Biodegradable CCK-receptor targeted nanoparticle for the treatment of Cancer

Categories:  “Cancer Therapeutics“

Reference #: 2016-020

OTC Contact: Ruchika Nijhara, Ph.D., MBA, CLP (Directory Information | Send a Message)

Description

Georgetown University investigators have developed targeted siRNA delivery system that selectively binds to cell surface receptors on tumor cells. The siRNA-polymer complex binds to a CCK ligand and allows for targeted delivery of siRNA into the cell. siRNA suppresses expression of cancer proteins that are responsible for tumor growth or metastasis. The nontoxic nanoparticle is designed to allow cellular entry of siRNA for specialized cancer treatment.

Pancreatic ductal Adenocarcinoma (PDAC) cells over-express the cholecystokinin-B(CCK-B) receptor and the re-expression of gastrin stimulates growth of the cancer by an autocrine mechanism through the CCK-B receptor. Down-regulation of GASTRIN mRNA by using RNAi inhibits cancer growth and metastasis. K-RAS expression is thought to bea driver of pancreatic cancer and down regulation of the same causes the carcinogenesis. The current delivery vehicle is designed to target both these genes and can safely bind to the cancer without off target toxicity.

Applications

• Targeted treatment of pancreatic ductal adenocarcinoma.
•  Treatment of any cancer that express CCK receptors
  • colorectal cancer
  • gastric cancer
  • distal esophageal adenocarcinoma
  • medullary thyroid cancer
  • small cell lung cancer 
  • carcinoid tumors
• Can be potentially utilized for delivery of other siRNA/mRNA/DNA to other tissues for other indications.

Advantages

• Effective delivery of siRNA to tumor site
• Biocompatible and biodegradable
• Prevents the degradation of siRNA in the nanoparticle core 
• The charge on the nanoparticle is neutral due to the binding of positively charged polymer and the negatively charged RNA
• Can act as prototype to treat cancers other than the CCK-receptor expressing cancers.

Stage of Development

The nanoparticle is made up of a thiol-functionalized block polymer conjugated to a known CCK ligand and theconstruct is complexed with the specific siRNA, such as GASTRIN and K-RAS. In-vivo efficacy is proved inPancreatic Ductal Adenocarcinoma xenograft models. Pre-clinical animal studies show a significantly decrease insize of the tumors and lack of metastasis in mice treated with the targeted siRNA construct.

Relevant Publications

• Smith JP, Whitcomb DC, Matters GL, Brand RE, Liao J, Huang YJ, and Frazier ML. Distribution of the CCK-B receptor genotype between pancreatic cancer patients and controls and its impact on survival. Pancreas, 44: 236-242. PMID: 25469546.
• Smith JP, Fonkoua LK, and Moody TW. The Role of Gastrin and CCK Receptors in Pancreatic Cancer and other Malignancies.  J. Biol. Sci 2016; 12(3): 283-291
• Smith, Jill P; Cooper, Timothy K; McGovern, Christopher O et al. (2014) Cholecystokinin receptor antagonisthalts progression of pancreatic cancer precursor lesions and fibrosis in mice. Pancreas 43:1050-9
• Smith, Jill P; Harms, John F; Matters, Gail L et al. (2012) A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer. Cancer Biol Ther 13:164-74
• Smith, Jill P; Liao, Jiangang; Matters, Gail L; McGovern, Christopher O; Gilius, Evan L et al. (2016) GermlineMutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer Clinical and Translational Gastroenterology (2016), e134; doi:10.1038/ctg.2015.61

Inventors

• Jill P. Smith
• Stephen Stern
• Abdullah Mahmud