Abstract/Details

Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases

Bajpayee, Ambika Goel. 
 Massachusetts Institute of Technology ProQuest Dissertations Publishing,  2015. 0830664.

Abstract (summary)

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 μM) to the negatively charged glycosaminoglycans, its long term retention was facilitated by large intratissue binding site density (NT ∼ 2,920 μM). 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. (Copies available exclusively from MIT Libraries, libraries.mit.edu/docs - [email protected])

Indexing (details)


Subject
Mechanical engineering
Classification
0548: Mechanical engineering
Identifier / keyword
Applied sciences
Title
Charge-based transport and drug delivery into cartilage for localized treatment of degenerative joint diseases
Author
Bajpayee, Ambika Goel
Number of pages
0
Degree date
2015
School code
0753
Source
DAI-B 76/12(E), Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Advisor
Grodzinsky, Alan Jay
University/institution
Massachusetts Institute of Technology
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertation or Thesis
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
0830664
ProQuest document ID
1706900680
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
https://www.proquest.com/docview/1706900680