Advances in Antiviral Delivery Systems and Chitosan-Based Polymeric and Nanoparticulate Antivirals and Antiviral Carriers

Abstract

Current antiviral therapy research is focused on developing dosage forms that enable highly effective drug delivery, providing a selective effect in the organism, lower risk of adverse effects, a lower dose of active pharmaceutical ingredients, and minimal toxicity. In this article, antiviral drugs and the mechanisms of their action are summarized at the beginning as a prerequisite background to develop relevant drug delivery/carrier systems for them, classified and briefly discussed subsequently. Many of the recent studies aim at different types of synthetic, semisynthetic, and natural polymers serving as a favorable matrix for the antiviral drug carrier. Besides a wider view of different antiviral delivery systems, this review focuses on advances in antiviral drug delivery systems based on chitosan (CS) and derivatized CS carriers. CS and its derivatives are evaluated concerning methods of their preparation, their basic characteristics and properties, approaches to the incorporation of an antiviral drug in the CS polymer as well as CS nanoparticulate systems, and their recent biomedical applications in the context of actual antiviral therapy. The degree of development (i.e., research study, in vitro/ex vivo/in vivo preclinical testing), as well as benefits and limitations of CS polymer and CS nanoparticulate drug delivery systems, are reported for particular viral diseases and corresponding antivirotics.

Keywords: antivirotic; chitosan; chitosan derivatives; chitosan nanocomposites; drug delivery; nanoparticles.

Figure 6

Synthesis of sulfated chitosan [217]. Reproduced with permission from Elsevier (Copyright © 2018).

Figure 1

Selected innovative dosage forms for antiviral therapy).

Figure 2

Different types of nanoparticles used as carriers for antiviral drugs.

Figure 3

Representative SEM images of TDF/FTC-NPs at the magnifications of (A) 15,250× (bar = 2 µm) and (B) 100,000× (bar = 0.5 µm). (C) Particle diameter distribution determined by SEM and corresponding Gauss fitting [82]. Reproduced with permission from Elsevier (Copyright © 2019).

Figure 4

Properties of chitosan and its biomedicinal applications.

Figure 5

Synthesis of quaternized chitosan (DMS–dimethylsulfate) [198]. Reproduced with permission from Elsevier (Copyright © 2015).

Figure 7

The reaction scheme for a CS derivative with sugar via the Maillard reaction [225]. Reproduced with permission from Elsevier (Copyright © 2016).

Figure 8

Crosslink reaction between chitosan and glutaraldehyde [228]. Reproduced with permission from Elsevier (Copyright © 2012).

Figure 9

Reaction scheme for the synthesis of β-CD-CS derivative [236]. Reproduced with permission from Elsevier (Copyright © 2013).

Figure 10

Preparation of COS from chitin and CS via physical, chemical, and enzymatic degradation methods [241]. Reproduced with permission from Elsevier (Copyright © 2021).

Figure 11

Different types of CS NPs in antiviral drug delivery systems.

Figure 12

Schematic representation of preparation methods of CS NPs applied for antivirals.

Figure 13

Main advantages of CS NPs in antiviral drug delivery systems.

Figure 14

Evaluation of cellular uptake of fluorescent N7G, N8G, and N9G samples (CS NPs loaded with foscarnet). HELF cells (human embryonic lung fibroblasts) were incubated with the formulation for the periods indicated and then analyzed by confocal laser scanning microscopy without fixation at 1, 3, and 24 h post-treatment (hpt). The upper panels show fluorescent images while the lower panels show fluorescent images merged with phase-contrast images [256]. Reproduced with permission from Elsevier (Copyright © 2014).

Figure 15

Representative SEM (scanning electron microscope) images and fiber size distributions (n = 300) of (a) drug-free nanofibrous mat (NF) and (b) tenofovir disoproxil fumarate-loaded nanofibrous mat (TDF-NF) prepared with CS and PEO at a ratio of 1:4 (w/w). SEM images magnifications: ×1000 and ×10,000 [258]. Reproduced with permission from Elsevier (Copyright © 2022).

Figure 16

Probable mechanism of antiviral activity by the nanocomposites [245]. Reproduced with permission from Elsevier (Copyright © 2022).

Figure 17

FESEM (field emission scanning electron microscopy) images of cell morphology of L929 cells exposed to the SPION NPs as well as GO/SPION nanocomposites in the presence or absence of a constant magnet [255]. Reproduced with permission from Elsevier (Copyright © 2022).

Figure 18

Properties of ACV-loaded SBE-β-CD (sulfobutyl ether-β-cyclodextrin)-decorated chitosan nanodroplets (NDs) [238]. Reproduced with permission from Elsevier (Copyright © 2020).