Translating chitosan to clinical delivery of nucleic acid-based drugs
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hitosan: Sources and properties Chitosan is a linear co-polymer of D-glucosamine and N-acetylD-glucosamine in a β-(1–4) linkage, in which glucosamine is the predominant repeating unit (Figure 1). The molar fraction of N-acetylated units defines the degree of acetylation (DA) of a given chitosan, expressed in molar percentage of N-acetylated units. Chitosan is soluble in lightly acidic aqueous solutions. At a pH lower than its pKa, ranging from ∼6.5 to ∼7, chitosan is a polycation, and at pH 4.0 and below, it is completely protonated.1 The cationic character of chitosan under mildly acidic conditions and its ability to complex and condense nucleic acid-based molecules are the basis for its use as a transfection agent. Chitosan is mostly obtained by deacetylation of chitin. The most commonly used sources of chitin are the exoskeleton of crustaceans and squids. The chitin present in squid pens is easier to deacetylate due to the absence of inter-sheet hydrogen bonding.2 To conduct the deacetylation process with chitin from crustaceans, harsher conditions need to be applied, and the resulting chitosan typically has lower molecular weight. Consequently, this has been the preferred source of chitosan for use in nucleic acid delivery, as smaller and less disperse
complexes can be formed when chitosan of lower molecular weight is used.3,4 In either case, the fact that chitosan has an animal origin has raised some concerns, as it might be a potential source of allergens. More recently, chitosan isolated from the cell walls of mushrooms has become commercially available. As compared to chitosan obtained from marine animal resources, chitosan isolated from fungi cultured under controlled growing conditions presents higher reproducibility among batches and traceability,5 which makes it of interest for application in medical and pharmaceutical products. Irrespective of the original source, chitosan of ultrapure grade can now be obtained. In addition to its ability to condense nucleic acid-based molecules and protect them from endonuclease degradation, a particular advantage of chitosan over other polycations proposed as non-viral vectors for nucleic acids relies on its low cytotoxicity and biodegradability. Besides chemical hydrolysis, enzymes can also mediate chitosan degradation in vivo.6 Among these, lysozyme has been identified as the main one being involved in this process.7,8 It can hydrolyze partially N-acetylated chitosans, with the active site of the enzyme binding six sugar rings, being three consecutive
Carla Pereira Gomes, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre, Portugal; [email protected] Cátia Daniela Ferreira Lopes, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre, Portugal; [email protected] Pedro Miguel Duarte Moreno, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre, Portugal; [email protected] Aida Varela-Moreira, Instituto de Engenharia Biomédica, Universidade do Porto, Rua do Campo Alegre, Portugal;
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