Abstract
Injectable nanobioplatforms capable of locally fighting the inflammation in osteoarticular diseases, by reducing the number of administrations and prolonging the therapeutic effect is highly challenging. β-Cyclodextrin cationic polymers are promising cartilage-penetrating candidates by intra-articular injection due to the high biocompatibility and ability to entrap multiple therapeutic and diagnostic agents, thus monitoring and mitigating inflammation. In this study, nanoassemblies based on poly-β-amino-cyclodextrin (PolyCD) loaded with the non-steroidal anti-inflammatory drug diclofenac (DCF) and linked by supramolecular interactions with a fluorescent probe (adamantanyl-Rhodamine conjugate, Ada-Rhod) were developed to manage inflammation in osteoarticular diseases. PolyCD@Ada-Rhod/DCF supramolecular nanoassemblies were characterized by complementary spectroscopic techniques including UV-Vis, steady-state and time-resolved fluorescence, DLS and ζ-potential measurement. Stability and DCF release kinetics were investigated in medium mimicking the physiological conditions to ensure control over time and efficacy. Biological experiments evidenced the efficient cellular internalization of PolyCD@Ada-Rhod/DCF (within two hours) without significant cytotoxicity in primary human bone marrow-derived mesenchymal stromal cells (hMSCs). Finally, polyCD@Ada-Rhod/DCF significantly suppressed IL-1β production in hMSCs, revealing the anti-inflammatory properties of these nanoassemblies. With these premises, this study might open novel routes to exploit original CD-based nanobiomaterials for the treatment of osteoarticular diseases.
Highlights
Osteoarthritis (OA) is a prevalent, chronic and severe degenerative disease that affects about 50% of the over-sixty population [1]
Even the efficacy and/or safety of already approved drugs and formulations, such as corticosteroids and hyaluronic acid (HA) dispersions, are debated for different reasons: i) the time of residence of free drugs in the joint upon intra-articular administration is inadequate because of adverse pharmacokinetics that behave with rapid lymphatic drainage and physiological turnover of the synovial fluids and ii) the diffusion of drug trough cartilage could be slower than its clearance because of the high density of anionic extracellular matrix and small pore size ( 15 nm), free drugs could not achieve the therapeutic concentrations in the target site
Among the ongoing research on supramolecular self-assemblies based on CD for controlled drug/gene delivery in osteoarticular regeneration [43,44], here we develop a nanoconstruct based on branched cationic β-CD (Poly-β-amino-cyclodextrin, PolyCD) [45] entrapping DCF and anchoring a probe fluorescent [46] by a supramolecular interaction
Summary
Osteoarthritis (OA) is a prevalent, chronic and severe degenerative disease that affects about 50% of the over-sixty population [1]. In this scenario, branched cationic CD polymers have been designed for several applications They increase the permeability of drugs to biological membranes [28], self-assemble into optimized nanocontainers for efficient intracellular delivery [29], form nanoemulsions for oral delivery [30], or systems for targeting antimicrobial effects in biofilms [31]. Among the ongoing research on supramolecular self-assemblies based on CD for controlled drug/gene delivery in osteoarticular regeneration [43,44], here we develop a nanoconstruct based on branched cationic β-CD (Poly-β-amino-cyclodextrin, PolyCD) [45] entrapping DCF and anchoring a probe fluorescent (adamantanyl-Rhodamine conjugate, Ada-Rhod) [46] by a supramolecular interaction. The biocompatibility of the system was assayed on human bone marrow-derived mesenchymal stromal cells (hMSCs) and the decrease of intrinsic levels of IL-1β production in hMSCs was detected to evaluate the protective activities against proinflammatory responses
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