Date of Award
Doctor of Philosophy (PhD)
George C. Wood, Ph.D.
Hassan Almoazen, Ph.D. Mostafa Waleed Gaber, Ph.D. James R. Johnson, Ph.D. Ram I. Mahato, Ph.D. Thaddeus A. Wilson, Ph.D.
Breast cancer, liposomes, paclitaxel, targeting, ultrasound
The objective of this work was to develop and evaluate paclitaxel-loaded liposomal formulations for targeted drug delivery to breast cancer. The liposomal formulation was optimized to maximize drug loading and physical stability. Cholesterol and saturated lipid content showed a negative influence on paclitaxel loading. Short-term stability studies showed that optimum drug-lipid ratio is necessary for adequate physical stability. Biodistribution studies in mouse xenografts bearing MDA-MB-231 breast cancer using near infrared fluorescence imaging showed that the accumulation of tumor vasculature targeted long-circulating liposomes (LCL) in the tumor was significantly less than non-targeted LCL at 48 h. The accumulation of these liposomes in the peritoneal cavity was higher suggesting that they were cleared rapidly by the reticuloendothelial system. The antitumor efficacy of paclitaxel-loaded tumor vasculature targeted LCL was compared with paclitaxel-loaded tumor cell targeted LCL. The antitumor efficacy was comparable for tumor vasculature targeted LCL, non-targeted LCL, and paclitaxel solution formulation with tumor volumes of ~ 60-70% of the control treatment on 39 days post tumor inoculation. In contrast, tumor cell targeted LCL showed a significantly higher antitumor efficacy compared to all other treatments with tumor volumes of ~ 30% of the control treatment. To improve the long-term stability, these liposomes were lyophilized. The leakage and vesicle size increase during lyophilization was minimized by using lyoprotectant sucrose in the formulation. Feasibility of developing gas-filled liposomes for ultrasound mediated drug delivery was evaluated using freeze drying gas entrapment method for the preparation. The in vitro measurements of echogenicity showed that these paclitaxel-loaded tumor vasculature targeted gas-filled liposomes were acoustically active and can be disintegrated by high intensity ultrasound pulses.
Kannan, Vinayagam , "Development and Evaluation of Paclitaxel-Loaded Liposomal Formulations for Targeted Drug Delivery to Breast Cancer" (2010). Theses and Dissertations (ETD). Paper 135. http://dx.doi.org/10.21007/etd.cghs.2010.0158.