Imaging of Folate Receptor Expressing Macrophages in the Rat Groove Model of Osteoarthritis: Using a New DOTA-Folate Conjugate

Abstract

ObjectiveTo evaluate the presence and localization of folate receptor expressing macrophages in the rat groove model of osteoarthritis and determine the suitability of a new folate conjugate with albumin-binding entity (cm09) for in vivo SPECT (single-photon emission computed tomography) analysis.DesignIn male Wistar rats, local cartilage damage was induced in addition to a standard (n = 10) or high-fat diet (n = 6). After 12 weeks, 111In labeled folate conjugates were administered, and SPECT/CT (computed tomography) imaging was performed after 24 hours. Subsequently, osteoarthritis severity and folate receptor expression were assessed using (immuno)-histological sections.ResultsIn vivo SPECT/CT imaging of the new folate conjugate (cm09) was as useful as a folate conjugate without albumin-binding entity in the groove model of osteoarthritis with less renal accumulation. Induction of cartilage damage on a standard diet resulted in no effect on the amount of folate receptor expressing macrophages compared with the contralateral sham operated joints. In contrast, inducing cartilage damage in the high-fat diet group resulted in 28.4% increase of folate receptor expression as compared with the nondamaged control joints. Folate receptor expressing cells were predominantly present in the synovial lining and in subchondral bone as confirmed by immunohistochemistry.ConclusionsFolate receptor expression, and thus macrophage activation, can clearly be demonstrated in vivo, in small animal models of osteoarthritis using the new 111In-folate conjugate with specific binding to the folate receptor. Increased macrophage activity only plays a role in the groove model of osteoarthritis when applied in a high-fat diet induced dysmetabolic condition, which is in line with the higher inflammatory state of that specific model.

Clinical-grade hDPSCs Suppressed the Activation of Osteoarthritic Macrophages and Attenuated Cartilaginous Damage in a Rabbit OA Model

“…Most importantly, the hDPSCs were capable of alleviating cartilaginous damage in OA knee joints, which implies the potential application of hDPSCs in the therapy of OA. Our ndings showed marked in ltration of in ammatory macrophages (CD11b + CD68+) in the subchondral bones and articular cartilage of OA rabbits, which have been reported to be involved in the osteochondral remodeling of OA joints [12,45,[52][53][54][55]. Promisingly, hDPSC infusion signi cantly reduced the number of in ammatory macrophages (CD11b + CD68+) in articular osteochondral tissue of OA rabbits.…”

Analgesic effects of the cathepsin K inhibitor L-006235 in the monosodium iodoacetate model of osteoarthritis pain

“…Studies using imaging methods such as SPECT/CT to study-activated macrophage involvement may shed light on the mechanisms of action of cathepsin K inhibitors in the future. 45…”

Leveraging Electrostatic Interactions for Drug Delivery to the Joint

“…Although active targeting modalities such as tuftsin peptides, 120 IL-1Ra, 121 vasoactive intestinal peptides, 122 avb3-targeted RGD, 123,124 folic acid, [125][126][127][128] or macrophagederived microvesicle proteins 129 have been used in various investigations to target cells in the arthritic synovium, there are minimal instances of electrostatic interactions being leveraged for targeting. However, electric charge has been manipulated in other cases to determine preferential targeting of key immune cells that are part of the arthritic synovium, such as phagocytic macrophages.…”