Cancer remains a major global health challenge, with breast cancer incidence steadily increasing in women. Its development involves uncontrolled cell proliferation and the ability of cancer cells to invade healthy tissues, forming tumors and metastases. Conventional therapies, including surgery, chemotherapy, and radiotherapy, face limitations such as damage to normal cells, systemic toxicity, and drug resistance. These challenges have spurred the development of targeted drug delivery systems, with nanoparticles emerging as a promising solution. Nanoparticles, due to their small size, high surface-to-volume ratio, and modifiable surfaces, can efficiently deliver therapeutic agents to target cells while reducing systemic exposure. Iron oxide (Fe3O4) nanoparticles offer magnetic and chemical properties that enable tumor-specific guidance and imaging. Surface modification with polyethylene glycol (PEG) enhances nanoparticle stability, prolongs circulation, and provides attachment sites for targeting ligands such as folic acid and glucose. Polylactic acid (PLA), a biodegradable polymer, improves drug-loading capacity and allows controlled release. Combining PLA with PEG and targeting ligands produces multifunctional nanoparticles capable of selective cancer cell recognition, controlled drug release, and reduced effects on healthy tissues.



In this study, dual-ligand PLA-PEG nanoparticles functionalized with folic acid and glucose and incorporating Fe3O4 were developed for targeted delivery of curcumin to triple-negative breast cancer cells (Hs-578T). Nanoparticles PPF (PLA-PEG-FA), PPG (PLA-PEG-Glu), and PPGF (PLA-PEG-Glu/FA) were synthesized via reaction of PLA-acrylate with the respective NH2-PEG derivatives, followed by dialysis and freeze-drying. Curcumin and Fe3O4-OA were incorporated using sonication and emulsification in PVA, followed by solvent removal, washing, and filtration to remove unencapsulated drug and large aggregates. Structural and chemical characterization was performed using 1H-NMR and FTIR spectroscopy, morphology was analyzed with TEM, and size and zeta potential were determined by dynamic light scattering. Drug encapsulation efficiency was measured spectrophotometrically, and release kinetics were evaluated at pH 7.4 and pH 4.5 to mimic normal and tumor environments. Cytotoxicity was assessed using MTT assays, while apoptosis induction was analyzed via Annexin V/propidium iodide staining and flow cytometry.



Results demonstrated that PLA-PEG-based nanoparticles were biocompatible with Hs-578T cells, showing minimal toxicity. Curcumin encapsulation enabled controlled and sustained release, particularly in acidic conditions representative of tumor microenvironments. Nanoparticles containing both folic acid and PEG (PPGF) exhibited higher drug release than PEG-only nanoparticles, emphasizing the role of targeting ligands in facilitating drug delivery. Cytotoxicity assays revealed significant inhibition of Hs-578T cell proliferation, with dual-ligand nanoparticles showing the lowest IC50 values. Flow cytometry confirmed that apoptosis, rather than necrosis, was the primary mode of cell death, indicating targeted activation of programmed cell death pathways. This enhanced apoptotic effect likely results from increased cellular uptake and precise intracellular delivery of curcumin.



The study confirms that multifunctional PLA-PEG nanoparticles, incorporating Fe3O4 and targeting ligands, provide an effective platform for cancer-specific drug delivery. They combine biocompatibility, controlled release, tumor-specific accumulation, and enhanced induction of apoptosis, collectively improving therapeutic efficacy while minimizing systemic toxicity. The nanoparticles’ pH-sensitive release ensures minimal drug exposure to normal tissues, reducing side effects and potentially allowing lower therapeutic doses. The use of dual ligands, folic acid and glucose, further increases targeting precision and drug accumulation in cancer cells. These findings support the potential of multifunctional nanocarriers as a promising strategy for next-generation targeted cancer therapies, offering a safe, efficient, and versatile approach for improving treatment outcomes and overcoming limitations associated with conventional chemotherapy.