Mito-DCA: A Mitochondria Targeted Molecular Scaffold for Efficacious Delivery of Metabolic Modulator Dichloroacetate

Tumor
growth is fueled by the use of glycolysis, which normal cells
use only in the scarcity of oxygen. Glycolysis makes tumor cells resistant
to normal death processes. Targeting this unique tumor metabolism
can provide an alternative strategy to selectively destroy the tumor,
leaving normal tissue unharmed. The orphan drug dichloroacetate (DCA)
is a mitochondrial kinase inhibitor that has the ability to show such
characteristics. However, its molecular form shows poor uptake and
bioavailability and limited ability to reach its target mitochondria.
Here, we describe a targeted molecular scaffold for construction of
a multiple DCA loaded compound, Mito-DCA, with three orders of magnitude
enhanced potency and cancer cell specificity compared to DCA. Incorporation
of a lipophilic triphenylphosphonium cation through a biodegradable
linker in Mito-DCA allowed for mitochondria targeting. Mito-DCA did
not show any significant metabolic effects toward normal cells but
tumor cells with dysfunctional mitochondria were affected by Mito-DCA,
which caused a switch from glycolysis to glucose oxidation and subsequent
cell death via apoptosis. Effective delivery of DCA
to the mitochondria resulted in significant reduction in lactate levels
and played important roles in modulating dendritic cell (DC) phenotype
evidenced by secretion of interleukin-12 from DCs upon activation
with tumor antigens from Mito-DCA treated cancer cells. Targeting
mitochondrial metabolic inhibitors to the mitochondria could lead
to induction of an efficient antitumor immune response, thus introducing
the concept of combining glycolysis inhibition with immune system
to destroy tumor.