Magnetite-PLGA Microparticles for Oral Delivery of Insulin
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Magnetite-PLGA Microparticles for Oral Delivery of Insulin Jianjun Cheng,1 Christopher H. Yim,1 Benjamin A. Teply,1 Dennis Ho,2 Omid C. Farokhzad,3,4 and Robert S. Langer1 1 Department of Chemical Engineering, 2 Department of Biology, 3 Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139 4 Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115
ABSTRACT Magnetic responsive particles were designed for use in oral delivery of insulin. Magnetite nanoparticles (12 nm average size) were synthesized and co-encapsulated with insulin into poly(lactide-co-glycolide) (PLGA) microparticles (4.6 ± 2.2 µm average particle size) through the double-emulsion method. The spherical structures of resulting microparticles were well maintained at magnetite content 5 wt % or less. Mice were gavaged with 125I-insulin-magnetitePLGA microparticles and a circumferential trans-abdominal magnetic field was applied forty minutes after administration to retard the transit of the microparticles in the intestinal tract. As control, mice were similarly dosed without the subsequent trans-abdominal magnetic field. Mice were sacrificed, and the intestinal radioactivity was 101% and 145% higher in treated mice versus the control at 6 h and 12 h, respectively. A single administration of 50 unit/kg Humulin Rmagnetite-PLGA microparticles to the fasted mice resulted in 66% reduction of blood glucose level in the presence of external magnetic field at 12 h, compared to 27% reduction in the absence of magnetic field.
INTRODUCTION Oral delivery of peptides and protein therapeutics has been extensively studied in the past several decades. This route of administration is preferred because it increases patient compliance and comfort compared to the parenteral route, which accounts for the administration of more than ninety percent of FDA approved protein drugs. However, clinically effective oral delivery systems for protein therapeutics have not been established [1]. Proteins administered orally result in extremely poor absorption into the circulatory system due to the degradation of proteins in harsh acidic and enzymatic conditions in the stomach, and low permeation of proteins across the intestinal membranes [1]. Several approaches have been proposed and evaluated for oral delivery of proteins, including permeation enhancers [2-4], pHsensitive hydrogels [5], enzyme inhibitors [6], liposomes [7-9] and protein-encapsulated submicron sized polymeric particles [10, 11]. Polymeric microparticles (MPs) are easy to prepare, encapsulate protein with high efficiency (usually greater than 50%), and effectively protect encapsulated proteins from degradation in gastrointestinal tract (GIT) [1]. The drawback of this approach is that the majority of the particles pass through small intestines without being absorbed. Retention of these proteincontaining particles in the small intestine for an extended period of time may result in an increase of the delivery efficiency th
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