Technological Development of Lipid-Based Microcylinders: Biocompatibility and Controlled Release
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TECHNOLOGICAL DEVELOPMENT OF LIPID-BASED MICROCYLINDERS: BIOCOMPATIBILITY AND CONTROLLED RELEASE t
Barry J. Spargo', Geoffrey E. Stilwell , Richard 0. Cliff, Rod L. Monroy*, Florence M. Rollwagen*, and Alan S. Rudolph*
"Naval Research Laboratory, Center for Biomolecular Science and Engineering, Washington, DC 20375 'Geo-Centers, Inc., Ft. Washington, MD 20744 t
Naval Medical Research Institute, Bethesda, MD. 20889
ABSTRACT We have developed a lipid-based microcylinder for the controlled release of biological response modifiers. Lipid microcylinders are composed of 1,2-ditricosa-10,12-diynoyt-snglycerol-3-phosphocholine which form hollow cylinders 50-250 pm in length with a diameter approximately 0-5-1.0 pm. Amphiphilic molecules such as ganglioside (5-6 mol%) can be incorporated into the bilayers of the microcylinder, modulating surface characteristics of the structure. In this study, we have examined the biocompatibility of lipid microcylinders and lipid microcylinders containing 6 mol% ganglioside. The interaction of microcylinders with peripheral blood monocytes and three cell lines: U937, a histocytic monocyte; K562, an erythroblast, and; a Jurkat derivative, a lymphoblast was assessed. Toxicity, as measured by proliferative status of the cell lines, was not evident at lipid concentrations up to 100 Jg/ml lipid. Peripheral blood monocytes were observed to closely associate, but not engulf lipid microcylinders. However, when ganglioside was present in the lipid microcylinders this interaction was markedly decreased. We have begun to measure the release rates of growth factors such as transforming growth factor-beta (TGF-fi) from lipid microcylinders. Release of TGF-fi from the microcylinders follows first-order kinetics. The rate of release can be modulated by increasing the temperature which results in a thermotrophic phase transition of the lipid at 43 *C.
INTRODUCTION The use of lipid-based vehicles for in vivo drug delivery has been well described [1]. Lipid vehicles such as liposomes, gels and emulsions are used in a variety of biological settings, including use as blood substitutes 12], and targeting vehicles for the delivery of chemotherapeutic agents [3]. The lipid vehicles provide a means to control the release of materials, decrease systemic toxicity by efficient localization, and inhibit biodegradation of labile molecules. We have developed a lipid-based microcylinder for the controlled release of biological molecules such as cytokines and growth factors [4]. This lipid microstructure is composed of 1,2-ditricosa- 10,12-diynoyl-sn-glycerol-3-phosphocholine (DClXPC), which under defined conditions spontaneously forms hollow cylinders ranging in length from 50-250 um with a diameter of 0.5-1.0 pm [5,61. In this study we examine the biocompatibility of microcylinders and their potential use as controlled release vehicles. As with many lipid-based drug delivery systems, clearance rates and toxicity are important aspects and often limit the utility of the vehicles for such purposes. In this study we d
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