Abstract
Methotrexate (MTX) has shown remarkable therapeutic effects against a variety of cancers. However, it is related to various challenges like dose-influenced side effects, compromised bioavailability, and poor tissue penetration. Henceforth, a poly-(lactic-co-glycolic acid) (PLGA)-based d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) conjugated MTX self-assembled nanoparticulate system was developed. The synthesized conjugate (MTX-PLGA-TPGS) was affirmed by FT-IR and NMR spectroscopy, and the developed self-assembled nanoparticles were characterized for particle size, zeta potential, surface charge, drug loading and drug entrapment. The evaluation studies included drug release at the plasma and cancer cell pH, compatibility with erythrocytes, plasma protein binding, in-vitro cytotoxicity on cancer cell lines, confocal laser scanning microscopy, and in-vivo pharmacokinetics. The FT-IR and 1H NMR confirmed the successful conjugation of the two macromolecules. The developed nanoparticulate system offered controlled drug release in a pH-dependent manner, releasing the maximum drug at the pH of cancer cells. The developed systems were not only found to be biocompatible with erythrocytes but also offered substantially enhanced cytotoxicity on MDA-MB-231 cells. The confocal laser scanning microscopy confirmed higher cellular uptake and pharmacokinetics in rodents offered markedly elevated AUC and substantially retarded elimination from the central compartment. The findings vouch for the immense promise of the designed nanosystem in enhancing the efficacy, permeation, safety and reducing the dose and dosing frequency of a well-established BCS class IV drug candidate.
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