Phospholipase A₂inhibitor-loaded micellar nanoparticles attenuate inflammation and mitigate osteoarthritis progression

Abstract

Treating osteoarthritis (OA) remains a major clinical challenge. Despite recent advances in drug discovery and development, no disease-modifying drug for knee OA has emerged with any significant clinical success, in part due to the lack of valid and responsive therapeutic targets and poor drug delivery within knee joints. In this work, we show that the amount of secretory phospholipase A2 (sPLA2) enzyme increases in articular cartilage in human and mouse OA cartilage tissues. We hypothesize that inhibition of sPLA2 activity may be an effective treatment strategy for OA. To develop a sPLA2-responsive and nanoparticle (NP)-based interventional platform for OA management, we incorporated a sPLA2 inhibitor (sPLA2i) into the phospholipid membrane of micelles. The engineered sPLA2i-loaded micellar nanoparticles (sPLA2i-NPs) were able to penetrate deep into the cartilage matrix, prolong retention in the joint space, and mitigate OA progression. These findings suggest that sPLA2i-NPs can be promising therapeutic agents for OA treatment.

Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain

“…The etiology of pain in OA, however, remains unclear. Currently, there is no OA-disease-modifying drug (OADMD) that can reverse or prevent OA progression [1][2][3][4]. A better understanding of the molecular mechanisms driving the pathology of OA will be essential to identify new and effective treatment avenues for OA.…”

Activating EGFR Signaling Attenuates Osteoarthritis Development Following Loading Injury in Mice

“…( 42 ) We previously designed a phospholipid micellar nanoparticles conjugated with secreted phospholipase A2 inhibitor (sPLA2i). ( 43 ) sPLA2 is a heterogeneous group of enzymes that specifically hydrolyzes the sn‐2 ester bond of membrane phospholipids to release free fatty acids, such as arachidonic acid and lysophospholipids, which are upstream mediators of inflammation in many chronic inflammatory diseases. ( 44 ) We demonstrated that these sPLA2i‐NPs are effective in reducing the amounts of p‐P65 and p‐P100, two downstream reporters of the NF‐κB inflammatory pathway, in mouse joints after loading.…”

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

“…2) The particularity of joint structure. The rapid clearance of drugs from the joint and therapeutic targets deep within the cartilage that drugs cannot reach pose significant delivery challenges for many promising drugs [ 291 , 292 ]. Possible approaches include A) changing the size or membrane potential of EVs to combat the steric and electrostatic hindrance of the cartilage matrix; B) improving the structure and targeting ability of EVs to prolong the residence time in the joint cavity; and C) combined with biomaterials to enhance the penetration ability of EVs into the cartilage and achieve sustained release.…”