Chitosan—A versatile semi-synthetic polymer in biomedical applications

Nanocarriers offer unique possibilities to overcome cellular barriers in order to improve the delivery of various drugs and drug candidates, including the promising therapeutic biomacromolecules (i.e., nucleic acids, proteins). There are various mechanisms of nanocarrier cell internalization that are dramatically influenced by nanoparticles' physicochemical properties. Depending on the cellular uptake and intracellular trafficking, different pharmacological applications may be considered. This review will discuss these opportunities, starting with the phagocytosis pathway, which, being increasingly well characterized and understood, has allowed several successes in the treatment of certain cancers and infectious diseases. On the other hand, the non-phagocytic pathways encompass various complicated mechanisms, such as clathrin-mediated endocytosis, caveolae-mediated endocytosis and macropinocytosis, which are more challenging to control for pharmaceutical drug delivery applications. Nevertheless, various strategies are being actively investigated in order to tailor nanocarriers able to deliver anticancer agents, nucleic acids, proteins and peptides for therapeutic applications by these non-phagocytic routes.

Nanocarriers’ entry into the cell: relevance to drug delivery

The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded as safe for human dietary use and approved for wound dressing applications. Chitosan has been used as a carrier in polymeric nanoparticles for drug delivery through various routes of administration. Chitosan has chemical functional groups that can be modified to achieve specific goals, making it a polymer with a tremendous range of potential applications. Nanoparticles (NP) prepared with chitosan and chitosan derivatives typically possess a positive surface charge and mucoadhesive properties such that can adhere to mucus membranes and release the drug payload in a sustained release manner. Chitosan-based NP have various applications in non-parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections which will be exemplified in this review. Chitosan shows low toxicity both in vitro and some in vivo models. This review explores recent research on chitosan based NP for non-parenteral drug delivery, chitosan properties, modification, toxicity, pharmacokinetics and preclinical studies.

https://www.mdpi.com/1999-4923/9/4/53/pdf

An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery

Formulation strategy and use of excipients in pulmonary drug delivery

Nanoparticles for drug delivery to the lungs.

The aim of this study was to compare the effect of liquid-covered culture (LCC) and air-interfaced culture (AIC) on Calu-3 cell layer morphology and permeability, thus assessing the fitness of these culture systems as models of airway epithelium barrier function. Cell layers were grown on 0.33 cm2 Transwell polyester cell culture supports. Cell layers grown using LCC and AIC were evaluated by using light and electron microscopy, transepithelial electrical resistance (TER), and permeability to the transepithelial flux of fluorescein sodium (flu-Na), and by varying molecular weight dextrans labeled with fluorescein isothiocyanate (FITC-dex). The tight junction protein, zona occludens protein-1 (ZO-1), was visualized by confocal microscopy and apical glycoprotein secretions were identified by using alcian blue. Cells grown via AIC produced a more columnar epithelium with a more rugged apical topography and greater glycoprotein secretion compared to cells grown via LCC. Apical protrusions appearing to be cilia-like structures were observed on occasional cells using AIC, but typical airway ciliated cell phenotypes were not produced under either condition. Secretory granules were observed in cells cultured under both conditions. Cells cultured using LCC exhibited higher levels of ZO-1 protein than the AIC counterpart. The maximal TER of cells using LCC, 1,086 ± 113 Ω cm2 at 11–16 days, was significantly greater than the TER of cells cultured using AIC, 306 ± 53 Ω cm2 at 11–13 days. Apparent permeability (P
 app
 ) values for the transport of flu-Na using LCC and AIC were 1.48 ± 0.19×10−7 and 3.36 ± 0.47×10−7 cm s−1, respectively. Transport rates of flu-Na and FITC-dex were inversely proportional to molecular weight, and were significantly lower (p < 0.05) in cell layers grown using LCC than AIC. Renkin analysis fitted the data to single pore populations of radii 7.7 and 11.0 nm for LCC and AIC, respectively. Distinct differences in morphology and permeability result when Calu-3 cells are grown using AIC or LCC. Cells cultured using AIC generate a model more morphologically representative of the airway epithelium than cells cultured using LCC.

Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier.

Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro.

The permeability of large molecular weight solutes following particle delivery to air-interfaced cells that model the respiratory mucosa.

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle propertie...

Christopher I. Grainger

Papers

Culture of Calu-3 cells at the air interface provides a representative model of the airway epithelial barrier.

Chitosan nanoparticles are compatible with respiratory epithelial cells in vitro.

The permeability of large molecular weight solutes following particle delivery to air-interfaced cells that model the respiratory mucosa.

Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence.