Malic acid grafted Fe3O4 nanoparticles for controlled drug delivery and efficient heating source for hyperthermia therapy

Highlights: • Fe₃O₄ magnetic nanocarriers for doxorubicin delivery and hyperthermia therapy. • Grafting of malic acid provides hydrophilicity and desired sites for drug binding. • Superparamagnetic nanocarriers with good external magnetic field responsivity. • pH dependent release and dose dependent toxicity of conjugated drug molecules. • Substantial cellular uptake of doxorubicin conjugated nanocarriers in MCF-7 cells. -- Abstract: Tailoring surface features is essential for creating specific functional properties on superparamagnetic Fe₃O₄ nanoparticles for biomedical applications. In this regard, we explored the use of malic acid as a surface passivating agent for designing biocompatible, highly water-dispersible Fe₃O₄ magnetic nanocarriers (MMNCs) for high payload of anticancer drug, doxorubicin hydrochloride (DOX). The efficacious grafting of malic acid onto the surface of Fe₃O₄ was apparent from infrared spectroscopy, dynamic light scattering, zeta-potential and thermogravimetric measurements. XRD and TEM analyses revealed the formation of highly crystalline single-phase Fe₃O₄ nanoparticles. They showed good aqueous colloidal stability, pH dependent surface charge characteristics and superparamagnetic behavior at room temperature. The electrostatic conjugation of drug onto the surface of MMNCs was optimized by varying the ratio of DOX to MMNCs, and a maximum loading efficiency of 72% was achieved at their 1:10 ratio. The DOX conjugated MMNCs (DOX-MMNCs) exhibited pH dependent controlled release characteristics. These DOX-MMNCs demonstrated dose dependent cellular uptake and retained considerable toxicity of DOX towards breast cancer (MCF-7) cell line. Further, our magnetic hyperthermia studies showed excellent heating efficiency of these MMNCs within the permissible limit of field strength and frequency reported for a safe application of hyperthermia to patients. Specifically, a water-dispersible surface decorated magnetic formulation was developed for pH-responsive controlled release of chemotherapeutic drug and efficient heating source for hyperthermia therapy.