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Cartilage-Targeting Drug Delivery: Can Electrostatic Interactions Help?

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Cartilage-Targeting Drug Delivery: Can Electrostatic Interactions Help? PERSPECTIVES and/or synovium. These techniques might OPINION be useful for delivering drugs for relieving pain and joint inflammation. However, Cartilage-targeting drug delivery: these approaches do not guarantee drug penetration into cartilage (or other target tissues) or reversible binding of drugs inside can electrostatic interactions help? cartilage. Both mechanisms are necessary to elicit the prolonged biological response Ambika G. Bajpayee and Alan J. Grodzinsky needed for cartilage protection. Abstract | Current intra-articular drug delivery methods do not guarantee Drug penetration and retention inside cartilage is a challenging problem. The sufficient drug penetration into cartilage tissue to reach cell and matrix targets at tissue’s ECM contains densely packed, highly the concentrations necessary to elicit the desired biological response. Here, we negatively charged aggrecan proteoglycans provide our perspective on the utilization of charge–charge (electrostatic) enmeshed within a complex collagen interactions to enhance drug penetration and transport into cartilage, and to network23; the ECM prevents sufficient enable sustained binding of drugs within the tissue’s highly negatively charged drug penetration, thereby enabling rapid clearance of the drug from the joint space24. extracellular matrix. By coupling drugs to positively charged nanocarriers that In this Perpsectives article, we first have optimal size and charge, cartilage can be converted from a drug barrier into describe candidate drugs for the treatment a drug reservoir for sustained intra-tissue delivery. Alternatively, a wide variety of of OA and PTOA, and then focus on drugs themselves can be made cartilage-penetrating by functionalizing them with mechanisms by which charge–charge specialized positively charged protein domains. Finally, we emphasize that interactions can increase drug penetration, appropriate animal models, with cartilage thickness similar to that of humans, must transport kinetics and retention within charged, avascular tissues such as be used for the study of drug transport and retention in cartilage. cartilage. We compare three approaches to intra-articular cartilage-targeted No disease-modifying osteoarthritis drugs in OA-associated cartilage pathogenesis5. delivery, and end with a discussion on the (DMOADS) are currently available. Several Drug penetration into cartilage is especially appropriate animal models to use for testing drugs have potential to inhibit cartilage important following traumatic joint injury, these systems. degeneration associated with osteoarthritis which can result in damage to articular (OA) and post-traumatic osteoarthritis cartilage, subchondral bone and nearby Candidate disease-modifying drugs (PTOA), and to promote cartilage repair1; soft tissues, initiating a sequence of Current therapies for OA provide only however, none of these drugs have yet inflammatory events that can progress to short-term relief of pain and inflammation translated to clinical practice, owing in part PTOA6. Biopsy-obtained samples of cartilage (for example, analgesics and hyaluronic to the lack of effective delivery systems that from anterior cruciate ligament injury have acid lubricants), but no protection against enable local, safe administration in low revealed degradative changes to cartilage further degeneration of cartilage and OA doses without off-target effects2,3. Direct as early as 3 weeks after injury, including progression25. Several therapeutics have intra-articular administration of drugs can loss of superficial zone proteoglycans and been identified as having the potential for minimize adverse systemic side-effects4. cell viability, even in cases where there is no disease-modifying inhibition of cartilage But even intra-articular injection remains obvious damage to cartilage or its collagen breakdown, including anticatabolic inadequate, as small compounds and large network, as visualized by arthroscopy7. glucocorticoids (such as dexamethasone and macromolecules are rapidly cleared from New drug-delivery systems have been triamcinolone)12,26,27, cytokine blockers28,29, the joint space via subsynovial capillaries proposed for sustained delivery in the proanabolic growth factors (including and lymphatics, respectively. For example, synovium and synovial fluid using polymeric insulin-like growth factor (IGF) 1 (REFS 30,31), the mean half-lives of NSAIDs in the nanoparticles8–11, microparticles12,13, fibroblast growth factor (FGF) 18 (REFS 32,33) synovial fluid are only 1–4 h (REF. 4). As liposomes14,15, drug-loaded hydrogels16–19, and bone morphogenetic protein (BMP) 7 a result, multiple