Wheat Germ Agglutinin Functionalized Complexation Hydrogels for Oral Insulin Delivery

Department of Biomedical Engineering, University of Texas at Austin, Austin, Texas 78712, USA.
Biomacromolecules (Impact Factor: 5.75). 05/2008; 9(4):1293-8. DOI: 10.1021/bm701274p
Source: PubMed


Insulin was loaded into hydrogel microparticles after two hours with loading efficiencies greater than 70% for both poly(methacrylic acid-grafted-ethylene glycol) (P(MAA-g-EG)) and poly(methacrylic acid-grafted-ethylene glycol) functionalized with wheat germ agglutinin (P(MAA-g-EG) WGA). The pH-responsive release results demonstrated that the pH shift from the stomach to the small intestine can be used as a physiologic trigger to release insulin from P(MAA-g-EG) and P(MAA-g-EG) WGA microparticles, thus limiting release of insulin into the acidic environment of the stomach. Microplates were successfully treated with PGM to create a surface that allowed for specific binding between mucins and lectins. The 1% PGM treatment followed by a 2 h BSA blocking step gave the most consistent results when incubated with F-WGA. In addition, the PGM-treated microplates were shown to create specific interactions between F-WGA and the PGM by use of a competitive carbohydrate. The 1% PGM treated microplates were also used to show that adhesion was improved in the P(MAA-g-EG) WGA microparticles over the P(MAA-g-EG) microparticles. The interaction between the PGM-treated microplate and P(MAA-g-EG) WGA was again shown to be specific by adding a competitive carbohydrate, while the interaction between P(MAA-g-EG) and the PGM-treated microplate was nonspecific. Cellular monolayers were used as another method for demonstrating that the functionalized microparticles increase adhesion over the nonfunctionalized microparticles. This work has focused on improving the mucoadhesive nature of P(MAA-g-EG) by functionalizing these hydrogel carriers with wheat germ agglutinin (WGA) to create a specific mucosal interaction and then evaluating the potential of these carriers as oral insulin delivery systems by in vitro methods. From these studies, it is concluded that the addition of the WGA on the microparticles produces a specific adhesion to carbohydrate-containing surfaces and that P(MAA-g-EG) WGA shows great promise as an oral insulin delivery system.

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    • "Nanoparticles have been employed for oral drug carrier with objectives of improvement of bioavailability of drug with poor absorption characteristics , delivery of antigens to the GALT, for controlled or sustained release of drug, reduction of gastrointestinal mucosa irritation caused by drugs, and for assurance of stability of drugs in the gastrointestinal tract (Rieux et al. 2006). Numerous studies have demonstrated the ability of lectins to bind with intestinal mucosa and their efficiency for enhancing intestinal uptake of orally administered particles (Lehr et al.1992; Irache et al. 1996; Ezpeleta et al. 1999; Montisci et al. 2001; Kim et al. 2005; Mo and Lim 2005; Keegan et al. 2006; Wood et al. 2008; Kadiyala et al. 2009; Bies et al. 2004). Therefore, lectins can be grafted onto the surface of drug carrier and mediate an adhesive interaction between the carrier and the biological surface (Clark et al. 2000; Harmony and Cordes 1975). "
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    ABSTRACT: Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modify-ing its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanopar-ticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment effi-ciency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.
    Full-text · Article · Sep 2012 · Journal of Nanoparticle Research
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    • "Surface modification was suggested as an interesting approach in further improving the efficacy of mucoadhesive delivery systems [6] [7]. Attachment of specific functional entities (such as lectins , thiols, etc.) to the polymer surface has proved effective in enhancing their mucoadhesion behaviour [8] [9]. In general, bioadhesive polymers display non-specific interactions with mucus layers . "
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    ABSTRACT: In the present study thiol functionalized polymethacrylic acid-polyethylene glycol-chitosan (PCP)-based hydrogel microparticles were utilized to develop an oral insulin delivery system. Thiol modification was achieved by grafting cysteine to the activated surface carboxyl groups of PCP hydrogels (Cys-PCP). Swelling and insulin loading/release experiments were conducted on these particles. The ability of these particles to inhibit protease enzymes was evaluated under in vitro experimental conditions. Insulin transport experiments were performed on Caco-2 cell monolayers and excised intestinal tissue with an Ussing chamber set-up. Finally, the efficacy of insulin-loaded particles in reducing the blood glucose level in streptozotocin-induced diabetic rats was investigated. Thiolated hydrogel microparticles showed less swelling and had a lower insulin encapsulation efficiency as compared with unmodified PCP particles. PCP and Cys-PCP microparticles were able to inhibit protease enzymes under in vitro conditions. Thiolation was an effective strategy to improve insulin absorption across Caco-2 cell monolayers, however, the effect was reduced in the experiments using excised rat intestinal tissue. Nevertheless, functionalized microparticles were more effective in eliciting a pharmacological response in diabetic animal, as compared with unmodified PCP microparticles. From these studies thiolation of hydrogel microparticles seems to be a promising approach to improve oral delivery of proteins/peptides.
    Full-text · Article · Feb 2010 · Acta biomaterialia
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    • "There are limitations to the P(MAA-g-PEG) system that could be improved upon in order to develop an optimal system for oral protein delivery. The presence of PEG in the hydrogel has been shown to delay protein release upon reaching intestinal pH levels (Nakamura et al., 2004) and P(MAA-g-PEG) does not provide full protection in gastric pH levels where drug release should be inhibited (Besheer et al., 2006; Wood et al., 2008). Furthermore, Moriyama et al. have reported that insulin partitioned into a PEG phase at physiological pH levels in the presence of a negatively charged polyelectrolyte (Moriyama et al., 1999). "
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    ABSTRACT: The combination of materials design and advances in nanotechnology has led to the development of new therapeutic protein delivery systems. The pulmonary, nasal, buccal and other routes have been investigated as delivery options for protein therapy, but none result in improved patient compliances and patient quality of life as the oral route. For the oral administration of these new systems, an understanding of protein transport is essential because of the dynamic nature of the gastrointestinal tract and the barriers to transport that exist.Models have been developed to describe the transport between the gastrointestinal lumen and the bloodstream, and laboratory techniques like cell culture provide a means to investigate the absorption and transport of many therapeutic agents. Biomaterials, including stimuli-sensitive complexation hydrogels, have been investigated as promising carriers for oral delivery. However, the need to develop models that accurately predict protein blood concentration as a function of the material structure and properties still exists.
    Preview · Article · Nov 2009 · Chemical Engineering Science
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