Magnetite-Silica Core-Shell Nanoparticles for Anticancer Drug-Mediated Chemo-Hyperthermia: A Box-Behnken Design Approach to Triple-Negative Breast Cancer Therapy

Abstract

Triple negative breast cancer (TNBC) is one of the most aggressive breast cancer subtypes that is characterized by the lack of clinical targets and the resistance of conventional chemotherapy. We have developed cyclophosphamide loaded magnetic mesoporous nanoparticles (CYP-MMNPs) and optimized the formulation systematically by Box – Behnken Design (BBD) coupled with Response Surface Methodology (RSM) in order to establish quantitative relationship between formulation parameters and critical quality attributes in chemo-hyperthermia.

The influence of Fe₃O₄ content (1.5–3.0 g), cetyltrimethylammonium bromide (CTAB) concentration (3.9–7.8 g) and the volume of tetraethyl orthosilicate (TEOS) (7–14 mL) on particle size, entrapment efficiency, saturation magnetization, and drug release were observed. The optimized formulation (F23) showed a particle size of 110.1 nm, entrapment efficiency of 84.8%, saturation magnetization of 70.4 emu/g and cumulative drug release of 91.2% under acidic conditions (pH 5.4). The high specific surface area (97.486 m²/g) and pore volume (1.086 cm3/g) confirmed by BET analysis favoured the efficiency of drug loading. The optimized nanoparticles exhibited near-superparamagnetic behavior and exhibited a specific loss power of 383.65 W/g, which produced a therapeutic hyperthermia (42–46 °C) under an alternating magnetic field (400 kHz, 15 kA/m). The release of the drugs showed Fickian diffusion kinetics (R2 = 0.9958, n = 0.2724).

In vitro studies on MDA-MB-231 cells showed increased cytotoxicity with hyperthermia treatment (IC₅₀ = 31.0 µg/mL) and decreased cell viability (≈ 15.67%) as compared to the same treatments without hyperthermia. Uptake studies also revealed higher accumulation of the CYP-MMNPs than free drug in the cell, AMF being the most effective. The in vitro cytotoxicity results should be taken into account when taking cyclophosphamide into consideration, because it needs metabolic activation in vivo. In conclusion, this study illustrates that magnetic mesoporous nanocarriers with desired physicochemical properties and improved in vitro chemo-hyperthermia efficiency can be produced by using the statistically guided optimization method, which should be further assessed through mechanistic biological studies and in vivo evaluations.

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Pradeep, S.R., Shanmugasundaram, S. Magnetite-Silica Core-Shell Nanoparticles for Anticancer Drug-Mediated Chemo-Hyperthermia: A Box-Behnken Design Approach to Triple-Negative Breast Cancer Therapy. BioNanoSci. 16, 548 (2026). https://doi.org/10.1007/s12668-026-02784-2

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