Hervault, AMM; (2017) Development of a Doxorubicin-Loaded Dual pH- and Thermo-Responsive Magnetic Nanocarrier for Application in Magnetic Hyperthermia and Drug Delivery in Cancer Therapy. Doctoral thesis , UCL (University College London).

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Abstract

Magnetic nanocarriers have attracted increasing attention for multimodal cancer therapy due to the possibility to deliver heat and drugs locally. The enhancement of the anti-cancer effect of chemotherapy with application of concurrent hyperthermia has been noticed more than thirty years ago. However, combining magnetic nanoparticles with drug molecules in the same nanoformulation has only recently emerged as a promising tool for the simultaneous application of hyperthermia and chemotherapy. In this work, initial experimentation was primarily focused on the synthesis of magnetic nanoparticles of high saturation magnetisation to develop efficient mediators of heat based on an iron core and a bismuth shell. However, such nanoparticles could not be obtained due to the impossibility to grow the bismuth shell on the iron nanoparticle surface. The rest of this study reports the development of a novel magnetic nanocomposites (MNCs) made of an iron oxide core and a pH- and thermo-responsive polymer shell, that can be used as both mediators of heat and drug carriers. The conjugation of the anticancer drug doxorubicin to the thermo-responsive MNCs via acid-cleavable imine linkers provides advanced features for the targeted delivery of doxorubicin via the combination of magnetic targeting, and dual pH- and thermo-responsive behaviour, which offers spatial and temporal control over the release of the drug. The nanoparticles exhibit a superparamagnetic behaviour with a saturation magnetization around 78 emu/g and good heating properties in an alternating magnetic field. Almost a complete doxorubicin release was obtained under acidic tumour pH and hyperthermia conditions. Finally, in vitro studies on human glioma and breast cancer cell lines and on a murine prostate carcinoma cell line confirmed that thermo-chemotherapy applied via the developed smart delivery system exhibits a substantial increase in cytotoxicity as compared to standalone therapies, and almost complete cell death was observed while applying low thermal and chemotherapeutic doses.

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