Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, February 2015.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2015
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| Online Access: | http://hdl.handle.net/1721.1/97832 |
| _version_ | 1810975435278778368 |
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| author | Bajpayee, Ambika Goel |
| author2 | Alan J. Grodzinsky. |
| author_facet | Alan J. Grodzinsky. Bajpayee, Ambika Goel |
| author_sort | Bajpayee, Ambika Goel |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, February 2015. |
| first_indexed | 2024-09-23T08:39:20Z |
| format | Thesis |
| id | mit-1721.1/97832 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T08:39:20Z |
| publishDate | 2015 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/978322019-04-09T19:01:06Z Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases Bajpayee, Ambika Goel Alan J. Grodzinsky. Massachusetts Institute of Technology. Department of Mechanical Engineering. Massachusetts Institute of Technology. Department of Mechanical Engineering. Mechanical Engineering. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Mechanical Engineering, February 2015. Cataloged from PDF version of thesis. "February 2015." Includes bibliographical references. Traumatic joint injuries significantly increase synovial fluid levels of pro-inflammatory cytokines that can initiate cartilage degeneration leading to osteoarthritis (OA). Articular cartilage is a highly negatively charged, avascular tissue, which relies on synovial fluid convection and electro-diffusion to transport proteins and therapeutics to tissue chondrocytes. No OA drug has yet passed the safety criteria of clinical trials due to ineffective intra-articular (i.a.) delivery methods, which require very high drug doses that cause systemic toxicity. There is a need to design local delivery mechanisms that can enable drugs or drug carriers to rapidly diffuse into the cartilage extracellular matrix to achieve intratissue therapeutic levels before these drugs are cleared from the joint space via lymphatics and synovium vasculature. This dissertation investigates the effects of size and charge of solutes on their penetration, binding and retention within negatively charged tissues such as cartilage. Based on this understanding we selected Avidin, a globular protein, as a drug carrier owing to its optimal size and high positive charge (66,000 Da, pI 10.5). Avidin resulted in a six-fold upward Donnan partitioning factor at the synovial fluid-cartilage interface, had a 400-fold higher uptake than its electrically neutral counterpart (Neutravidin), and remained bound within cartilage for at least 15 days. Competitive binding experiments revealed that despite Avidin's weak and reversible ionic binding (dissociation constant, KD ~150 [mu]M) to the negatively charged glycosaminoglycans, its long term retention was facilitated by large intratissue binding site density (NT ~ 2,920 [mu]M). Thus, structures like Avidin are ideal candidates for local i.a. drug delivery into cartilage. In vivo animal studies revealed that Avidin retained inside the joint space for extended time periods resulting half-life of 154h in rabbit cartilage which was 5-6 times longer than that in the thinner rat cartilage. This was confirmed to be consistent with the concept that diffusion-binding kinetics scale as the square of tissue thickness, emphasizing the necessity of using larger animal models for studying joint space transport and pharmacokinetics. Avidin's neutral counterpart (Neutravidin) was completely cleared from the joint space of both rats and rabbits within 24h. We then conjugated Avidin with the glucocorticoid, dexamethasone, using chemical linkers to enable its sustained release. Avidin delivered dexamethasone into cartilage deep zones where majority of chondrocytes reside thereby successfully inhibiting cytokine-induced catabolic activity in cartilage explants in-vitro. A single i.a. injection of Avidin-conjugated drug can thereby enable sustained drug delivery in low doses and therefore has the potential to replace the current clinical practice of using multiple injections of high dose glucocorticoids in patients. The biological efficacy of this system in rescuing degenerative mechanisms of OA is currently being validated in a well-accepted rabbit model of post-traumatic OA as part of a preclinical study. by Ambika Goel Bajpayee. Ph. D. 2015-07-17T19:51:14Z 2015-07-17T19:51:14Z 2015 Thesis http://hdl.handle.net/1721.1/97832 913384861 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 127 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Mechanical Engineering. Bajpayee, Ambika Goel Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title | Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title_full | Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title_fullStr | Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title_full_unstemmed | Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title_short | Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| title_sort | charge based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases |
| topic | Mechanical Engineering. |
| url | http://hdl.handle.net/1721.1/97832 |
| work_keys_str_mv | AT bajpayeeambikagoel chargebasedtransportanddrugdeliveryintocartilageforlocalizedtreatmentofdegenerativejointdiseases |