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Engineering a drug delivery platform that responds to the Warburg effect of tumors


“Smart” polymers are polymers that respond to certain external stimuli. Specifically, pH- and temperature-responsive polymers have been explored extensively for cancer drug delivery. However, pH-responsive polymers do not provide adequate specificity for tumors, and temperature-responsive polymers do not sufficiently differentiate cancerous and healthy cells. Alternatively, we have been engineering polymers that respond to the Warburg effect. The Warburg effect describes cancer cells’ preference in generating energy through aerobic glycolysis instead of oxidative phosphorylation; the direct result of the Warburg effect is the increased concentration of lactate in the local tumor environment. We have incorporated thermophilic lactate dehydrogenase (LDH) as a lactate recognition moiety in a network of poly(N-isopropylacrylamide) (NIPAm) and N,N’-methylenebisacrylamide (BIS) as cancer-specific delivery platform using lactate as stimulus. DLS measurements and TEM images have confirmed that the protein-polymer hybrid nanoparticles resulted in monodisperse particles with average hydrodynamic diameters of 177 ± 0.8 nm at 37°C. Circular dichroism (CD) and kinetic assays showed that the incorporated LDH remained correctly folded and active in the polymer, demonstrating intact protein structure within the polymer. Upon addition of lactate, the particle hydrodynamic diameter swelled up to 99.2 ± 13.5 %, showing the material’s stimuli-responsive behavior. Furthermore, we showed that by incorporating mutant LDH with weaker binding compared to wtLDH did not induce swelling.

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