Nanoparticle-Cartilage Interaction: Pathology-Based Intra-articular Drug Delivery for Osteoarthritis Therapy

Abstract

Osteoarthritis is the most prevalent chronic and debilitating joint disease, resulting in huge medical and socioeconomic burdens. Intra-articular administration of agents is clinically used for pain management. However, the effectiveness is inapparent caused by the rapid clearance of agents. To overcome this issue, nanoparticles as delivery systems hold considerable promise for local control of the pharmacokinetics of therapeutic agents. Given the therapeutic programs are inseparable from pathological progress of osteoarthritis, an ideal delivery system should allow the release of therapeutic agents upon specific features of disorders. In this review, we firstly introduce the pathological features of osteoarthritis and the design concept for accurate localization within cartilage for sustained drug release. Then, we review the interactions of nanoparticles with cartilage microenvironment and the rational design. Furthermore, we highlight advances in the therapeutic schemes according to the pathology signals. Finally, armed with an updated understanding of the pathological mechanisms, we place an emphasis on the development of "smart" bioresponsive and multiple modality nanoparticles on the near horizon to interact with the pathological signals. We anticipate that the exploration of nanoparticles by balancing the efficacy, safety, and complexity will lay down a solid foundation tangible for clinical translation.

Keywords: Articular cartilage; Drug delivery; Nanomedicine; Nanoparticle; Osteoarthritis.

Fig. 1

Pathological changes of OA. a Drawing of structural changes and signaling pathways of OA. b Histologic cross section of normal cartilage (left picture) and cartilage affected by end-stage OA (right picture). End-stage OA is characterized by articular cartilage injury, chondrocyte proliferation and hypertrophy, tidemark duplication, subchondral bone thickening, and vascular invasion. Reproduced with permission [277]. Copyright 2016, Elsevier Inc. Abbreviations: IL-1β, interleukin 1β; IL-6, interleukin 6; ADAMTS-4, a disintegrin and metalloproteinase with thrombospondin-like motifs 4; ADAMTS-6, a disintegrin and metalloproteinase with thrombospondin-like motifs 6; MMP-1, matrix metalloproteinases-1; MMP-13, matrix metalloproteinases-13; OA, osteoarthritis

Fig. 2

Properties and application schemas of nanoparticles for the treatment of cartilage disease. a Size of nanoparticles compared with different components in joint. b Application schemas of nanoparticles for intra-articular delivery

Fig. 3

Interaction of nanoparticles with cartilage. a Clearance and biodistribution of nanoparticles within joint cavity. b Cartilage layers as barriers of drug penetration. c Retention of nanoparticles in OA and the contralateral joints in rats with different ages. Reproduced with permission [33]. Copyright © 2020 Elsevier B.V. d Penetration of 25.93 nm nanoparticles within bovine articular cartilage with similar joint cartilage thickness to human. Reproduced with permission [34]. Copyright © 2021 American Association for the Advancement of Science. e Penetration of 25.93 nm nanoparticles within bovine articular cartilage [40]. Reproduced with permission Copyright © 2018 American Association for the Advancement of Science. f Penetration of different sizes of nanoparticles into the cartilage matrix. Penetration depths of nanoparticles within cartilage matrix is in a size-dependent manner. Surface-modified nanoparticles with large size can be functionalized binding to the cartilage surface for drug release. Penetration of nanoparticles increases in OA cartilage compared with healthy cartilage Copyright © 2020 Elsevier B.V. d Penetration of 25.93 nm nanoparticles within bovine articular cartilage with similar joint cartilage thickness to human. Reproduced with permission [34]. Copyright © 2021 American Association for the Advancement of Science. e Penetration of 25.93 nm nanoparticles within bovine articular cartilage [40]. Reproduced with permission Copyright © 2018 American Association for the Advancement of Science. f Penetration of different sizes of nanoparticles into the cartilage matrix. Penetration depths of nanoparticles within cartilage matrix is in a size-dependent manner. Surface-modified nanoparticles with large size can be functionalized binding to the cartilage surface for drug release. Penetration of nanoparticles increases in OA cartilage compared with healthy cartilage

Fig. 4

Nanoparticle design for cartilage targeting therapy. a Strategies for passive and active targeting. b Effects of passive and active targeting on the penetrations of nanoparticles within healthy and OA cartilage. c Interactions of passive and active targeting nanoparticles with healthy and OA-mimicked cartilage. Reproduced with permission [54]. Copyright 2019, Acta Materialia Inc. Published by Elsevier Ltd.

