Chitosan-Polyphenol Conjugates for Human Health

Abstract

Human health deteriorates due to the generation and accumulation of free radicals that induce oxidative stress, damaging proteins, lipids, and nucleic acids; this has become the leading cause of many deadly diseases such as cardiovascular, cancer, neurodegenerative, diabetes, and inflammation. Naturally occurring polyphenols have tremendous therapeutic potential, but their short biological half-life and rapid metabolism limit their use. Recent advancements in polymer science have provided numerous varieties of natural and synthetic polymers. Chitosan is widely used due to its biomimetic properties which include biodegradability, biocompatibility, inherent antimicrobial activity, and antioxidant properties. However, due to low solubility in water and the non-availability of the H-atom donor, the practical use of chitosan as an antioxidant is limited. Therefore, chitosan has been conjugated with polyphenols to overcome the limitations of both chitosan and polyphenol, along with increasing the potential synergistic effects of their combination for therapeutic applications. Though many methods have been evolved to conjugate chitosan with polyphenol through activated ester-modification, enzyme-mediated, and free radical induced are the most widely used strategies. The therapeutic efficiency of chitosan-polyphenol conjugates has been investigated for various disease treatments caused by ROS that have shown favorable outcomes and tremendous results. Hence, the present review focuses on the recent advancement of different strategies of chitosan-polyphenol conjugate formation with their advantages and limitations. Furthermore, the therapeutic applicability of the combinatorial efficiency of chitosan-based conjugates formed using Gallic Acid, Curcumin, Catechin, and Quercetin in human health has been described in detail.

Keywords: antioxidant; chitosan; human health; oxidative stress; polyphenol.

Figure 1

Pictorial representation of different classes and subclasses of polyphenols, including their chemical structures and sources, adapted from Ref. [11].

Figure 2

Mechanism of action underlying the therapeutic activities of phenolics in different diseases, adapted from Ref. [52].

Figure 3

Flow diagram of limitations of chitosan and polyphenol, and advantages of chitosan-polyphenol.

Figure 4

Proposed mechanism for chemical synthesis of polyphenol-chitosan conjugate (A) using only EDC, adapted with permission from Ref. [101], © 2022 The Society for Biotechnology, Japan, Elsevier B.V. (B) using EDC/NHS, adapted with permission from Ref. [102], © 2022 The Royal Society of Chemistry.

Figure 5

Proposed mechanism for polyphenol-chitosan conjugate through (A) enzyme-mediated strategy, adapted with permission from Ref. [103], © 2022 Elsevier B.V., and (B) free radical induced reaction, adapted from Ref. [93].

Figure 6

Overview of chitosan-polyphenol conjugates for treatment of various diseases.

Figure 7

Ester modification synthesis of chitosan-GA conjugation.

Figure 8

(I) Antioxidant activity of chitosan hydrogels enriched with GA (a), PG (b), and without tannins (c) before and after mineralization. (II) Antibacterial activity of chitosan hydrogels enriched with GA and PG. (a) Growth of E. coli in liquid culture in presence of hydrogels (b) Relative colony-forming ability of E. coli on agar after incubation with hydrogels (CFU counts were normalized to values at time 0 h). Mean values are shown (n = 4). Error bars show standard deviation, adapted with permission from Ref. [112], © 2022 Elsevier Ltd.

Figure 9

Radical Scavenging Activity obtained with the DPPH test, the values are expressed in percentage, and they were evaluated at 4 and 24 h of soaking in the DPPH solution. The bars that share at least one letter are not significantly different (p < 0.05 calculated with Tukey’s test), adapted with permission from Ref. [88], © 2022 American Chemical Society.

Figure 10

Chemical synthesis of chitosan-curcumin conjugation, adapted with permission from Ref. [122], © 2022 Elsevier Ltd.

Figure 11

Images of HeLa cells as visualized under inverted fluorescent microscope, adapted with permission from Ref. [117], © 2022 Elsevier Inc.

