Intra-articular drug delivery systems for osteoarthritis therapy: shifting from sustained release to enhancing penetration into cartilage

Abstract

Osteoarthritis (OA) is a progressive chronic inflammation that leads to cartilage degeneration. OA Patients are commonly given pharmacological treatment, but the available treatments are not sufficiently effective. The development of sustained-release drug delivery systems (DDSs) for OA may be an attractive strategy to prevent rapid drug clearance and improve the half-life of a drug at the joint cavity. Such delivery systems will improve the therapeutic effects of anti-inflammatory effects in the joint cavity. Whereas, for disease-modifying OA drugs (DMOADs) which target chondrocytes or act on mesenchymal stem cells (MSCs), the cartilage-permeable DDSs are required to maximize their efficacy. This review provides an overview of joint structure in healthy and pathological conditions, introduces the advances of the sustained-release DDSs and the permeable DDSs, and discusses the rational design of the permeable DDSs for OA treatment. We hope that the ideas generated in this review will promote the development of effective OA drugs in the future.

Keywords: Drug delivery system; intra-articular; osteoarthritis; permeability; sustained-release.

Figure 1.

Three types of micro/nano drug carriers: suspension drug carriers, binding drug carriers, permeable drug carriers, and their characteristics.

Figure 2.

Structural changes of joints before and after OA and schematic diagram of aggrecan. Structural comparison of healthy joints and osteoarthritis (OA) joints. OA involves synovitis, cartilage degeneration, osteophyte formation and joint pain. Small molecular GAG is like a mane on a test tube brush. It binds to the core protein by a covalent bond and radiates outward with the core protein in the center, and then binds to the hyaluronic acid trunk to form an aggrecan. (Created with BioRender.com).

Figure 3.

Schematic diagram of DDSs retention and clearance characteristics of different intra-articulate osteoarthritis (OA) drug delivery systems. Free drugs, hydrogels, nanoparticles, and microparticles could retain in the joint cavity for hours, weeks, and months, respectively. Macromolecules (>10 kDa) were eliminated through the lymphatics, while small molecules (<10 kDa) were eliminated through blood vessels. (Created with BioRender.com).

Figure 4.

Characterization of siNP-μPLs. (A) Particle size distribution of Cy5-siNPs before and after acetonitrile exposure. (B) MicroPlate size distribution. (C) μPLs loaded with Cy5-siNPs SEM image. (D) PVA template containing Cy5-siNPs (red) dispersed within PLGA paste (yellow-green) confocal microscopy image. (E) Harvested Cy5-siNP loaded CURC-μPLs confocal microscopy image. (F) Cy5-siNP-μPLs without CURC (red) confocal microscopy image. Reprinted with permission from ACS Publications (Bedingfield et al., 2021).

Figure 5.

Multi-arm avidin drug delivery system. (A) The nano-constructed multi-arm avidin and the small molecular drug dexamethasone (mAV-Dex) was assembled through the hydrolyzable ester conjugates succinic acid, glutaric acid and phthalic anhydride. The particles penetrate through the cartilage quickly through electrostatic action and reversibly bind to articular cartilage to transform it into a drug repository, (B) Drug release profiles of Dex from different formulations. (C) Histological and immunohistochemical analysis of cartilage. After 16 days of culture, the cartilage explants were stained with lycopene-O and solid green (GAG) or type II collagen immunostaining to determine the protective effect of mAV-Dex on cartilage matrix. Reprinted with permission from Elsevier (He et al., 2020).

Figure 6.

PEGylated dendrimer-IGF-1 conjugates were designed for penetrating cartilage for chondrocyte drug delivery. (A) Schematic illustration for the fates of particles with different sizes and surface potential after intra-articular injection. (B) Chemical structure of G4 PAMAM dendrimer. (C) IVIS images of rat knee joints after intra-articular administration of fluorescent IGF-1 for 28 days. (D) Quantitative analysis of IVIS images over time. (E) Time at therapeutic concentration for each delivery method. (F) 3 D reconstruction of multi photon microscopy images of cartilage at day 6 post injection. Reprinted with permission from AAAS (Geiger et al., 2018).

Figure 7.

Permeation and retention characteristics of ctLP-NPs in the cartilage. (a) Representative fluorescence images of DiD-labeled LP-NPs (top) or ctLP-NPs (bottom) in femoral head sections. (b) Relative fluorescence intensity of cartilage incubated with LP-NPs or ctLP-NPs for 24 h. (c) Quantitative analysis of penetration depth of nanoparticles. (d) Fluorescence images of ctLP-NPs and LP-NPs at different time points. (e) Fluorescence intensity of the nanoparticles in the knee joints. Reprinted with permission from Wiley (Ai et al., 2021).

Figure 8.

Single-walled carbon nanotubes with PEG modification (PEG-SWCNT) were prepared for antisense oligonucleotide delivery into chondrocytes. (A) schematic introduction for the fate of PEG-SWCNT after intra-articular injection. (B) Joint sections stained with Safranin-O and counterstained with Fast green and Hematoxylin. (C) IL-1 and TNF-α expressions were examined by immunohistochemical assay. Reprinted with permission from ACS publications (Sacchetti et al., 2014).

Figure 9.

(A) Confocal images of non-functionalized Cd-Se QDs after 24 h absorption in normal cartilage explants. (B) Confocal images of non-functionalized Cd-Se QDs after 24 h desorption in normal cartilage explants. (C) Confocal images of amine-functionalized QDs after 24 h absorption in normal cartilage explants. (D) Confocal images of amine-functionalized QDs after 24 h desorption in normal cartilage explants. (E) Confocal images of non-functionalized Cd-Se QDs after 24 h absorption in trypsin treated cartilage explants. (F) Confocal images of non-functionalized Cd-Se QDs after 24 h desorption in trypsin treated cartilage explants. (G) Confocal images of amine-functionalized QDs after 24 h absorption in trypsin treated cartilage explants. (H) Confocal images of amine-functionalized QDs after 24 h desorption in trypsin treated cartilage explants. (I) Quantitative analysis of cadmium in the bath of Cd-Se red and green QDs that were absorbed into normal and trypsin treated bovine cartilage explants in 24 h. (J) Quantitative analysis of cadmium absorbed in 24 h that was retained inside the cartilage explants after 24 h desorption into 1X PBS for red and green QDs and into 10X PBS for green QDs only. Reprinted with permission from Elsevier (Bajpayee et al., 2014).

Figure 10.

The relationship of avidin half-life with GAG concentration or density. (A) In different tissues, the relation of GAGs concentration with Avidin half-lives. (B) The correlation of Avidin half-lives with GAGs concentration* tissue thickness square for different tissue types. Reprinted with permission from Bajpayee et al. (2015).

Figure 11.

In the future, the enhanced sustained release of DDS to the enhanced permeable DDS is expected to advance into clinical practice to improve the prevention or treatment of osteoarthritis.