Fig. 5

Possible interactions of nanoparticles with targeted cells

Fig. 6

Compositions and properties of biomimetic nanoparticles for the treatment of cartilage disease

Fig. 7

Uptake pathways and therapeutic mechanisms of nanoparticles in OA. The major mechanisms include a lubrication improvement, b chondrogenic hypertrophy prevention, c cell survival regulation, d pain relief by inflammation inhibition, e anti-oxidative damage, f recruitment of endogenous stem cells, and g chondrogenesis promotion. Abbreviations: ACAN, aggrecan; BMP 4/7/13, bone morphogenetic proteins 4/7/13; CCL 2/3/20, C–C motif chemokine ligand 2/3/20; COL2a1, collagen type II alpha 1 chain; COX 2, Cyclooxygenase-2; CXCL 8/12, chemokine (C-X-C motif) ligand 8/12; Erk1/2, extracellular signal‑regulated protein kinase 1/2; FGF, fibroblast growth factors; FK506, tacrolimus; IGF, Insulin-like growth factor; IL 1β/6, Interleukin 1β/6; iNOS, inducible nitric oxide synthase; KGN, kartogenin; MMP 9, matrix metalloproteinases; NF-κB, nuclear factor kappa-B; NSAID, nonsteroidal anti-inflammatory drugs; PDGF, Platelet-derived growth factor; PTHrP, parathyroid hormone-related protein; Rac1, Ras-related C3 botulinum toxin substrate 1; ROS, reactive oxygen species; SOX 9, SRY-Box transcription factor; TGFs, transforming growth factors; TNF, tumor necrosis factor

Fig. 8

Other potential target tissues in addition to cartilage according to the known pathological mechanisms. a Schematic graph illustrates nanoparticles-based therapy targeting synovial membrane and subchondral bone. b Schematic graph illustrates nanoparticles-based therapy targeting nerves and blood vessels. Abbreviations: VEGF-A, vascular endothelial growth factor A; NGF, nerve growth factor; TrkA, tropomyosin-receptor-kinase A; p75NTRs, p75 neurotrophin receptors

Fig. 9

Potential therapeutic strategies by using stimuli-responsive nanoparticles for control delivery in OA. a–c Schematic graphs illustrate external-responsive nanoparticles for OA therapy. d–h Schematic graphs illustrate internal stimuli-responsive nanoparticles for OA therapy. Reproduced with permission [242]. Copyright © 2015 American Chemical Society. i Example of pH responsive nanoparticles for OA imaging and therapy. j Example of enzyme responsive nanoparticles for OA therapy. Reproduced with permission [53]. Copyright © 2019 Elsevier Ltd. Abbreviations: OA, osteoarthritis Copyright © 2015 American Chemical Society. i Example of pH responsive nanoparticles for OA imaging and therapy. j Example of enzyme responsive nanoparticles for OA therapy. Reproduced with permission [53]. Copyright © 2019 Elsevier Ltd. Abbreviations: OA, osteoarthritis

Fig. 10

Multiples applications of nanoparticles in OA. a Schematic graph illustrates application of nanoparticles in OA diagnosis. b Schematic graphs illustrate application of nanoparticles in cell tracking. c Example of fluorescent labeled nanoparticles in cartilage diseases. Reproduced with permission [252]. Copyright © 2020 Wiley‐VCH GmbH. d Example of magnetic nanoparticles in OA diagnosis. Reproduced with permission [186]. Copyright 2020, Ivyspring International Publisher. e Example of magnetic nanoparticles in cell tracking. Reproduced with permission [260]. Copyright 2012, Springer Nature. Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; OA, osteoarthritis; PET, positron emission tomography; SPECT, single-photon emission computed tomography