Novel bio-reducible polymer compositions which combine the ability to act as a CXCR4 antagonist and simultaneously provide enhanced gene delivery through the formation of inert nanocarrier polyplexes have been developed. As would be expected for biodegradable polymers, the cytotoxicity of these nanocarrier compositions are very low with measured IC50 values 50 to 100 times higher than conventional polyethylenimines (PEI) controls. Significantly, the known CXCR4 antagonist drug AMD3100 has successfully been incorporated into the polymer composition and shown to retain activity comparable or better than the drug alone with or without the formation of a nanocarrier polyplexes. Successful gene delivery by the nanocarrier polyplexes has been demonstrated through fluorescence imaging studies and measurements of transfected gene expression levels. Preliminary results of two different animal studies confirm the CXCR4 antagonist response of this novel composition for both lung cancer metastasis and inflammatory bowel disease (IBD).
Benefits:
Novel treatment strategy for metastatic cancers (i.e. Bone, Breast, Prostrate): The trans-membrane cell receptor CXCR4 has been implicated in the spread of cancer throughout the body through the seed-and-soil hypothesis. Inhibition of cancer cell invasion through specific CXCR4 antagonism was shown to be effective using these nanocarrier polyplexes. This inhibition provides an attractive benefit if combined with targeted systemic delivery of cancer gene therapies not be available through viral vectors.
Stage of Development:
• Pre-Clinical, 2 different animal models tested
Applications:
• Metastatic Cancer agent (Combined CXCR4 antagonist and gene delivery)
• Anti-inflammatory agent (CXCR4 antagonist alone - suitable for oral delivery)
• Imaging agent (Binds Cu64 - possible imaging agent PET, MRI)
•Theragnostics applications (Combination imaging agent & CXCR4 antagonist or gene delivery)
Data Availability:
Low cyto-toxicity confirmed using HepG2 cells and U2OS cells >450 micrograms/mL
Mouse model 1 - lung cancer metastasis (4T1.luc) monitored by whole body bioluminescence imaging and whole lung tissue section staining
Mouse model 2 - DSS-induced Acute Colitis (testing both oral and intraperitoneal injection) monitored by histopathology
References:
1) “Dual-function CXCR4 Antagonist Polyplexes to Deliver Gene Therapy and Inhibit Cancer Cell Invasion” Angewandte Chemie Int. Ed. 51 (35) August 27 2012 p8740-8743
News Highlights:
http://www.media.wayne.edu/2012/09/10/wayne-state-university-research-team-proposes-new\
Patent Status:
Patent filing pending