Dissertation
A study of the effects of membrane modification on the acoustic susceptibility of liposomes for tunable controlled drug delivery
Doctor of Philosophy (Ph.D.), Drexel University
Jun 2014
DOI:
https://doi.org/10.17918/etd-4561
Abstract
This study considers the effects of membrane modification on the ultrasound-induced leakage, or acoustic susceptibility, of liposomes. Liposomes, versatile and biocompatible drug delivery vesicles, have been surface-engineered to enable active targeted delivery but the efficacy of ligand-targeted liposomes has been undermined by several obstacles, i.e. premature leakage of encapsulants, non-internalization, and binding-site barriers. To overcome these limitations, external triggers for controlled release have been studied. Low-frequency ultrasound (here considered to be on the order of 20 kHz) is a promising external trigger for controlled delivery that does not affect the chemical integrity or potency of the drug, assists without any irreversible damage to the skin, and can be tuned in terms of sonification parameters to elicit a specific release rate at the target location. Liposome composition, polyethylene glycol-grafting, and liposome echogenicity have been individually shown to affect acoustic susceptibility, although the mechanisms of action remain unclear. The purpose of this study was to systematically analyze the interactions of liposome phase, PEG-grafting, and echogenicity, and the resultant effect on acoustic susceptibility. The effect of hydrophobic drug concentration on the acoustic susceptibility of non-echogenic and echogenic liposomes was also explored. Additionally, the potential of echogenic liposomes as ultrasonic cavitation nuclei was examined as a mechanistic investigation. This work was pursued with the goal of furthering a customizable means of drug delivery. A wide range of liposome formulations (combinations of two liposome phases, two configurations of PEG-grafting, and echogenicity) were exposed to 20 kHz, 2.2 W/cm2 ultrasound and the release of calcein, a fluorescent hydrophilic dye, was monitored to quantify acoustic susceptibility. Release kinetics were fit with simple first order mathematical models to facilitate comparison between the release profiles. The results showed that each factor investigated significantly affected acoustic susceptibility, with liposome echogenicity as the most effective enhancer. Whereas release from non-echogenic liposomes generally followed a model consisting of two first order processes, release from echogenic liposomes followed a model with a single first order process. These results suggest that acoustic susceptibility is strongly dependent on liposome chemistry and bilayer defects and a better understanding of this system will enable the development of a customizable drug delivery system.
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Details
- Title
- A study of the effects of membrane modification on the acoustic susceptibility of liposomes for tunable controlled drug delivery
- Creators
- An Thien Nguyen - DU
- Contributors
- Peter Andreas Lewin (Advisor) - Drexel University (1970-)Steven P. Wrenn (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 4561; 991014632585004721