Al-Jamal, Wafa' Tayseir Yousef; (2008) Engineering Liposome-Quantum Dot Hybrids for Biological Applications. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Quantum dots (QD) are being widely explored as fluorescent probes for long term imaging purposes in vitro and in vivo. The present work describes engineering a variety of liposome-quantum dot hybrid vesicles, by encapsulating QD with different sizes and surface hydrophilicity into different liposome types. Hybrid self-assembly was dependent on the QD characteristics. Small (< 5 nm) hydrophobic QD were incorporated into the lipid bilayer, rendering the QD compatible with the aqueous environment and fluorescently labelled the lipid bilayers, while lipid-PEG coated QD were encapsulated inside the liposome aqueous core. These two types of hybrid were characterised by dynamic light scattering, zeta potential, cryogenic electron microscopy and confocal laser scanning microscopy (CLSM). The engineered hybrid vesicles revealed dramatic improvement in cellular binding and internalisation compared to QD alone, observed usmg tumour cell monolayer cultures. Deeper penetration into 3-D multicellular tumour spheroids was also obtained by modifying appropriately the lipid bilayer characteristics of the hybrid system. Moreover, direct injection of the hybrid vesicles into solid tumour xenografts led to extensive fluorescent staining of the tumour mass, as shown by CLSM imaging of tumour sections. The cytotoxicity of these hybrid vesicles was highly dependent on the QD type and concentration, hybrid composition and surface charge, exposure time and the type of cell line. The liposome-QD hybrid vesicles showed high stability in vivo following intravenous administration and different tissue biodistribution profiles and tissue affinities were observed depending on the lipid bilayer characteristics. These studies were carried out both by tracking radiolabelled lipid bilayers by scintigraphy and correlating with elemental (cadmium) analysis of the different tissues. Immediate blood clearance was observed with cationic hybrid, while incorporation of PEG at the surface of zwitterionic vesicles dramatically prolonged their blood circulation half-life after systemic administration. The tumour accumulation of liposome-QD hybrids in vivo after systemic administration did not show improved tumour targeting primarily due to their short blood circulation half-life but accelerated tumour accumulation was achieved compared to lipid- PEG coated QD. Liposome-QD hybrid vesicles can constitute a versatile tool for very efficient labelling of cells ex vivo and in vivo , particularly when long-term imaging and tracking of cells is sought. Moreover, liposome-QD hybrid vesicles offer many opportunities for the development of combinatory therapeutic and imaging modalities by incorporating both drug molecules and QD within the different compartments of a single vesicle.

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