Comparative efficacy of free and PNAGA-encapsulated antimalarial drugs: temperature-dependent modulation of Plasmodium falciparum growth

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Introduction: Poly(N-acryloyl glycinamide) (PNAGA) was evaluated as a temperature-responsive carrier for antimalarial drugs. Methods: PNAGA was synthesized and characterized by DSC and TGA, and its sol-gel transition was determined by the reverse test-tube method. Encapsulation efficiency (EE%) of mefloquine hydrochloride and pyrimethamine in PNAGA was determined by UV-Vis spectrophotometry, using dialysis to separate free from encapsulated drug and calibration curves at each drug's characteristic absorbance maximum (284 nm for mefloquine hydrochloride, 272 nm for pyrimethamine). Free drugs and PNAGA-encapsulated formulations were introduced to Plasmodium falciparum cultures, alongside PNAGA alone and a negative control, and parasitemia was assessed after 24 h at 37 °C and again after 24 h at 4 °C. Results: DSC and TGA analyses demonstrated PNAGA's amorphous, thermoreversible nature and established its thermal stability limits. The sol-gel transition was 22.6 °C ± 1 °C, confirming UCST behavior. PNAGA efficiently encapsulated mefloquine hydrochloride and pyrimethamine, with encapsulation efficiencies of 93.3% and 94.7%, respectively. After 24 h at 37 °C, parasitemia was significantly lower in cultures treated with free drugs than with polymer-bound formulations, indicating that encapsulation delayed drug release and reduced immediate efficacy. PNAGA alone showed no inhibitory effect. After 24 h at 4 °C (below the sol-gel transition), PNAGA-mefloquine matched free mefloquine in efficacy, while PNAGA-pyrimethamine remained less effective than free pyrimethamine. Discussion: These findings confirm that PNAGA is a reproducible, temperature-responsive hydrogel that efficiently encapsulates antimalarial drugs and modulates their availability according to its UCST, with reduced immediate efficacy at 37 °C (above the sol-gel transition) and higher efficacy below the sol-gel transition (4 °C) for PNAGA-mefloquine.

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