The major impediment to the delivery of therapeutics to the brain is the presence of the blood-brain barrier (BBB). The BBB allows for the entrance of essential nutrients while excluding harmful substances, including most therapeutic agents; hence, brain disorders, especially tumours, are very difficult to treat. Chitosan is a well-researched polymer that offers advantageous biological and chemical properties, such as mucoadhesion and the ease of functionalisation. Chitosan-based nanocarriers (CsNCs) establish ionic interactions with the endothelial cells, facilitating the crossing of drugs through the BBB by adsorptive mediated transcytosis. This process is further enhanced by modifications of the structure of chitosan, owing to the presence of reactive amino and hydroxyl groups. Finally, by permanently binding ligands or molecules, such as antibodies or lipids, CsNCs have showed a boosted passage through the BBB, in both in vivo and in vitro studies which will be discussed in this review.
Clustered regularly interspaced short palindromic repeat (CRISPR) and the associated Cas endonuclease (Cas9) is a cutting-edge genome-editing technology that specifically targets DNA sequences by using short RNA molecules, helping the endonuclease Cas9 in the repairing of genes responsible for genetic diseases. However, the main issue regarding the application of this technique is the development of an efficient CRISPR/Cas9 delivery system. The consensus relies on the use of non-viral delivery systems represented by nanoparticles (NPs). Chitosan is a safe biopolymer widely used in the generation of NPs for several biomedical applications, especially gene delivery. Indeed, it shows several advantages in the context of gene delivery systems, for instance, the presence of positively charged amino groups on its backbone can establish electrostatic interactions with the negatively charged nucleic acid forming stable nanocomplexes. However, its main limitations include poor solubility in physiological pH and limited buffering ability, which can be overcome by functionalising its chemical structure. This review offers a critical analysis of the different approaches for the generation of chitosan-based CRISPR/Cas9 delivery systems and suggestions for future developments.
with a DDA ranging between 70% and 85% becomes soluble in dilute acidic solutions such as acetic acid or formic acid. [1] Indeed, the primary amino groups of chitosan have a pK a of ≈6.5 so that, following protonation, they confer upon chitosan the feature of solubility in weakly acidic aqueous solution, allowing the polymer to be easily manipulated. [3] The DDA of chitosan plays a key role in determining its physicochemical properties, which are affected by the proportion of free amino groups (-NH 2) remaining on the polymeric chain upon deacetylation. Both the primary amino and secondary hydroxyl groups behave as reactive functional groups on chitosan. Indeed, these groups allow chitosan to be susceptible to chemical modifications such as acylation, tosylation, quaternization, alkylation, and O-carboxymethylation. [4] As a result, the chitosan structure can be functionalized and optimized to improve drug loading or release. [5] Chitosan-based nanocarriers (ChNCs), including nanoparticles (NPs), micelles, or polyplexes, have received significant attention for their numerous advantageous features such as natural sourcing, biodegradability, easy functionalizations, and low toxicity. [6] The mucoadhesive property of chitosan is key for drug delivery purposes. [7] Indeed, chitosan is a positively charged polymer that can form electrostatic bonds with the negatively charged mucous layer, made of mucin glycoproteins that cover the epithelial cells of the mucosa. The establishment of these bonds allows drug-loaded ChNCs to exhibit higher absorption and retention times at the target, while reducing dosing frequency. [8] Furthermore, chitosan is used as permeation enhancer since increases the uptake of the drugs through a transient and reversible opening of the tight junctions (TJs) protecting the paracellular pathway between endothelial cells in the so-called blood-brain barrier (BBB). [9] This is due to F-actin depolymerization and leakage of the TJ protein zonula occludens-1. [7] The small size and large surface area of NCs allow their passage through biological membranes, such the BBB, and accumulation at the intracellular (such as lysosomes) or intranuclear (DNA or RNA) target site. [10] ChNCs are distinctive for their ability to protect the encapsulated therapeutic agent and improve its bioavailability by altering the pharmacokinetics. [10] The endocytic mechanisms responsible for the internalization of ChNCs as a drug delivery system may differ according to the cell type and the drug to be delivered. Numerous biological and pharmacological properties characterize chitosan. These include antitumor, antifungal, antioxidant, immunoenhancing, and wound healing properties. [11] Furthermore, chitosan is Chitosan-based nanocarriers (ChNCs) are considered suitable drug carriers due to their ability to encapsulate a variety of drugs and cross biological barriers to deliver the cargo to their target site. Fluorescein isothiocyanatelabeled chitosan-based NCs (FITC@ChNCs) are used extensively in biomedical and pharmacological...
Oral administration of drugs is one of the most patient-friendly drug delivery routes. However, drug bioavailability via the oral route remains poor due to the harsh gastrointestinal environment. In recent years, many nanocarriers have been designed to overcome this limitation. Among those, chitosan nanoparticles (ChNPs) have proved to be quite a popular choice. Here, we highlight the use of fluorescein isothiocyanate-tagged ChNPs (FITC@ChNPs) as an invaluable tool to monitor the fate of ChNPs encapsulating oral drugs, leading to an in-depth understanding of drug biodistribution and, in turn, shedding a light on ways to improve bioavailability.
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