Localized hyperthermia and the targeted release of the chemotherapy drug are one of the most challenging problems in chemo-hyperthermia therapy. In the present study, magnetite nanoparticles as a carrier of Temozolomide (TMZ) functionalized with folic acid-ligand (TMZ-MNP-FA) were designed and developed for targeted chemotherapy and radiofrequency hyperthermia of cancer cells. Nanoparticles were synthesized and characterized for hydrodynamic diameter, zeta potential, morphology, drug loading capacity, and in vitro RF-triggered release. Their cytotoxicity and efficacy as targeted drug delivery systems were evaluated in both cancer and normal cells and the therapeutic efficacy was analyzed on the C6 glioblastoma cancer cells. The C6 cells were treated with the nanoparticles and subjected to an alternating magnetic field (AMF) to reach a typical hyperthermia temperature of 43 °C. Then induction of apoptotic cells and the proliferation capacity of cancer cells were evaluated. The in vitro release studies exhibited that the drug release from TMZ-loaded magnetite nanoparticles was minimal at 37 °C but was noticeably boosted under an AMF irradiation. The developed targeted magnetite nanoparticles revealed higher cytotoxic effect and cellular uptake in folate-receptor overexpressing C6 cancer cells compared to OLN-93 normal cells. All results showed that combined magnetite chemo-hyperthermia (AMF + TMZ-MNP-FA) treatment was significantly more efficacious in cancer cells than hyperthermia, chemotherapy, or chemo-hyperthermia treatments (P < 0.0001). In conclusion, TMZ-MNP-FA had a key role to convert the externally delivered radiofrequency energy to heat in cancer cells. Additionally, localized hyperthermia triggered a TMZ release from the nanocarriers that resulted in cancer cell damage with synchronizing hyperthermia and chemotherapy.
Keywords: Alternating magnetic field hyperthermia; Chemo-hyperthermia; Glioblastoma; Magnetite nanoparticle; Targeted drug delivery.
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