injections of high-dose phase transitioning elastin-like (REF. 34)) and chondrogenic biomolecules35. drugs are sometimes used in attempts to polypeptides20, silk constructs21, and Given that OA affects the entire joint, suppress pain, inflammation and cartilage electrospun fibres22. These drug carriers have DMOAD development and associated destruction, an approach that can cause prolonged residence times due to their large clinical trials have targeted cartilage systemic toxicity3. size (micron) or viscous and/or aggregating breakdown (with protease or cytokine Drugs need to penetrate the full depth properties that prevent them from leaving blockers), bone remodelling (with of cartilage to reach the chondrocytes and the joint space rapidly, thereby enabling bisphosphonates, BMP7 or calcitonin), extracellular matrix (ECM) targets involved rapid drug release within the synovial fluid and synovial and inflammatory mediators NATURE REVIEWS | RHEUMATOLOGY VOLUME 13 | MARCH 2017 | 183 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. PERSPECTIVES Table 1 | Examples of potential drugs for OA treatment under experimental or clinical trial testing Drug type Drug action Examples Molecular Mechanism of therapy Target location and/or target weight inside joint NSAIDs Pain relief • Ibuprofen <500 Da Inhibit COX enzymes • Vasculature of the joint • Naproxen capsule and cartilage– • Celecoxib bone interface • Free nerve endings Monoclonal antibodies Biologic agents for • Tanezumab ~150 kDa Bind to and inhibit NGF, of sensory neurons in against NGF pain relief • Fluranumab which is produced by soft tissues (e.g. patella OA synovial cells and ligament and below the chondrocytes and acts synovial layer) directly on sensory neurons Monoclonal antibodies Biologic agents as TNF inhibitors* ~150 kDa Directly bind target Cytokine targets against iflammatory DMOADs • Infliximab (except cytokines, preventing them hypothesized to be cytokines • Adalimumab Etanercept, from binding with their in the synovium, the • Etanercept ~50 kDa) respective cell-surface synovial fluid and found receptors to initiate throughout the full IL-1β inhibitors* signalling depth of the cartilage • Canakinumab extracellular matrix Receptor antagonists Biologic agents as IL-1 receptor ~17 kDa Competitively bind with DMOADs antagonists* cell-surface cytokine • Anakinra receptors thereby blocking cytokine activity Glucorticoids Pain relief at Salts of dexamethasone, <1 kDa Bind with intracellular Full depth of cartilage as high doses (and triamcinolone and glucocorticoid well as neighbouring soft anticatabolic prednisone receptors and inhibit tissues and synovium effects in cartilage cytokine-induced catabolic at low doses) activity Growth factors Biologic agents as IGF-1, FGFs, BMPs 10–20 kDa Bind with cell surface Full depth of cartilage, DMOADs growth factor receptors to meniscus and other stimulate repair tissues Protease inhibitors and DMOADs Inhibitors of MMPs, <1 kDa Bind with the catalytic zinc Full depth of cartilage, pro-protein convertase aggrecanases atom at the MMP active synovium and joint blockers (ADAMTS-4, site (for MMP inhibitors) capsule space ADAMTS-5), cathepsins, to inhibit cartilage ECM PACE4, and others breakdown Viscosupplements Pain relief and joint Hyaluronan‡. lubricin 2–6 MDa Intended to restore Synovial fluid, joint lubrication (proteoglycan 4)and joint lubrication, and capsule, synovial others hypothesized to bind with membrane and superficial CD44 receptors to induce zone of cartilage chondroprotection ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; BMP, bone morphogenetic protein; COX, cyclooxygenase; DMOAD, disease-modifying osteoarthritis drug; ECM, extracellular matrix; FGF, fibroblast growth factor; IGF-1, insulin like growth factor 1; MMP, matrix metalloproteinase; NGF, β-nerve growth factor; OA, osteoarthritis. *Currently used for systemic treatment of rheumatoid arthritis. ‡Approved but no longer recommended for patients with symptomatic knee OA, according to American Academy of Orthopaedic Surgeons 2013 evidence-based guidelines82. (with cytokine blockers)36. TABLE 1 is a For example, a multicentre, randomized, Another randomized, double-blind, representative list of such therapeutics that are double-blind, placebo-controlled study placebo- controlled, multiple-dose study currently being considered for OA treatment. (NCT00110916 (REF. 38)) was performed (NCT00110942) used subcutaneous injection Biologic agents such as monoclonal to evaluate the clinical response, safety or infusion of a monoclonal antibody antibodies against IL-1β (canakinumab) and and tolerability of a single intra-articular (AMG 108) that binds the IL-1 receptor TNF (infliximab, adalimumab), and other injection of anakinra (an IL-1 receptor type 1 (IL-1R1), thereby inhibiting the anti-IL-1 or anti-TNF agents
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