Emerging role of chondroitin sulfate based nanocarriers in improving the therapeutic outcome of NSAIDs in the treatment of osteoarthritis through the TDDDS

  • Rabia Gul Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.
  • Faryal Jahan Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
  • Faiza Naseer Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan
Keywords: Osteoarthritis, Bio-inspired polymer, chondroitin sulfate, transdermal drug delivery system (TDDDS)


Osteoarthritis is characterized by joint destruction followed by severe inflammation caused by variety of proinflammatory mediators released due to upregulation of nuclear translocation of nuclear factor (NF-kB). Current treatment involves chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs) that is associated with bewildering array of systemic adverse effects. Transdermal drug delivery system address challenges of systemic toxicities but toxic chemical penetration enhancers limit its utility.  Novel drug delivery system explores the potential of bio-inspired materials for designing of safe and effective carriers that specifically deliver drug to site of action with enhanced transdermal penetration of the drug. Chondroitin sulfate, a biopolymer that mimic extracellular matrix, binds specifically with its overexpressed receptors (CD44, RHAMM and ICAM-I) at inflammatory site, biodegradable and possess intrinsic anti-inflammatory properties. These attributes render chondroitin sulfate an ideal carrier for the drug delivery in osteoarthritis. Chondroitin sulfate based nanocarriers serve as a potential drug delivery system that not only deliver anti-arthritis drug through the skin but also produce synergistic effect to improve therapeutic outcome. In this review, molecular mechanism of intrinsic anti-inflammatory effects of chondroitin sulfate in osteoarthritis is discussed in detail. Moreover, potential of chondroitin sulfate to perform dual role of therapeutic agent as well as serve as nanocarrier in transdermal drug delivery for the treatment of osteoarthritis is elaborated. 


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Author Biographies

Rabia Gul, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.

Lecturer, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan.

Faryal Jahan, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan

Senior Lecturer, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan

Faiza Naseer, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan

Senior Lecturer, Shifa College of Pharmaceutical Sciences, Shifa Tameer-e-Millat University, Islamabad, Pakistan


White GE, Iqbal AJ, Greaves DR. CC chemokine receptors and chronic inflammation—therapeutic opportunities and pharmacological challenges. Pharmacol Rev. 2013; 65(1):47-89.

DOI: https://doi.org/10.1124/pr.111.005074

Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond. J Pharm Pharm Sci. 2008; 11(2):81s-110s.

DOI: https://doi.org/10.18433/J3T886

Rahmani Del Bakhshayesh A, Akbarzadeh A, Alihemmati A, Tayefi Nasrabadi H, Montaseri A, Davaran S, et al. Preparation and characterization of novel anti-inflammatory biological agents based on piroxicam-loaded poly-ε-caprolactone nano-particles for sustained NSAID delivery. Drug Delivery. 2020;27(1):269-82.

DOI: https://doi.org/10.1080/10717544.2020.1716881

4. Mitragotri S, Yoo J-W. Designing micro-and nano-particles for treating rheumatoid arthritis. Arch Pharm Res. 2011;34(11):1887-97.

DOI: https://doi.org/10.1007/s12272-011-1109-9.

5. Nugraheni RW. Transdermal delivery of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): a mini review. Farmasains: J Farmasi dan Ilmu Kesehatan. 2020;4(2):15-9.

DOI: https://doi.org/10.1002/jps.20745.

6. Anand K, Rahman M, Ray S, Karmakar S. Insights into the Approach, Fabrication, Application, and Lacunae of Nanoemulsions in Drug Delivery Systems. Crit Rev Ther Drug Carrier Syst. 2020; 37(6).

DOI: https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2020030291

Cevc G, Vierl U. Nanotechnology and the transdermal route: A state of the art review and critical appraisal. J Control Release. 2010; 141(3):277-99.

Doi: https://doi.org/10.1016/j.jconrel.2009.10.016

Reis CP, Neufeld RJ, Ribeiro AJ, Veiga F. Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine: Nanotechnology, Bio Med. 2006; 2(1):8-21.

