Mansoor M. Amiji, Shashi K. Murthy
Date of Award
Master of Science
Department or Academic Unit
Bouvé College of Health Sciences. Department of Pharmaceutical Sciences.
Pharmaceutical sciences, Anaplastic thyroid cancer, Thyroid cancer, Hyperthermia, Liposomes
Pharmacy and Pharmaceutical Sciences
ATC (Anaplastic thyroid cancer) and MTC (medullary thyroid cancer) account for 1-2% and 5-10% of all thyroid cancer cases, respectively. These also represent the most metastatic forms of thyroid cancer. The 5-year survival rate for metastatic MTC is around 40%, while ATC is known to have one of the most dismal prognoses amongst all cancers with 5-year survival rates from 1-7%. Currently, the main treatment options for thyroid cancer are restricted to surgery, radioiodine therapy and external radiation. However, these two forms of thyroid cancer are somewhat radio-resistant and are unable to concentrate radioiodine. No effective chemotherapy options are thus available for treatment, and amongst those that have been investigated, doxorubicin is the most effective agent with a 30% partial response.
The main objective of our investigation was to use a multi-modality approach to treat thyroid cancer. We aim to develop a delivery system (magnetic cationic liposomes) for treating aggressive thyroid cancer which uses a combination of magnetic drug targeting and hyperthermia effectively in enhancing the effects of the chemotherapeutic agent. We characterized our formulation in terms of size, charge, iron content, magnetization measurements and hyperthermia producing effects. We also observed its effect on the viability of the cell lines used, as well as its ability to accumulate in the thyroid cancer and endothelial cells in vitro. We prepared DOX-loaded (Doxorubicin) magnetic cationic liposomes with different concentrations of magnetite (MAG-C) and observed their ability to release drug over a range of temperatures in addition to various characterization parameters. Finally, we observed the effect of varying MAG-C concentrations on the physical properties of relatively novel liposome preparation types, and selected the optimal formulation on the basis of particle size, cationic charge potential (which would allow it to target the tumor vasculature) and sufficient iron content (to respond to an external magnet as well as to induce heating effects in an AC field).
The MCLs showed particle sizes and zeta potentials from 125±4.0 nm and 26±5.2 mv without MAG-C to 255±11.1 nm and 11±3.1 mv with 20 mg/ml MAG-C. The iron content varied from about 1.5 mg/ml for 2.5 mg/ml MAG-C to about 10.2±4.8mg/ml for 20 mg/ml MAG-C. The MCLs accumulated well in the thyroid cancer cell lines CAL-62 and TT respectively up to a concentration of 1000 nmol/ml, as observed quantitatively by cell association and qualitatively from fluorescence microscopy studies. At concentrations ≤1000 nmol/ml, the MCLs were not toxic to either TT or CAL-62 cells. However, HMEC-1, the endothelial cell line was more sensitive to the effects of MCLs and started showing toxic effects at 500nmol/ml of MCLs. We observed a trend which suggested that upon increasing the MAG-C concentration, it became possible to reach a particular temperature in a much shorter duration of time when compared to formulations containing less MAG-C. We also observed that higher MAG-C concentrations stabilized the liposomes and retained significantly more DOX than liposomes with low concentrations of MAG-C. Higher temperatures also favored the release of DOX from liposomes for all MAG-C concentrations. A pilot study making use of a combination of magnetic drug targeting as well effects of heat was also undertaken with the ATC cell line. The DOX-loaded liposomes thus prepared and characterized are expected to show benefits in vitro as well as in vivo as supported by literature, as well as our current and previous investigations.
Jhaveri, Aditi, "Magnetic nanomedicine and hyperthermia for the treatment of thyroid cancer" (2009). Pharmaceutical Science Master's Theses. Paper 7. http://hdl.handle.net/2047/d10017100
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