Multifunctional Superparamagnetic Iron Oxide Nanoparticles for Biomedical Applications in Cancer Treatment | Shiv Nadar University
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Multifunctional Superparamagnetic Iron Oxide Nanoparticles for Biomedical Applications in Cancer Treatment

Magnetic nanoparticles – especially superparamagnetic iron oxide nanoparticles (SPIONs – magnetite (Fe3O4)/maghemite (Fe2O3) nanoparticles) are utilized in several biomedical applications for cancer treatments including magnetic fluid hyperthermia (MFH) based thermotherapy, where these SPIONs are primarily used to induce localized heating inside the cancer cells to therapeutic temperatures (ranging from 42-45 °C) on exposure to the externally applied alternating magnetic fields (AMFs). However, there is still a need for synthesizing high quality SPIONs – with controlled sizes with narrow distributions, good water solubility/ dispersibility, better cytocompatibility, high magnetization and enhanced heating efficacies – to improve their therapeutic feasibility for treating cancers via MFH. So, in this thesis work, initially high-quality hydrophilic SPIONs are synthesized via one-pot chemical co-precipitation/thermolysis methods, followed by in-situ surface functionalization with short-chained molecules such as terephthalic acid (TA), 2-aminoterephthalic acid (ATA), trimesic acid (TMA), pyromellitic acid (PMA), 1,4- diaminobenzene (DAB), 4-aminobenzoic acid (ABA) and 3,4-diaminobenzoic acid (DABA) individually (i.e., single-surfactant) and in combination (i.e., dual-surfactants). Moreover, hydrophilic SPIONs are also synthesized via thermolysis process by using liquid based solvent-surfactants (LSS) made of polyamines such as diethylene triamine (DETA), triethylene tetraamine (TETA), tetraethylene pentamine (TTEPA), and pentaethylene hexamine (PEHA) – individually or in combination with polyols (such as diethylene glycol (DEG), triethylene glycol (TEG), tetraethylene glycol (TTEG)). Furthermore, hydrophilic superparamagnetic iron oxide nanoclusters (IONCs) are also prepared by using triethanolamine (TEA) and polyol (DEG/TTEG) based LSS combinations through thermolysis process. Then, the as-synthesized SPIONs and IONCs are systematically characterized to investigate their physicochemical (for instance – morphology, surface structure, crystallinity, and dispersibility) and magnetic properties (for e.g., saturation magnetization). Based on their magnetic properties (i.e., high Ms values), and water dispersibility (i.e., high zeta potential values), the selected SPIONs/IONCs samples based ferrofluids are further investigated for the calorimetric MFH (CMFH) studies, where the influence of vital aspects such as (i) concentrations, (ii) AMFs (in terms of amplitude (H) * frequency (f) - near to Hergt's biological safety limit), and (iii) dispersion media on their intrinsic heating effects/efficacies (i.e., specific absorption rate (SAR)/intrinsic loss power (ILP) values)  are thoroughly inspected. Then, on the basis of the CMFH results, selected ferrofluids (at lower concentrations) with higher heating efficacies are subsequently investigated for their (i) biocompatibility, (ii) cellular uptake and (iii) in vitro therapeutic efficacy in liver (HepG2) cancer cells at hyperthermia temperature in a concentration-dependent manner. Herein, the as-synthesized SPIONs and IONCs have revealed faster thermal response to the applied AMFs by exhibiting high heating efficacies – i.e., SAR and ILP values as compared to the literature. Moreover, the as-synthesized SPIONs and IONCs have (i) demonstrated very good cytocompatibility (without MFH) and intracellular uptake, and (ii) achieved higher therapeutic efficiency in HepG2 liver cancer cells. In addition, high-quality oleylamine coated hydrophobic SPIONs are also synthesized, and consequently co-encapsulated inside the poly(lactic-co-glycolic acid) (PLGA) nanoparticles –individually, and along with the drugs such as curcumin (Cur, a chemotherapeutic drug (CHD)), or/and verapamil (Ver, a calcium channel blocker (CCB)) – to develop multifunctional magnetic polymeric nanoparticles (MMPNs) or multifunctional SPIONs. Later, the hydrodynamic sizes, encapsulation efficiencies (EE%), water dispersibility, magnetic properties, heating efficacies, and biocompatibility of the as-developed MMPNs are investigated and/or optimized. Based on these results, the SPIONs and dual-drugs (Cur and Ver) co-loaded PLGA NPs (MMPNs) are further investigated for calorimetric MFH studies and therapeutic efficacies (SAR/ILP values) using the HepG2 liver cancer cells. Herein, MMPNs have demonstrated relatively high EE%, good water solubility/dispersibility, improved Ms, faster time-dependent temperature raise, better cytocompatibility and enhanced therapeutic efficacies via multimodal therapies (thermotherapy and chemotherapy). Hence, the MMPNs have great potential for efficiently treating the cancer cells.  In conclusion, it can be established that (i) the as-synthesized hydrophilic SPIONs and IONCs are very promising heat-inducing agents to be used as individual-therapeutic agents for cancer thermotherapy, and (ii) the as-prepared hydrophobic SPIONs/dual-drugs (Cur and Ver) co-loaded PLGA NPs based MMPNs are very promising therapeutic candidates for effective cancer treatments by utilizing multimodal therapies (via combined thermotherapy and chemotherapy).

Department: 
Mechanical Engineering
Year: 
2018
Student Name: 
K. Ganeshlenin

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