DOI: https://doi.org/10.1016/j.nano.2005.12.003

Alexander A, Dwivedi S, Giri TK, Saraf S, Saraf S, Tripathi DK. Approaches for breaking the barriers of drug permeation through transdermal drug delivery. J Control Release. 2012; 164(1):26-40.

DOI: https://doi.org/10.1016/j.jconrel.2012.09.017

Raeisi F, Raeisi E. Mini review of polysaccharide nanoparticles and drug delivery process. Adv Applied NanoBio-Technol. 2020;1(2):33-44.

Song HQ, Fan Y, Hu Y, Cheng G, Xu FJ. Polysaccharide–Peptide Conjugates: A Versatile Material Platform for Biomedical Applications. Adv Funct Mater. 2021; 31(6):2005978.

DOI: https://doi.org/10.1002/adfm.202005978

Ozkahraman B, Emeriewen K, Saleh GM, Thanh NTK. Engineering hydrogel nanoparticles to enhance transdermal local anaesthetic delivery in human eyelid skin. RSC Advances. 2020; 10(7):3926-30.

DOI: https://doi.org/10.1039/C9RA06712D

Wang H, Zhou Y, Sun Q, Zhou C, Hu S, Lenahan C, et al. Update on Nanoparticle-Based Drug Delivery System for Anti-inflammatory Treatment. Front Bioeng Biotechnol. 2021; 9:106.

DOI: https://doi.org/10.3389/fbioe.2021.630352

Caldas BS, Nunes CS, Panice MR, Scariot DB, Nakamura CV, Muniz EC. Manufacturing micro/nano chitosan/chondroitin sulfate curcumin-loaded hydrogel in ionic liquid: A new biomaterial effective against cancer cells. Int J Biol Macromol. 2021; 180:88-96.

DOI: https://doi.org/10.1016/j.ijbiomac.2021.02.194

Neves MI, Araújo M, Moroni L, da Silva RM, Barrias CC. Glycosaminoglycan-inspired biomaterials for the development of bioactive hydrogel networks. Molecules. 2020; 25(4):978.

DOI: https://doi.org/10.3390/molecules25040978

Sodhi H, Panitch A. Glycosaminoglycans in Tissue Engineering: A Review. Biomolecules. 2021; 11(1):29.

DOI: https://doi.org/10.3390/biom11010029

Gul R, Ahmed N, Shah KU, Khan GM, Rehman Au. Functionalised nanostructures for transdermal delivery of drug cargos. J Drug Target. 2018; 26(2):110-22.

DOI: https://doi.org/10.1080/1061186X.2017.1374388

Peat G, Thomas MJ. Osteoarthritis year in review 2020: epidemiology & therapy. Osteoarthritis and Cartilage. 2020.

DOI: https://doi.org/10.1016/j.joca.2020.10.007

Ansari MY, Ahmad N, Haqqi TM. Oxidative stress and inflammation in osteoarthritis pathogenesis: Role of polyphenols. Biomedicine & Pharmacotherapy. 2020; 129:110452.

DOI: https://doi.org/10.1016/j.biopha.2020.110452

Foell D, Wittkowski H, Roth J. Mechanisms of disease: a'DAMP'view of inflammatory arthritis. Nat Clin Pract Rheumatol. 2007; 3(7):382-90.

DOI: https://doi.org/10.1038/ncprheum0531.

Wang T, Hao Z, Liu C, Yuan L, Li L, Yin M, et al. MiR-193b modulates osteoarthritis progression through targeting ST3GAL4 via sialylation of CD44 and NF-кB pathway. Cellular Signalling. 2020; 76:109814.

DOI: https://doi.org/10.1016/j.cellsig.2020.109814

Xia B, Chen D, Zhang J, Hu S, Jin H, Tong P. Osteoarthritis pathogenesis: a review of molecular mechanisms. Calcif Tissue Int. 2014; 95(6):495-505.

DOI: https://doi.org/10.1007/s00223-014-9917-9.

Fayet M, Hagen M. Pain characteristics and biomarkers in treatment approaches for osteoarthritis pain. Pain Manag. 2021; 11(1):59-73.

