Abstract
The development of biodegradable nanoparticles (NPs) for delivering anticancer drugs, such as letrozole (LTZ), offers a targeted approach for cancer therapy. In this study, we synthesized poly(ε-caprolactone)-co-poly(ethylene glycol) (PCL-co-PEG) and fabricated LTZ-loaded PCL-co-PEG NPs (LTZ-NPs) via emulsion-solvent evaporation. Folic acid (FA), a folate receptor-targeting molecule, was conjugated to the LTZ-loaded NPs (LTZ-FNPs) to enhance treatment efficacy against hormone receptor-positive breast cancer cells. Both NPs and FNPs exhibited a spherical morphology (60-90 nm), with FNPs showing higher drug entrapment efficiency and controlled release. LTZ release was minimal at physiological pH but increased in acidic, cancer-like environments, following the Korsmeyer-Peppas model, indicating a combination of Fickian and non-Fickian diffusion. In cytotoxicity assays, LTZ-FNPs exhibited higher toxicity against MCF-7 cells than LTZ-NPs. Controlled LTZ release altered gene expression, reducing B-cell leukemia/lymphoma 2 protein (Bcl2) and increasing caspase 8 (Casp8), promoting apoptosis. A shift to the SubG1 phase further confirmed enhanced LTZ-FNP-mediated cell death. Furthermore, p53 expression increased, while matrix metalloproteinase 9 (MMP-9) decreased, inhibiting cell invasion. This study introduces a biodegradable system with FA-functionalized, pH-sensitive NPs for the targeted and controlled delivery of LTZ. This approach holds great potential for selective, efficient treatment while minimizing systemic toxicity in breast cancer therapy.