Mitochondria Targeting Kills Cancer Cell Without Acquired Drug Resistance (Brandeis Ref. 2018-002)

A bioinspired system which selectively generates the assemblies of redox modulators (e.g., triphenyl phosphimium (TPP)) in the pericellular space of cancer cells for uptake, allows selectively targeting the mitochondria of cancer cells. The attachment of TPP to a pair of enantiomeric, phosphorylated tetrapeptidic produces the precursors that form oligomers. The cancer cell uptake these assemblies of TPP via endocytosis, mainly via caveolar/raft dependent pathway. The assemblies of TPP-peptide conjugates will be released from lysosome, induce dysfunction of mitochondria to release cytochrome and result cell death. The conceptual system has been tested ex vivo on several cancer cell lines. The merit of this technology is the repeated stimulation of the cancers by the precursors unexpectedly sensitizes the cancer cells to the precursors. The invention is the first example of the integration of subcellular targeting and the spatial control of the assemblies of non-specific cytotoxic agents by EISA as a promising molecular process for selectively killing cancer cells without inducing acquired drug resistance. The invention also the first time to report controlling peptide self-assembly inside organelle of mitochondria of live cells, which provides new opportunity for therapeutics against cancer and some immune-deficient disease. Rong Zhou zhourong@brandeis.edu 7817368753