Nanoparticles for Improved Local Retention after Intra-Articular Injection into the Knee Joint
To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity.
In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography.
Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro. In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week.
This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis.
- Centers for Disease Control and Prevention [Internet]. Arthritis, 2012 February 14. Available from: http://www.cdc.gov/arthritis.html.
- Pelletier JP, Martel-Pelletier J. DMOAD developments, present and future. Bull NYU Hosp Jt Dis. 2007;65(3):242–8.
- Little CB, Fosang AJ. Is cartilage matrix breakdown an appropriate target in osteoarthritis—insights from studies of aggrecan and collagen proteolysis? Curr Drug Targets. 2010;11(5):561–75. CrossRef
- Owen SG, Francis HW, Roberts MS. Disappearance kinetics of solutes from synovial fluid after intra-articular injection. Brit J Clin Pharmacol. 1994;30:349–55. CrossRef
- Butoescu N, Jordan O, Doelker E. Intra-articular drug delivery systems for the treatment of rheumatoid diseases: a review of the factors influencing their performance. Eur J Pharm Biopharm. 2009;73:205–18. CrossRef
- Shaw IH, Knight CG, Dingle JT. Liposomal retention of a modified anti-inflammatory steroid. Biochem J. 1976;158:473–6.
- Bonanomi MH, Velvart M, Stimpel M, Roos KM, Fehr K, Weder HG. Studies of pharmacokinetics and therapeutic effects of glucocorticoids entrapped in liposomes after intra-articular application in healthy rabbits and in rabbits with antigen-induced arthritis. Rheumatol Int. 1987;7:203–12. CrossRef
- Williams AS, Camilleri JP, Goodfellow RM, Williams BD. A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis. Brit J Rheumatol. 1996;35:719–24. CrossRef
- Hou S-M, Yu H-Y. Comparison of systemic absorption of aqueous and liposomal lidocaine following intra-articular injection in rabbits. J Formosan Med Assoc. 1997;96:141–2.
- Chowdhary RK, Ratkay LG, Canaan AJ, Waterfield JD, Richter AM, Levy JG. Uptake of verteporfin by articular tissues following systemic and intra-articular administration. Biopharm Drug Dispos. 1998;19:395–400. CrossRef
- Edwards SHR, Cake MA, Spoelstra G, Read RA. Biodistribution and clearance of intra-articular liposomes in a large animal model using a radiographic marker. J Liposome Res. 2007;17:249–61. CrossRef
- Liang LS, Wong W, Burt HM. Pharmacokinetic study of methotrexate following intra-articular injection of methotrexate loaded poly(L-lactic acid) microspheres in rabbits. J Pharm Sci. 2005;94(6):1204–15. CrossRef
- Horisawa E, Kubota K, Tuboi I, Sato K, Yamamoto H, Takeuchi H, et al. Size-dependency of DL-lactide/glycolide copolymer particulates for intra-articular delivery system on phagocytosis in rat synovium. Pharm Res. 2002;19:132–9. CrossRef
- Bargdon B, Bertone AL, Hardy J, Simmons EJ. Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel impregnated polymeric microspheres. J Invest Surg. 2001;14:169–82. CrossRef
- Bozdağ S, Calis S, Kas HS, Ercan MT, Peksoy I, Hincal AA. In vitro evaluation and intra-articular administration of biodegradable microspheres containing naproxen sodium. J Microencapsul. 2001;18:443–56. CrossRef
- Lu L, Stamatas GN, Mikos AG. Controlled release of transforming growth factor. J Biomed Mater Res. 2000;50:440–51. CrossRef
- Liang LS, Jackson J, Min W, Risovic V, Wasan KM, Burt HM. Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint. J Pharm Sci. 2004;93:943–56. CrossRef
- Zille H, Paquet J, Henrionnet CJ, Scala-Bertola JC, Leonard MJ, Six JLM, et al. Evaluation of intra-articular delivery of hyaluronic acid functionalized biopolymeric nanoparticles in healthy rat knees. Biomed Mater Eng. 2010;20(3–4):235–42.
