Journal of translational medicine · 2026
Influence of poly(styrene-co-maleic anhydride) molecular weight on nanoparticle-mediated drug delivery in breast cancer.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Dalela Manu, Shrivastav T G, Mohanty Sujata, Singh Harpal
Аннотация
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.
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.