Targeting aberrant cancer kinome using rationally designed nano-polypharmaceutics

M. Koyakutty, A. Ratnakumary, P. Chandran, A. Ashokan, S. Nair
Amrita Centre for Nanoscience and Molecular Medicine, IN

Keywords: nanomedicine, core-shell, cancer kinase, polypharmaceutics

Summary:

In the present talk, we discuss our approaches to target critically aberrant cancer kinases using rationally designed polymer-protein and protein-protein core-shell nanomedicines. We have used both genomic and proteomic approaches to identify many intimately cross-linked and complex aberrant protein kinases behind the drug resistance and uncontrolled proliferation of refractory leukemic cells derived from patients. Small molecule inhibitors targeted against oncogenic pathways in these cells were found ineffective due to the involvement of alternative survival pathways. This demands simultaneous inhibition more than one oncogenic kinases using poly-pharmaceutics approach. For this, we have rationally designed core-shell nanomedicines that can deliver several small molecules together for targeting multiple cancer signalling. We have also used combination of small molecules and siRNA for combined gene silencing together with protein kinase inhibition in refractory cancer cells. Optimized nanomedicines were successfully tested in patient samples and found enhanced cytotoxicity and molecular specificity in drug resistant cases. Nano-polypharmaceutics represents a new generation of nanomedicines that can tackle multiple cancer mechanisms simultaneously. Considering the complexity of the disease, such therapeutic approaches are not simply an advantage, but indispensable.