- Ratcliffe JH, Hunneyball IM, Wilson CG, Smith A, Davis SS. Albumin microspheres for intra-articular drug delivery: investigation of their retention in normal and arthritic knee joints of rabbits. J Pharm Pharmacol. 1986;39:290–5. CrossRef
- Tuncay M, Calis S, Kas HS, Ercan MT, Peksoy I, Hincal AA. In vitro and in vivo evaluation of diclofenac sodium loaded albumin microspheres. J Microencapsul. 2000;17:145–55. CrossRef
- Thakkar H, Sharma RK, Mishra AK, Chuttani K, Murthy RSR. Efficacy of chitosan microspheres for controlled intra-articular delivery of celecoxib in inflamed joints. J Pharm Pharmacol. 2004;56:1091–9. CrossRef
- Hellstern D, Schultze K, Schopf B, Petri-Fink A, Steitz B, Kamau S, et al. Systemic distribution and elimination of plain and with Cy3.5 functionalized poly(vinyl alcohol) coated superparamagnetic maghemite nanoparticles after intra-articular injection in sheep in vivo. J Nanosci Nanotechnol. 2006;6:3261–8. CrossRef
- Butoescu N, Jordan O, Burdet P, Stadelmann P, Petri-Fink A, Hofmann H, et al. Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: physicochemical and magnetic properties, in vitro and in vivo drug release. Eur J Pharm Biopharm. 2009;72(3):529–38. CrossRef
- Thakkar H, Kumar Sharma R, Murthy RSR. Enhanced retention of celecoxib-loaded solid lipid nanoparticles after intra-articular administration. Drugs R&D. 2007;8(5):275–85. CrossRef
- Beltre H. A thermally responsive biopolymer for intra- articular drug delivery. J Control Release. 2006;115:175–82. CrossRef
- Song J, Suh CH, Park YB, Lee SH, Yoo NC, Lee JD, et al. A Phase I/IIa study on intra-articular injection of holmium-166-chitosan complex for the treatment of knee synovitis of rheumatoid arthritis. Eur J Nucl Med. 2001;28:489–97. CrossRef
- Rothenfluh D, Bermudez H, O’Neil CP, Hubbell JA. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat Mater. 2008;7:1–7. CrossRef
- Liggins R, Cruz T, Min W, Liang LS, Hunter WL, Burt HM. Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits. Inflamm Res. 2004;53:363–72. CrossRef
- Miller WK, Morgen MM, Bloom CJ. Cationic dextran polymer derivatives, U.S. patent pending, published as World Intellectual Property Organization Application No. WO 11/060250; 2011.
- Babcock WC, Friesen DT, McCray SB, inventors; Bend Research Inc., assignee. Method and device for evaluation of pharmaceutical compositions. United States patent US20097611630; 2009 Nov 3.
- Sabaratnam S, Coleman PC, Mason RM, Levick JR. Interstitial matrix proteins determine hyaluronan reflection and fluid retention in rabbit joints; effect of protease. J Physiol. 2006;578:291–9. CrossRef
- Levick JR. Blood flow and mass transport in synovial joints. In: Renkin M, Michel CC, editors. Handbook of physiology, section 2: the cardiovascular system: volume IV. Microcirculation. Chapter 19. Bethesda: American Physiology Society; 1984. p. 917–47.
- Sabaratnam S, Arunan V, Coleman PJ, Mason RM, Levick JR. Size-selectivity of hyaluronan molecular sieving by extracellular matrix in rabbit synovial joints. J Physiol. 2005;567:569–81. CrossRef
- Scott D, Coleman PJ, Mason RM, Levick JR. Action of polysaccharides of similar mass but different molecular volume and charge on fluid drainage through synovial interstitium. J Physiol. 2000;528:609–18. CrossRef
- Levick JR. Synovial fluid and trans-synovial flow in stationary and moving normal joints. In: Helminen H, Kiviranta I, Tammi M, Saamaren AM, Paukkonen K, Jurvelin J, editors. Joint loading: biology and health of articular structures. Bristol: Wright & Sons; 1987. p. 149–86.
- Larsen C. Dextran prodrugs—structure and stability in relation to therapeutic activity. Adv Drug Deliv Rev. 1989;3:103–54. CrossRef
- Nanoparticles for Improved Local Retention after Intra-Articular Injection into the Knee Joint
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Volume 30, Issue 1 , pp 257-268
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- cross-linked hydrogels
- increased retention
- intra-articular injection
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- Author Affiliations
- 1. Bend Research Inc., 64550 Research Road, Bend, Oregon, 97701, USA
- 2. BioMed Valley Discoveries, Kansas City, Missouri, USA
- 3. Departments of Medicine and Bioengineering, University of California—San Diego, San Diego, California, USA
- 4. Rush University Medical Center, Chicago, Illinois, USA
- 5. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Beijing, China