Optimization of combination liposome and hyperthermia therapy for cancer.

摘要

Despite much basic science and clinical research in the field, cancer remains a disease that lacks a definitive therapy in many instances.; In Chapter 1, I review the current literature regarding liposomes and hyperthermia. Hyperthermia can increase liposomal delivery to tumor by increasing vascular blood flow and permeability. Additionally, specially formulated thermosensitive liposomes can be triggered for drug release by hyperthermia at the tumor site.; Hyperthermia has been shown to increase extravasation in some cases. In Chapter 2, I investigate the role of hyperthermia in augmenting liposome extravasation into tumor interstitium. In the human tumor xenograft model studied, 100nm liposomes were unable to extravasate under normothermic conditions but extravasated significantly at 42°C. The amount of liposome extravasation into tumor interstitium was inversely related to liposome size. Hyperthermia's ability to augment liposome extravasation was limited to tumor vasculature, as 100nm liposomes did not extravasate from normal vessels at 42°C.; In Chapter 3, I explore the temperature dependence of liposome extravasation, the temporal dependence, and possible role of thermotolerance. In the model studied, 100nm liposome extravasation did not occur between 34°C and 39°C. At 40°C, some liposomal extravasation occurred. Extravasation increased with temperature until 42°C, above which tumor vessels collapsed and hemorrhaged.; In Chapter 4, I compare ten different treatment groups (saline, free doxorubicin, and three liposomal forms of doxorubicin with and without hyperthermia) based on tumor drug concentration achieved, drug fluorescence in tissue sections, and tumor growth delay. For all three measurements, the thermosensitive liposome that was formulated to release drug quickly, at the temperatures attainable by hyperthermia, showed the largest effect. Additionally, this liposome in combination with hyperthermia resulted in 60-day local control in 17/20 tumors.; In Chapter 5, I give some final perspectives on my thesis research. Liposomal therapy in combination with hyperthermia holds promising therapeutic potential for many reasons. (Abstract shortened by UMI.)