Hyaluronic Acid-Based Nanosystems for CD44 Mediated Anti-Inflammatory and Antinociceptive Activity

Abstract

The nervous and immune systems go hand in hand in causing inflammation and pain. However, the two are not mutually exclusive. While some diseases cause inflammation, others are caused by it. Macrophages play an important role in modulating inflammation to trigger neuropathic pain. Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan that has a well-known ability to bind with the cluster of differentiation 44 (CD44) receptor on classically activated M1 macrophages. Resolving inflammation by varying the molecular weight of HA is a debated concept. HA-based drug delivery nanosystems such as nanohydrogels and nanoemulsions, targeting macrophages can be used to relieve pain and inflammation by loading antinociceptive drugs and enhancing the effect of anti-inflammatory drugs. This review will discuss the ongoing research on HA-based drug delivery nanosystems regarding their antinociceptive and anti-inflammatory effects.

Keywords: CD44; anti-inflammatory; antinociceptive; hyaluronic acid; nanosystems.

Figure 1

Molecular weights of hyaluronic acid in different parts of the human body.

Figure 2

Mechanism of action of HYAL2 on the degradation of HMW HA to LMW HA.

Figure 3

HA-based nanosystems with factors affecting their synthesis and production.

Figure 4

Schematic illustration of the absorbable thioether grafted hyaluronic acid nanofibrous hydrogel for synergistic modulation of the inflammation microenvironment to accelerate chronic diabetic wound healing. Illustration of the preparation procedure of FHHA-S/Fe, dressing of FHHA-S/Fe on full-thickness wound model in diabetic C57BL/6 mouse, and the mechanism of FHHA-S/Fe for enhanced chronic wound healing effect. Copyright Wiley-VCH Verlag GmbH. Reprinted with permission from [82].

Figure 5

(a) Scheme of the fabrication of LBL-LA/NLCs. (b) In vitro permeation profiles of LA from different formulations. (c) TEM images of the structural morphology of the LBL-LA/NLCs and LA/NLCs. Image 3-2 shows different shades of gray that indicate the multiple layers of coating from C being the innermost and A being the outermost. (d) In vivo TFL test for the evaluation of the local anesthetic effects of LA-containing formulations. Adapted with permission from [89].

Figure 6

(a) Schematic illustration of pDNA encapsulation into HA-PEI nanoparticles for the re-polarization of pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages. (b) Size distribution of HA-PEI/pDNA (9:1) in PBS by DLS. (c) TEM image of HA-PEI/pDNA in PBS (9:1). (d) Confocal microscopy and FACS analysis of CD44 expression in J774A.1 macrophages. (e) Uptake of HA-PEI/pDNA nanoparticles in J774A.1 macrophages. Reprinted with permission from [91].

Figure 7

Characteristics of HA-NPs. (A) Schematic illustration of HA-NPs for treatment of OA. (B) TEM images and size distribution of HA-NP. Scale bar, 100 nm. (C) Time-dependent changes in particle size and surface charge of HA-NP in PBS and DMEM. Data are presented as mean ± SEM (n = 5). (D) Generation of N-acetyl-glucosamine after treatment of 1 mg/mL free HAs (10 kDa LMW and 2000 kDa HMW) or HA-NP with 100 IU/ml HYAL-II. Data are presented as mean ± SEM (n = 4). *** p < 0.001. (E) Representative serial images (25–41 μm depth at intervals of 4 μm) from the femoral cartilages after i.a. injection of Cy5.5 and Cy5.5-labeled HA-NP into normal mice. Scale bars, 100 μm. (F) Three-dimensional lateral view of the femoral cartilages after i.a. injection of Cy5.5 and Cy5.5-labeled HA-NP into normal mice. Scale bars, 100 μm. Reprinted with permission from [111].