Heterogenous lipid membranes: Basic studies on giant vesicles and potential therapeutic applications of small liposomes.

摘要

Environmentally responsive lipid bilayer membranes are described in this thesis. The findings described herein include basic studies on the self-assembled material itself, and evaluation of potential applications of this material in the form of lipid based drug delivery carriers.;In particular, fluorescence microscopy on Giant Unilamellar Vesicles was used to describe domain formation induced by pH. Different biophysical properties of the lipid membranes were systematically varied and their effect on the induced domain formation was studied. Based on these studies, pH-triggered liposome carriers were engineered from gel-phase bilayers where pH could be used as a knob to alter membrane properties such as surface topography and reactivity so as to achieve selective cell targeting and to alter the membrane permeability for faster drug release via formation of transiently defective interfacial phase boundaries. The effect of the different type of titratable lipid headgroups, the difference in hydrocarbon chain lengths, the different targeting molecules and their grafting density on affecting the specific targeting to cancer cells was evaluated in vitro. In vivo, the findings presented herein show that pH-triggered liposomes demonstrate better tumor control, and thereby, may improve control of tumor growth at the same or even lower administered doses relative to FDA approved liposomal chemotherapy. Radiolabeled targeted liposomes were also developed and evaluated for anti vascular therapy for solid tumors. The developed targeted liposomes loaded with an atomic-sized alpha-particle generator Actinium-225 (225Ac) were shown to demonstrate higher killing efficacy of different cancer cell lines and also by endothelial cells induced to overexpress a receptor uniquely observed on human neovasculature. These studies show the potential of targeted 225Ac loaded liposomes for selective targeted radiotherapy of tumor vasculature.