NANOPARTICLES IN THE TREATMENT OF DIABETES Introduction: Diabetes mellitus, is caused by decrease in insulin secretion by pancreatic islet cells, leading to increase in blood glucose level (hyperglycemia). Diabetes mellitus is characterized by * excessive weight loss * increased urge for urination (polyuria) * increased thirst (polydipsia) * and an excessive desire to eat (polyphagia). Diabetes mellitus has been classified as * Type 1, or insulin-dependent diabetes * Type 2, or non- insulin-dependent diabetes and * Gestational diabetes. * Polymeric Nanoparticles: Polymeric nanoparticles have been used as carriers of insulin. These are biodegradable polymers, with the polymer-insulin matrix encloseed by the nanoporous membrane containing grafted glucose oxidase. A rise in blood glucose level triggers a change in the surrounding nanoporous membrane, resulting in biodegradation and subsequently release insulin. The glucose/glucose oxidase reaction causes a reducing the pH in the delivery system's. This can cause an increase in the swelling of the polymer system, leading to an increased release of insulin. The polymer systems examined for such applications include copolymers such as N,N-dimethylaminoethyl methacrylate and polyacrylamide. This "molecular gate" system is composed of an insulin reservoir and a delivery rate-controlling membrane made of poly[methacrylic acid-g-poly(ethylene glycol)] copolymer. The polymer swells in size at normal body pH (pH = 7.4) and closes the gates. It shrinks at low pH (pH = 4) when the blood glucose level increases, thus opening the gates and releasing the insulin from the nanoparticles. These systems release insulin by swelling caused due to changes in blood pH. The control of the insulin delivery depends on the size of the gates, the concentration of insulin, and the rate of gates' opening or closing (response rate). These self-contained polymeric delivery systems are still under research, whereas the delivery of oral insulinwith polymeric nanoparticles has progressed to a greater extent in the recent years. Oral Insulin Administration by Using Polysaccharides and Polymeric Nanoparticles: The improved oral insulin administration is very essential for the treatment of diabetes mellitus to overcome the problem of daily subcutaneous injections. Insulin, when administered through orally, it undergoes degradation in the stomach due to gastric contents (enzymes). Thus, insulin should be encapsulated in a matrix like system to protect against gastric enzymes. This can be achieved by encapsulating the insulin molecules in polymeric nanoparticles. In one such study revealed , calcium phosphate-poly(ethylene glycol)-insulin combination was combined with casein (a milk protein). The casein coating protects the insulin from the gastric enzymes . Due to casein's mucoadhesive property, the formulation remained concentrated in the small intestine for a prolonged period, resulting in sustained absorption and longer bioavailability in the bloodstream. In another study, insulin-loaded polymeric nanoparticles were used in the form of pellets for oral delivery of insulin in diabetic rats. The results showed a drastic decrease in blood sugar level following the administration of insulin through the buccal cavity. Polysaccharides, such as chitosan, dextran sulfate, and cyclodextrin, have been used to deliver the insulin molecules with polymeric nanoparticles as carrier systems. Although chitosan was used for nasal delivery of insulin, it has also been tested for oral delivery. Insulin Delivery Through Inhalable Nanoparticles: Inhalable, polymeric nanoparticle-based drug delivery systems have been developed for the treatment of tuberculosis. Such approaches can be directed toward insulin delivery through inhalable nanoparticles. Insulin molecules can be encapsulated within the nanoparticles and can be administered into the lungs by inhaling the dry powder formulation of insulin. The nanoparticles should be small enough to avoid clogging up the lungs but large enough to avoid being exhaled. Such a method of administration allows the direct delivery of insulin molecules to the bloodstream without undergoing degradation. A few studies have been done to test the potential use of ceramic nanoparticles (calcium phosphate) as drug delivery Agents. . BioMEMS for Insulin Delivery: Implantable biological micro electro mechanical systems (BioMEMS) can be used as insulin pumps for controlled release of insulin when there is an increase in blood glucose level. Another proposed BioMEMS device has a drug reservoir compartment filled with insulin molecules. Biosensors and nonporous membranes with pores of 6-nm diameter are located in the exterior to detect the changes in blood glucose level and for insulin release. Other Nanoparticulate Systems for Insulin Delivery and Diabetes-Associated Symptoms Treatment: Other than the ceramic and polymeric nanoparticles, gold nanoparticles have also been tested as insulin carriers. Gold nanoparticles synthesized with chitosan as a reducing agent ere tested as a carrier for insulin. The nanoparticles showed long-term stability in terms of aggregation and good insulin loading of 53%. The use of chitosan served dual purpose by acting as a reducing agent in the synthesis of gold nanoparticles and also promoting the penetration and uptake of insulin across the oral and nasal mucosa in diabetic rats. The study concluded that oral and nasal administration of insulin-loaded, chitosan-reduced gold nanoparticles improved pharmacodynamic activity of insulin. References: Kuzuya T, Nakagawa S, Satoh J, et al. Report of the Committee on the classification and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract 2002; 55(1):65-85. 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