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The clearance and biodistribution of magnetic composite nanoparticles in healthy and osteoarthritic rat knees.

ABSTRACT: Intra-articular injections are the most direct route for administering osteoarthritis (OA) therapies, yet how drug carriers distribute within the joint remains understudied. To this end, we developed a magnetic composite nanoparticle that can be tracked with fluorescence in vivo via an in vivo imaging system (IVIS), and quantified ex vivo via electron paramagnetic resonance (EPR) spectroscopy. Using this particle, the effects of age and OA pathogenesis on particle clearance and distribution were evaluated in the medial meniscus transection model of OA (5-, 10-, and 15-month old male Lewis rats). At 9 weeks after meniscus transection, composite nanoparticles were injected and joint clearance was assessed via IVIS. At 2 weeks after injection, animals were euthanized and particle distribution was quantified ex vivo via EPR spectroscopy. IVIS and EPR spectroscopy data indicate a predominant amount of particles remained in the joint after 14 days. EPR spectroscopy data suggests particles cleared more slowly from OA knees than from the contralateral control, with particles clearing more slowly from 15-month old rats than from 5- and 10-month old rats. This study demonstrates the importance of including both age and OA as factors when evaluating nanoparticles for intra-articular drug delivery.

SUBMITTER: Partain BD

PROVIDER: S-EPMC7942179 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Understanding intra-articular biodistribution is imperative as candidate osteoarthritis (OA) drugs become increasingly site-specific. Cartilage has been identified as opportunistic for therapeutic intervention, but poses numerous barriers to drug delivery. To facilitate drug delivery to cartilage, nanoscale vehicles have been designed with different features that target the tissue's matrix. However, it is unclear if these targeting strategies are influenced by OA and the associated structural changes that occur in cartilage. The goal of this work was to study the effectiveness of different cartilage-targeting nanomaterials with respect to cartilage localization and retention, and to determine how these outcomes change in OA. To address these questions, a nanoparticle (NP) system was developed, and the formulation was tuned to possess three distinct cartilage-targeting strategies: (1) passive targeting cationic NPs for electrostatic attraction to cartilage, (2) active targeting NPs with binding peptides for collagen type II, and (3) untargeted neutrally-charged NPs. Ex vivo analyses with bovine cartilage explants demonstrated that targeting strategies significantly improved NP associations with both healthy and OA-like cartilage. In vivo studies with collagenase-induced OA in rats revealed that disease state influenced joint biodistribution for all three NP formulations. Importantly, the extent of cartilage accumulation for each NP system was affected by disease differently; with active NPs, but not passive NPs, cartilage accumulation was increased in OA relative to healthy knees. Together, this work suggests that NPs can be strategically designed for site-specific OA drug delivery, but the biodistribution of the NPs are influenced by the disease conditions into which they are delivered. STATEMENT OF SIGNIFICANCE: As emerging drugs for osteoarthritis are becoming increasingly site-specific, the need for targeted intra-articular drug delivery has evolved. To improve drug delivery to cartilage, targeting strategies for nanomaterials have been developed, but the manner in which these targeted systems accumulate at different sites within the joint remains poorly understood. Moreover, it is unclear how nanomaterial-tissue interactions change in osteoarthritic conditions, as tissue structure and composition change after disease onset. By understanding how nanomaterials distribute within healthy and disease joints, we can advance targeted drug delivery strategies and improve therapeutic outcomes for emerging drugs.

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The clearance and biodistribution of magnetic composite nanoparticles in healthy and osteoarthritic rat knees.

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