DOI: https://doi.org/10.2217/pmt-2020-0055

Ren Y, Yang Q, Luo T, Lin J, Jin J, Qian W, et al. Better clinical outcome of total knee arthroplasty for rheumatoid arthritis with perioperative glucocorticoids and disease-modifying anti-rheumatic drugs after an average of 11.4-year follow-up. J Orthop Surg Res. 2021; 16(1):1-9.

DOI: https://doi.org/10.1186/s13018-021-02232-9.

Huddleston HP, Maheshwer B, Wong SE, Chahla J, Cole BJ, Yanke AB. An Update on the Use of Orthobiologics: Use of Biologics for Osteoarthritis. Oper Tech Sports Med. 2020; 28(3):150759.

DOI: https://doi.org/10.1016/j.otsm.2020.150759

Grässel S, Muschter D. Recent advances in the treatment of osteoarthritis. F1000Research. 2020; 9.

DOI: https://doi.org/10.12688/f1000research.22115.1.

Dannhardt G, Kiefer W. Cyclooxygenase inhibitors–current status and future prospects. Eur J Med Chem. 2001; 36(2):109-26.

DOI: https://doi.org/10.1016/S0223-5234(01)01197-7

Solomon DH, Katz JN, Jacobs JP, La Tourette AM, Coblyn J. Management of glucocorticoid‐induced osteoporosis in patients with rheumatoid arthritis: Rates and predictors of care in an academic rheumatology practice. Arthritis & Rheumatism. 2002; 46(12):3136-42.

DOI: https://doi.org/10.1002/art.10613

Simon L. DMARDs in the treatment of rheumatoid arthritis: current agents and future developments. Int J Clin Pract. 2000; 54(4):243-9.

DOI: https://doi.org/10.1053/sarh.2000.16641.

Van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol. 2009; 5(10):531-41.

DOI: https://doi.org/10.1038/nrrheum.2009.182.

Magni A, Agostoni P, Bonezzi C, Massazza G, Menè P, Savarino V, et al. Management of Osteoarthritis: Expert Opinion on NSAIDs. Pain Ther. 2021; 1-26.

DOI: https://doi.org/10.1007/s40122-021-00260-1

Derwich M, Mitus-Kenig M, Pawlowska E. Orally Administered NSAIDs—General Characteristics and Usage in the Treatment of Temporomandibular Joint Osteoarthritis—A Narrative Review. Pharmaceuticals. 2021; 14(3):219.

DOI: https://doi.org/10.3390/ph14030219.

Nagadev C, Rao M, Venkatesh P, Hepcykalarani D, Prema R. A Review on Transdermal Drug Delivery Systems. Asian J Pharm Clin Res. 2020; 10(2):109-14.

DOI: https://doi.org/10.5958/2231-5659.2020.00021.1

Pastore MN, Kalia YN, Horstmann M, Roberts MS. Transdermal patches: history, development and pharmacology. Br J Pharmacol. 2015; 172(9):2179-209.

DOI: https://doi.org/10.1111/bph.13059.

Kamble OS, Sanket AS, Samal SK, Dubey SK, Kesharwani P, Dandela R. Advances in transdermal delivery of nanomedicine. Theory and Applications of Nonparenteral Nanomedicines: Elsevier; 2021. p. 383-408.

Mishra B, Bonde GV. Transdermal drug delivery. Controlled Drug Delivery Systems: CRC Press; 2020. p. 239-75.

Supe S, Takudage P. Methods for evaluating penetration of drug into the skin: A review. Skin Res Technol. 2020.

DOI: https://doi.org/10.1111/srt.12968

Sivasankarapillai V, Das S, Sabir F, Sundaramahalingam M, Colmenares J, Prasannakumar S, et al. Progress in natural polymer engineered biomaterials for transdermal drug delivery systems. Mater Today Chem. 2021; 19:100382.

DOI: https://doi.org/10.1016/j.mtchem.2020.100382

Ghosh S, Mishra P, Dabke A, Pathak A, Bhowmick S, Misra A. Targeting Approaches Using Polymeric Nanocarriers. Applications of Polymers in Drug Delivery: Elsevier; 2021. p. 393-421.

