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Current Nanoscience, 2013, 9, 46-55
Nanoparticulate Carrier Mediated Intranasal Delivery of Insulin for the Restoration of Memory Signaling in Alzheimer’s Disease Pankaj Dwivedi1, Rakesh Kumar Tekade2,3,* and Narendra Kumar Jain3 1
Cipla Ltd. Phase II, Sector 3, Pharma Zone, Pithampur, Dhar- 454774 (M.P), India; 2Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar 470 003, (M.P), India; 3School of Pharmacy and Pharmaceutical Sciences, University of Central Lancashire, Preston PR1 2HE (England) United Kingdom Abstract: The present study was aimed to determine the therapeutic potential of novel carriers to deliver insulin into brain, by passing the BBB. PLGA nanoparticles and PEGylated PLGA nanoparticles were prepared by double emulsification method. PEG-PLGA copolymer was synthesized and characterized by FTIR, NMR and Mass spectroscopies. The release profiles of drug in various formulations were studied in PBS (pH 7.4). Results showed more sustained release of drug with Tween-80 based formulation in comparison with Tween-20 and PVA based formulations. A more sustained and extended release was observed upon chitosan coating of PEG-PLGA nanoparticles. Blood glucose level monitoring suggested that glucose level was not decreased significally in the peripheral region (p>0.05), when chitosan coated insulin loaded PEGylated nanoparticle was administered by intranasal route. This outcome in particular along with expected mucoadhesive and targeted benefit associated with chitosan based formulation drove us to conclude this formulation to be working best for the undertaken brain delivery issue.
Keywords: Co-polymer nanoparticle, insulin, Alzheimer, biodistribution study, restoration of memory signaling. 1. INTRODUCTION Alzheimer's disease (AD), one form of dementia, is a progressive, degenerative brain disease. The pathological hallmarks of AD are senile plaques, which are spherical accumulations of protein amyloid (A ) accompanied by degenerating neuronal processes and neurofibrillary tangles, composed of paired helical filaments and other proteins. It impairs neuronal activities with impairment of synaptic function and the induction of cell death [1]. It affects memory, thinking, and behavior [2]. Insulin is an amphoteric pancreatic protein, which likely modulates memory via other molecular events such as long-term potentiation (LTP), a cellular model of learning [3,4]. Insulin not only regulates blood sugar levels but also acts as a growth factor on all cells including neurons in the CNS. Disturbance in insulin signaling appears to be the most common impairment that affects cell growth and differentiation, cellular repair mechanism, energy metabolism and glucose utilization. Insulin can modulate cognition and other selective brain functions through effects on local cerebral glucose metabolism as well as through effects on neurotransmission. The insulin/Insulin Receptors (IR) distributed in the hippocampus and cerebral cortex are involved in brain cognitive functions. The number of brain IR densities decreases significantly in Alzheimer’s disease. This impairment in insulin signaling in the brain is considered unique in development and distribution and has been termed ‘Type3 Diabetes’ by some researchers [1]. Patients with Alzheimer’s disease have lower CSF insulin levels, higher plasma insulin levels and reduced insulin-mediated glucose disposal, a pattern consistent with insulin resistance. Insulin modulates levels of the A peptide, the aggregation of which is a neuropathological hallmark of AD. Thus, in patients with AD, high peripheral insulin levels and low brain insulin levels would result in reduced clearance of A both in brain and in the periphery [1]. In normal individuals, during neuronal activity, insulin is released and it binds to the -subunit of the receptor, which, *Address correspondence to this author at the Pharmaceutics Research Laboratory, Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University, Sagar 470 003, India; Tel: +91-9425438689; Fax: +91-7582-264712; E-mail:
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in turn, activates the tyrosine kinase phosphorylation of the subunit [5]. In patients of AD, Insulin receptors desensitize and this phenomenon affects neuronal metabolism and causes the development of AD [1]. The epithelial tissue within the nasal cavity has an extensive blood supply, which drains blood from the nasal mucosa directly to the systemic circulation [6-8], thus providing a potential conduit for drug delivery which circumvents first-pass metabolism. In humans, the respiratory mucosa covers most of the total nasal surface area and is the major site for drug absorption into the systemic circulation [9-11]. Intranasal drug delivery takes the advantages of an incomplete BBB in the olfactory epithelium. The olfactory nerves are able to completely bypass the BBB and drugs that can be taken up by these neurons can be transported directly into the brain [12, 13]. Peripherally administered insulin is not a viable treatment for AD, due to risk of hypoglycemia. After intranasal administration, insulin follows extra cellular pathways to the brain and largely bypasses the periphery, directly accessing the CNS, and circumventing the risk of hypoglycemia [14-18]. Nanoparticles are solid, colloidal particles consisting of macromolecular substances that vary in size from 10 nm to 1000 nm [17-19]. Biodegradable nanoparticles formulated from poly DLlactide co-glycolide (PLGA) and polylactide (PLA) have been developed for intracellular sustained drug delivery, especially for drugs with an intracellular target [20-22]. Another characteristic function of nanoparticles is their ability to deliver drugs across several biological barriers to the target site [23-34]. The brain delivery of a wide variety of drugs is markedly hindered because they have great difficulty in crossing the BBB .The application of nanoparticles to brain delivery is a promising way of overcoming this barrier [25]. At present, nasal delivery of insulin to the brain is the major problem due to digestion of insulin by amino-peptidase in nasal pathway and low absorption through the nasal epithelium. The olfactory neuronal pathway provides both an intraneuronal and extraneuronal access to the brain. The extraneuronal pathway allows therapeutic agent to reach the CNS within a few minutes. The transport of drugs across the nasal membrane and the bloodstream may involve passive diffusion of drug molecule through the pores © 2013 Bentham Science Publishers
