Send Orders for Reprints to reprints@benthamscience.ae Current Pharmaceutical Design, 2015, 21, 000-000 1 1381-6128/15 $58.00+.00 © 2015 Bentham Science Publishers Mucoadhesive Chitosan Derivatives as Novel Drug Carriers Mohammad Ariful Islam 1,2+ , Tae-Eun Park 3+ , Emma Reesor 1,4 , Kondareddy Cherukula 5 , Anwarul Hasan 6,7,8 , Jannatul Firdous 3 , Bijay Singh 3 , Sang-Kee Kang 9 , Yun-Jaie Choi 3 , In-Kyu Park 5** and Chong-Su Cho 3* 1 Laboratory of Nanomedicine and Biomaterials, Harvard Medical School, Boston, MA 02115, USA; 2 Laboratory for Nanoengineering & Drug Delivery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; 3 Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea; 4 Department of Nanotechnology Engineering, University of Waterloo, Waterloo, ON N2L 3G1, Canada; 5 Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-746, Korea; 6 Biomedical Engineering, and Department of Mechanical Engineer- ing, Faculty of Engineering and Architecture, American University of Beirut, Beirut 1107 2020, Lebanon; 7 Center for Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Massachusetts 02139, USA; 8 Harvard-MIT Division of Health Sciences and Technology, Massachu- setts Institute of Technology, Cambridge, Massachusetts 02139, USA; 9 Institute of Green-Bio Science and Tech- nology, Seoul National University, Kangwon-do 232-916, Korea Abstract: Chitosan on its own is a well-established natural polymer and is widely regarding as a biodegradable, biocompatible and non- toxic material for drug delivery applications. Although unmodified chitosan has some mucoadhesive properties on its own its bioavail- ability is limited due to its short retention time in the body. Moreover, the high solubility of chitosan at acidic pH levels limits its use for mucosal drug delivery (especially through the oral route). Chemically-modified mucoadhesive chitosan, especially thiolated chitosan, has arisen as an alternative to create novel mucosal drug delivery systems. The mucoadhesive properties that are conferred to the thiolated chitosan certainly set this novel class of second or third-generation thiomers apart. To understand the significance of mucoadhesive chito- san, we first present the mechanism of mucoadhesion and provide comprehensive coverage of description of a variety of chemical modi- fications to prepare mucoadhesive thiolated chitosan derivatives. We then present the plethora of applications of these modified chitosan variants in a wide range of drug delivery fields, including the delivery of antigens, proteins and genes through a variety of routes, includ- ing oral, nasal, pulmonary, vaginal and others. By presenting the range of applications for mucoadhesive chitosan drug carriers we herein demonstrate that chemically-modified thiolated chitosan is a versatile and effective material for a new class of drug delivery vehicles. Keywords: ??????????????. INTRODUCTION Chitosan is a widely used polymer that can be synthesized from the naturally occurring material chitin, the most plentiful natural amino polysaccharide. It is similar in structure to cellulose; made from linear -(14)-linked monosaccharides [1]. Chitin is most commonly sourced from crab and shrimp shells (from food indus- trial processes) and is isolated by dissolving the calcium carbonate in the shells and then treating with sodium hydroxide to create chi- tosan as the N-deacetylated derivative [2]. It can be used for a vari- ety of applications, including contact lenses [3], photography [4] and solid state batteries [5] and most importantly for diverse medi- cal applications. In the biomedical field there is a range of applica- tions of chitosan including artificial skin [6, 7], wound dressings [8- 10] and drug delivery [11-14]. Its widespread biomedical use is due to its excellent bioavailability, biocompatibility, low toxicity and adhesive capabilities. Of all these applications, drug delivery is a very appealing field because of this versatile material’s mucoadhe- sive abilities and favourable release profile. Chitosan has been used widely in its unmodified form for this purpose to encapsulate a variety of drugs and many reports have described the design and application of (unmodified) chitosan formulation for drug delivery [1, 15-20]. However, chitosan in its unmodified form also has *Address correspondence to these authors at the Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea; Tel: + 82-2-880-4868; Fax: + 82-2-875-2494; E-mail: chocs@snu.ac.kr ** 5 Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-746, Korea; E-mail: pik96d@gmail.com or pik96@chonnam.ac.kr + These authors contributed equally to the work. serious drawbacks, most importantly its high solubility at acidic pH levels [21] and rapid clearance from the body [22]. The use of chitosan in its unmodified form can be thought of a first-generational use in the drug delivery field. Chitosan by itself has mucoadhesive properties that can be invaluable for drug deliv- ery. In brief, vehicles made of a mucoadhesive substance-loaded with an active agent can remain at the target site for an extended period of time and help to ensure that the drug can confer its in- tended effect. This is particularly important for mucosal (especially, oral and nasal) drug delivery since any administered substances must successfully interact with mucosal membranes to remain at the site for a longer period to provide maximum drug effect. Many researchers have pushed this further and have developed useful chemical modifications of chitosan, which can be referred to as second-generation chitosan derivatives. Specifically, thiolated chitosan has been developed by a number of groups using different strategies and chemical agents to immobilize the thiol groups. The most commonly used chemical modifications, chitosan-TGA and chitosan-TBA (thioglycolic acid and 4-thiobutylamidine respec- tively), entail the use of 2-iminotiolane HCl with a variety of rea- gents to create mucoadhesive chitosan with optimized thiol content [23, 24]. As will be described later in detail, these modified chito- san derivatives can also be used as hybrid formulations with other materials such as polymeric cores [25, 26], alginate [27, 28] and clay composites, to specifically increase the mucoadhesive abilities of these substrates. Using the different variants researchers have been able to synthesize particles which favourably adhere to very specific sites or environments, which is quite a useful development for targeted therapy. Please provide corresponding author(s) photograph size should be 4" x 4" inches