Development of a PLA-b-PEG Drug Delivery Carrier Design Framework and ROS pH Responsive Methotrexate Carriers for RA
DOI:
https://doi.org/10.62051/rbcycj58Keywords:
Targeted Drug Delivery; Rheumatoid Arthritis; Methotrexate Treatment; Block Copolymer; Self-Assembly.Abstract
Methotrexate (MTX) remains the first-line treatment for rheumatoid arthritis (RA), but its clinical use faces substantial challenges due to poor water solubility and systemic side effects. To address these limitations, this study develops a framework for designing polymer-based drug delivery carriers by investigating the relationship between polymer parameters, self-assembly behavior, and pharmacokinetic properties of PLA-b-PEG block copolymers. A multiparameter analysis examined the effects of block ratio, crystallinity (PLLA vs. PDLLA), polymer architecture (triblock vs. 4-arm), and solvent conditions on nanoaggregate morphology and drug release kinetics. Six PLA-b-PEG copolymers were synthesized and characterized using ¹H NMR, GPC, and TEM. Self-assembly via co-solvent methods generated diverse morphologies, which were explained using critical packing parameter theory and Hansen solubility parameters. Drug loading efficiency ranged from 32.5% to 61.81%, with capacity reaching up to 18.54%. Release kinetics followed the Korsmeyer-Peppas model, revealing molecular weight-dependent trends. From these findings, a retrosynthetic design framework was established to link polymer parameters to desired therapeutic outcomes. Two optimized formulations were developed for RA treatment, PLLA₃.₄ₖ-PEG₅ₖ-PLLA₃.₄ₖ and 4-arm PEG₅ₖ-PLLA₃.₆ₖ. Notably, the 4-arm architecture demonstrated better performance with 83.0% drug loading efficiency compared to 73.3% for linear. Both formulations responded synergistically to reactive oxygen species (ROS) conditions, demonstrating their ability to target inflamed locations (63.73% faster release under combined acidic pH 6.5/H₂O₂), and exhibited excellent biocompatibility (<0.3% hemolysis). Functionally, both formulations displayed significant anti-inflammatory efficacy, reducing key cytokines (TNF-α, IL-6, IL-1β) by 45-65% and promoting a shift in macrophage polarization from M1 to M2 phenotypes.
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