Rabiei M, Kashanian S, Samavati SS, Derakhshankhah H, Jamasb S, McInnes SJ. Nanotechnology application in drug delivery to Osteoarthritis (OA), Rheumatoid arthritis (RA), and Osteoporosis (OSP). J Drug Deliv Sci Technol. 2020:102011.

DOI: https://doi.org/10.1016/j.jddst.2020.102011

Chang M-C, Chiang P-F, Kuo Y-J, Peng C-L, Chen K-Y, Chiang Y-C. Hyaluronan-Loaded Liposomal Dexamethasone–Diclofenac Nanoparticles for Local Osteoarthritis Treatment. Int J Mol Sci. 2021; 22(2):665.

DOI: https://doi.org/10.3390/ijms22020665

Siddiqui B, Rehman AU, Haq I-U, Ahmad NM, Ahmed N. Development, optimisation, and evaluation of nanoencapsulated diacerein emulgel for potential use in osteoarthritis. J Microencapsul. 2020; 37(8):595-608.

DOI: https://doi.org/10.1080/02652048.2020.1829140

Jerosch J. Effects of glucosamine and chondroitin sulfate on cartilage metabolism in OA: outlook on other nutrient partners especially omega-3 fatty acids. Int J Rheum Dis. 2011; 2011.

DOI: https://doi.org/10.1155/2011/969012

Reginster J-Y, Veronese N. Highly purified chondroitin sulfate: a literature review on clinical efficacy and pharmacoeconomic aspects in osteoarthritis treatment. Aging Clin Exp Res. 2020:1-11.

DOI: https://doi.org/10.1007/s40520-020-01643-8.

Korotkyi O, Huet A, Dvorshchenko K, Kobyliak N, Falalyeyeva T, Ostapchenko L. Probiotic Composition and Chondroitin Sulfate Regulate TLR-2/4-Mediated NF-κB Inflammatory Pathway and Cartilage Metabolism in Experimental Osteoarthritis. Probiotics Antimicrob Proteins. 2021:1-15.

DOI: https://doi.org/10.1007/s12602-020-09735-7.

Bishnoi M, Jain A, Hurkat P, Jain SK. Aceclofenac-loaded chondroitin sulfate conjugated SLNs for effective management of osteoarthritis. J Drug Target. 2014; 22(9):805-12.

DOI: https://doi.org/10.3109/1061186X.2014.928714.

Onishi H, Ikeuchi-Takahashi Y, Kawano K, Hattori Y. Preparation of chondroitin sulfate-glycyl-prednisolone conjugate nanogel and its efficacy in rats with ulcerative colitis. Biol Pharm Bull. 2019; 42(7):1155-63.

DOI: https://doi.org/10.1248/bpb.b19-00020.

Hu Q, Luo Y. Chitosan-based nanocarriers for encapsulation and delivery of curcumin: A review. Int J Biol Macromol. 2021.

DOI: https://doi.org/10.1016/j.ijbiomac.2021.02.216.

De Witte TM, Wagner AM, Fratila‐Apachitei LE, Zadpoor AA, Peppas NA. Immobilization of nanocarriers within a porous chitosan scaffold for the sustained delivery of growth factors in bone tissue engineering applications. J Biomed Mater Res A. 2020; 108(5):1122-35.

DOI: https://doi.org/10.1002/jbm.a.36887

Gul R, Ahmed N, Ullah N, Khan MI, Elaissari A. Biodegradable ingredient-based emulgel loaded with ketoprofen nanoparticles. AAPS PharmSciTech. 2018; 19(4):1869-81.

DOI: https://doi.org/10.1208/s12249-018-0997-0.

How to Cite
Gul R, Jahan F, Naseer F. Emerging role of chondroitin sulfate based nanocarriers in improving the therapeutic outcome of NSAIDs in the treatment of osteoarthritis through the TDDDS. JSTMU [Internet]. 1Aug.2021 [cited 27Oct.2021];4(1):55-. Available from: https://j.stmu.edu.pk/ojs/index.php/jstmu/article/view/133
Review Article (without Meta-analysis)