Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Chronic inflammation observed in arthritis and other autoimmune disorders is mediated primarily by pro-inflammatory reactive macrophages. Systemic administration of anti-inflammatory agents does not selectively target the affected tissue, or the reactive macrophages and often has significant side effects. Hydroxyl dendrimers have been observed to selectively target reactive macrophages and have been well tolerated in humans. Hydroxyl dendrimer-drug conjugates may provide a superior method for treating localized inflammation, from systemic administration.
Methods: The binding affinity of the dendrimer-alendronate conjugate (D-ALN) was evaluated against hydroxyapatite (HAP) using UV/Vis spectrophotometry. Lewis rats were immunized with an emulsion of type II bovine collagen in incomplete Freund’s adjuvant intradermally on Day 1 and Day 7 to establish collagen-induced arthritis (CIA). Groups of CIA rats and naïve rats (N=5/group) were administered by IV on Day 19 either hydroxyl dendrimer labelled with Cy5 (D-Cy5), D-Cy5 conjugated with alendronate (ALN-D-Cy5), or vehicle control. On Day 21, animals were sacrificed for imaging of hind limbs, kidney and liver. Immunohistochemistry was also performed on hind limbs using CD68 (macrophages), CathK (osteoclasts) and DAPI.
Results: In vitro, D-ALN demonstrated strong binding affinity toward HAP with >85% of D-ALN bound to HAP in less than 10 minutes. Upon intravenous administration, more than 100-fold greater radiant intensity from Cy5 was noted in the paw and knee joint of the CIA rats compared to the naïve rats, indicating significant selective uptake of the D-Cy5 into the regions of inflammation. While a comparable radiant intensity was noted in the joints of CIA rats treated with D-Cy5 or ALN-D-Cy5, a two-fold greater radiant intensity was noted in the paws for CIA rats treated with D-Cy5. A single dose of ALN-D-Cy5 reduced paw volumes by in CIA rats ~10% after 2 days and clinical scores were comparable in all CIA groups.
Conclusion: Systemically administered hydroxyl dendrimer-drug conjugates localize to sites of inflammation in arthritic tissues. Alendronate, which binds bone, conjugated to the hydroxyl dendrimer appears to concentrate only in regions of the bone with potentially less uptake in reactive macrophages away from the bone. These results indicate the types of dendrimer constructs to utilize for drug conjugates to treat inflammation or bone metabolism. Efficacy studies are planned with dendrimer drug conjugates to evaluate modulators of bone resorption and inflammation.
To cite this abstract in AMA style:Cleland J, Sharma R, Sun M, Appiani La Rosa S, Kannan R. Systemic Administration of Novel Hydroxyl Dendrimers to Target Inflammation in Arthritic Tissues [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/systemic-administration-of-novel-hydroxyl-dendrimers-to-target-inflammation-in-arthritic-tissues/. Accessed January 26, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/systemic-administration-of-novel-hydroxyl-dendrimers-to-target-inflammation-in-arthritic-tissues/