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(632h) Controlled Release from an Injectable Biopolymer-Liposome Gel Using Focused Ultrasound

Arora, J. S., Tulane University
Ashe, S., Tulane University
Murad, H., Tulane University
Halliburton, G., Tulane University
Khismatullin, D., Tulane University
John, V. T., Tulane University
Raghavan, S. R., University of Maryland

In the emerging field of hybrid biomaterials, polymer-liposome gels are promising injectables. Liposomes are self-assembled lipid containers which can encapsulate hydrophilic and hydrophobic moieties. Fabricating polymer-liposome gels can make the liposomes more stable and protect them from the immune system of the host as compared to bare liposomes. Furthermore, when a drug is encapsulated within liposomes and the liposomes are used to form a gel network, the drug has to diffuse out from the liposomes and then through the gel network ensuring a longer sustained release. Raghavan and coworkers have reported shear thinning of liposome-polymer gels fabricated from hydrophobically modified chitosan (hm-chitosan). Hm-chitosan is a modified biopolymer with hydrophobes covalently attached to the chitosan backbone. These hydrophobes have a tendency to insert themselves in the bilayer of liposomes. At low concentrations, hm-chitosan forms a coating on the liposomes in solution and at higher concentrations, a gel network is formed. In this network, liposomes act as nodes between hm-chitosan chains. Raghavan and coworkers reported that upon shearing, the viscosity of the liposome-hm-chitosan gels decreased making them injectable. When the shear was stopped, the gel network quickly re-established.

The objective of this study is to formulate a stimuli responsive hybrid gel using hm-chitosan and temperature sensitive liposomes (TSLs) and to control the release kinetics using focused ultrasound. TSLs can be tuned to rapidly release their contents above a certain transition temperature. High intensity focused ultrasound (HIFU) is a powerful technology for noninvasive treatment of cancer. HIFU deposits a large amount of acoustic energy at the focal region within the target tissue (for example a tumor), causing localized heating and necrosis. HIFU exposure can be employed to increase the temperature in a controlled manner which can trigger the rapid release of encapsulated drugs from TSLs. Hm-chitosan – TSL gel networks were fabricated which were exposed to HIFU to increase the temperature just above the transition temperature of the TSLs. HIFU exposure increased the rate of diffusion of a dye from within the TSLs. This lead to a faster release of dye from the HIFU treated hm-chitosan – TSL gels as compared to hm-chitosan and liposome gels made from non-temperature sensitive liposomes. To make the release even faster, α-cyclodextrin was also encapsulated within the TSLs which is known to break the hm-chitosan – liposome gels as it has a higher affinity for the hydrophobes of the hm-chitosan. When the hm-chitosan – TSL gel with the α-cyclodextrin encapsulated in the TSLs was exposed to HIFU, the α-cyclodextrin diffused rapidly out of the liposomes and formed an inclusion complex with the hydrophobes of the hm-chitosan which led to dissolution of the gel network. Cryo scanning electron microscopy and cryo transmission electron microscopy were used to image the effects of the HIFU treatment on the hm-chitosan – TSL gels and these results will be presented. Thus, a novel injectable hybrid biomaterial is fabricated with a wide range of release kinetics which can find applications in biomedical engineering.  

Acknowledgments: Authors acknowledge funding from National Science Foundation, Department of Defense, Louisiana Board of Regents, Newcomb-Tulane College, and Tulane Center for Engaged Learning and Teaching.