Formulation and Evaluation of Paclitaxel-Loaded Polymeric Nanoparticles for Breast Cancer Therapy, Improving Drug Solubility and Bioavailability

Paclitaxel (PTX) is still a mainstay chemotherapy drug in breast cancer, including triple-negative breast cancer (TNBC). Nevertheless, it has a very low bioavailability, non-specific biodistribution, systemic toxicity, and is susceptible to P-glycoprotein (P-gp)-mediated multidrug resistance, as well as having a very low aqueous solubility, necessitating toxic solubilizers such as Cremophor EL, which induces hypersensitivity reactions. This study aims to prepare and characterize paclitaxel-loaded polymeric nanoparticles (PTX-NPs) using biodegradable polymers that are approved by the FDA to improve solubility, sustained and targeted drug release, and anti-cancer activity against breast cancer cells. PTX-NPs were developed by the nanoprecipitation technique and optimized through Design of Experiments (DoE) technique. The optimized formula was described in terms of particle size, polydispersity index (PDI), zeta potential, morphology (TEM/SEM), encapsulation efficiency (HPLC), and drug-polymer interactions (DSC, FT-IR, XRD). The in vitro release profiles were determined in pH 7.4 and 5.5. The cellular uptake, cytotoxicity (MTT assay), apoptosis, and cell cycle of MCF-7 and MDA-MB-231 cell lines of breast cancer were assessed. Plasma stability and hemocompatibility were also evaluated. PTX-NPs were optimized to have a uniform spherical geometry with a mean particle size of 156.3 + 4.2 nm, low PDI (0.12 + 0.02), and negative zeta potential (-28.5 + 1.8 mV). The encapsulation efficiency (86.5 ± 3.1) and drug loading (8.2 ± 0.5) were high, PTX being in the amorphous state in the polymer matrix. In vitro release had a sustained biphasic release during 96 hours with pH-responsive characteristics where release was faster at tumor-mimicking acidic pH 5.5 (72.4%) compared to physiological pH 7.4 (58.6%). The cellular uptake experiments indicated a great increase in internalization of nanoparticles in MDA-MB-231 cells. Compared to free PTX (0.48 ± 0.06 µg/mL), PTX-NPs had better cytotoxicity and lower IC50 values (0.15 ± 0.03 µg/mL) against TNBC cells, induced higher apoptotic cell death (42.5% vs. 28.3%), and caused greater G2/M phase arrest Formulation exhibited good hemocompatibility (Less than 5 percent hemolysis) and stability in the plasma. PTX-polymeric nanoparticles are effective in overcoming the major shortcomings of traditional paclitaxel formulation, namely the use of toxic solubilizers, sustained and pH-responsive release, cellular uptake, and remarkably improved anti-cancer effect on breast cancer cells. The nanoformulation is an exciting approach to safer and more effective treatment of breast cancer.

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