Influence of poly(styrene-co-maleic anhydride) molecular weight on nanoparticle-mediated drug delivery in breast cancer.

BACKGROUND

Paclitaxel (PTX) is a first-line chemotherapeutic agent widely used in the treatment of multiple malignancies; however, its clinical utility is limited by poor aqueous solubility, low bioavailability, lack of tumor specificity, and systemic toxicity. Nanocarrier-based targeted delivery systems offer a promising strategy to overcome these limitations. In this study, we systematically investigated the influence of polymer molecular weight on nanoparticle performance using poly(styrene-alt-maleic anhydride) (PSMA) as a model amphiphilic polymer for breast cancer therapy.

METHODS

PSMA polymers with distinct molecular weights were synthesized by modulating initiator concentration, solvent system, and reaction temperature. Folic acid (FA) was covalently conjugated to surface carboxyl groups to enable tumor-targeted delivery. PTX-loaded nanoparticles were formulated from high-molecular-weight (FA-PSMAC31K-PTX NPs) and low-molecular-weight (FA-PSMAC6K-PTX NPs) polymers and evaluated for physicochemical properties, drug loading efficiency, stability, cellular uptake, cytotoxicity, biodistribution, and antitumor efficacy in vitro and in Ehrlich Ascites Tumor (EAT) tumor-bearing syngeneic BALB/c mice.

RESULTS

High-molecular-weight FA-PSMAC31K-PTX nanoparticles demonstrated superior drug encapsulation efficiency and enhanced stability in physiological media compared with FA-PSMAC6K-PTX nanoparticles. In vitro studies revealed significantly higher cellular uptake, increased apoptosis induction, and greater cytotoxicity towards high molecular weight nanoparticles (FA-PSMAC31K-PTX NPs). In vivo investigations further showed prolonged systemic circulation, enhanced tumor accumulation and penetration, and improved tumor growth inhibition with minimal off-target organ distribution for the high-molecular-weight formulation relative to the low molecular weight polymeric nanoparticles (FA-PSMAC6K-PTX NPs) and free PTX.

CONCLUSIONS

Polymer molecular weight critically governs nanoparticle stability, biodistribution, and therapeutic efficacy. Folate-targeted high-molecular-weight PSMA nanoparticles significantly enhance PTX delivery and antitumor activity, highlighting molecular weight as a key design parameter in the rational development of targeted nanocarrier systems for breast cancer therapy.