1, 2, 3, and 4, which can deliver the ART analog directly into cancer cells. Significantly, DZ-ART conjugates can also re-sensitize therapeutically resistant pancreatic cancer cells to conventional chemotherapeutics. The approach of the translation study will refine and scale up a DZ-ART analog as an active pharmaceutical ingredient for preclinical efficacy and toxicology studies. Once the proposed 3-year project is completed, we will apply for the approval of DZ-ART as an Investigational New Drug (IND) to initiate a phase I clinical trial to assess the safety and efficacy of the DZ-ART in human pancreatic cancer treatment. The goals of this proposal are: (1) To evaluate the in v
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210553
Entities
People
- Stephen J Pandol
Organizations
- Cedars-Sinai Medical Center
- United States Army