Figure 12

In vivo efficacy of curcumin-PBCA NPs and empty PBCA NPs in HepG2 hepatocellular cancer xenograft. (A) The images of HepG2 xenograft-bearing mice treated with curcumin-PBCA NPs, empty PBCA NPs and control tumor; changes in body weight of animals (B) and tumor volume (C) as a function of time in subcutaneous HepG2 xenograft. Straight line: physiological saline; dashed line: empty PBCA NPs; double dot dashed line: curcumin PBCA NPs, adapted with permission from Ref. [118], © 2022 Elsevier B.V.

Figure 13

% Apoptosis of SCC25 cells by CUR determined by Annexin V-FITC/PI staining and flow cytometry (i) control cells, (ii) CUR, (iii) CUR-CS, (iv) CUR-CD-CS, adapted with permission from Ref. [120], © 2022 Elsevier B.V.

Figure 14

(A) Representative photographs of wounds following full thickness skin excision at 3, 6, 9, 12, and 15 days after surgery; (B) Percentage wound closure is presented at the indicated time points, adapted with permission from Ref. [121], © 2022 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater.

Figure 15

Free radical mechanism of chitosan-catechin conjugation, adapted with permission from Ref. [126], © 2022 Elsevier Ltd.

Figure 16

Comparative effects of nonencapsulated EGCG and nano-EGCG on markers of apoptosis, cell cycle, and Proliferation markers in tumors isolated from nude mice. (A) Protein expression of Bax, Bcl2, and the Bax/Bcl2 ratio and PARP. (B) Protein expression of Cyclins A, B1, E, E2, CDK 4, and CDK6. The cells were treated with each agent and harvested 24 h after treatment. Equal loading was confirmed by stripping the membrane and reprobing it with β-actin. Each experiment was repeated twice with similar results. (C) Effect of the treatments on expression of Ki-67 and PCNA in tumor tissues isolated from athymic nude mice. Tumor sections were stained using specific antibodies as detailed in Materials and Methods. Counterstaining was performed with hematoxylin. Scale bar, 50 μm. Photomicrographs (magnification, 20×) show representative pictures from two independent samples, adapted with permission from Ref. [128], © 2022 Elsevier Inc.

Figure 17

(I) (A) Effect of Chit-nanoEGCG on expression of Ki-67 and PCNA in tumor tissues of athymic nude mice. Tumor sections from athymic nude mice were stained using specific antibodies as detailed in Materials and Methods. Counterstaining was performed with hematoxylin. Scale bar, 50 μm. Photomicrographs (magnification, ×20) show representative pictures from two independent samples. (B) Proliferation index for Ki-67 (left panel) and PCNA (right panel) is shown. * p < 0.05 and ** p < 0.01 and *** p < 0.001, versus control group. (II) (A) Effect of Chit-nanoEGCG on expression of CD31 and VEGF in tumor tissues of athymic nude mice. Tumor sections from athymic nude mice were stained using specific antibodies as detailed in Materials and Methods. Counterstaining was performed with hematoxylin. Scale bar, 50 μm. Photomicrographs (magnification, 20×) show representative pictures from two independent samples. (B) Tumor microvessel density (left panel) and VEGF immunoreactivity score (right panel) was scored as 0+ (no staining), 1+ (weak staining), 2+ (moderate staining), 3+ (strong staining), and 4+ (very strong staining). * p < 0.05 and ** p < 0.01 and *** p < 0.001, versus control group, adapted with permission from Ref. [130], © 2022 Oxford University Press.

Figure 18

Synthesis of chitosan-quercetin conjugate by free radical strategy, adapted with permission from Ref. [94], © 2022 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 19

Photographic evaluation of wound closure on different days of healing in control and CF and Q-CF treated rats, adapted with permission from Ref. [134], © 2022 Elsevier B.V.

Figure 20

Histological sections of adenocarcinomas from Wistar rat colon. Paraffin embedded sections were stained with H&E. (A) Cancerous control group, (B) Treatment group; cancerous rats were administered by Qu loaded CS NPs through enema. The black arrows indicate apoptotic bodies and the white and green arrows indicate mitotic cells and microvasculars, respectively (400×) Adapted from Ref. [137].