Therapeutic effect of induced pluripotent stem cell -derived extracellular vesicles in an in vitro and in vivo osteoarthritis model.

Background/Objective: Osteoarthritis (OA) is a multifactorial joint disease associated with the deterioration of chondrocytes and inflammation. Treatment of OA is only aimed at reducing pain and improving joint function. Recently, extracellular vesicles (EVs) secreted from stem cells have emerged as a cell regenerative tool in several degenerative diseases, including OA. We hypothesised that induced pluripotent stem cell (iPSC)-derived EVs would be beneficial for regenerating chondrocytes and OA therapy. Therefore, we aimed to investigate iPSC-EVs' effects on chondrocyte behaviour in an interleukin 1 beta (IL-1ß)-induced in vitro OA model and anterior cruciate ligament transection (ACLT)-induced in vivo OA model of rabbit articular cartilage. Methods: The iPSC-EVs were isolated by sequential ultracentrifugation from a 48-h-incubated conditional medium of iPSC. The isolated iPSC-EVs were characterised by transmission electron microscopy, western blot analyses, and dynamic light scatter. The effects of iPSC-EVs on the viability of human primary chondrocytes and cell senescence were analysed. Premature senescence of cells was induced by long-term incubation with low doses of hydrogen peroxide. To investigate the therapeutic effect of iPSC-EVs on OA chondrocytes in vitro, IL-1ß was used to induce chondrocyte damage. Inflammatory macrophages were activated from THP-1 monocytes to observe the impact of iPSC-EV on macrophage polarisation. The phenotypes of the macrophages exposed to iPSC-EVs were evaluated by ELISA and western blot analyses. The primary chondrocytes were co-cultured with different phenotypes of macrophages to observe the expression of collagen II and catabolic enzymes in chondrocytes. iPSC-EVs were injected intraarticularly into the rabbit with an ACLT-induced OA model. The progression of lesions was assessed through macroscopic and histopathological studies. Results: We showed that iPSC-EVs significantly stimulated the proliferation of primary human chondrocytes and suppressed cell senescence by regulating the expression of p21 and collagen II. iPSC-EVs reduced matrix degradation enzymes and IL-6 expression and attenuated IL-1ß-mediated cell death of chondrocytes. Furthermore, iPSC-EVs modulated macrophage polarisation, resulting in the rescue of damaged chondrocytes in an inflammatory microenvironment. In the rabbit ACLT model, the OA-like lesions, including inflammation, subchondral bone protrusion, and articular cartilage destruction, were ameliorated by iPSC-EV. A histopathological study consistently revealed that iPSC-EVs attenuated ACLT-mediated alteration of MMP13 and ADAMTS5 and collagen II expression. Conclusion: iPSC-EVs protected chondrocytes by enhancing cell proliferation, suppressing premature senescence, and maintaining homeostasis of collagen II synthesis and matrix degradation enzymes such as matrix metalloproteinases (MMPs) and ADAMTS5. iPSC-EVs also reduced cell death in IL-1ß-mediated chondrocyte cell damage. In the rabbit ACLT-induced OA model, iPSC-EV injection reduced cartilage destruction, as indicated by the upregulation of collagen II and down-regulation of MMP13 and ADAMTS5. Overall, our results suggest that iPSC-EVs possess therapeutic potential and may be used as an OA treatment option. The translational potential of this article: This study highlights the potential of iPSC-EVs as a therapeutic option for chondrocyte regeneration and OA treatment.

Synergic Activity Against MCF-7 Breast Cancer Cell Growth of Nanocurcumin-Encapsulated and Cisplatin-Complexed Nanogels.

Nanogel-based systems loaded with single anticancer drugs display miscellaneous effectiveness in tumor remission, gradually circumventing mutation and resistance in chemotherapy. Hence, the existence of dual-drug delivered nano-sized systems has been contemporaneous with drug development and preceded the conventional-dose chemotherapy. Among outstanding synergistic drug nanoplatforms, thermosensitive copolymer heparin-Pluronic F127 (Hep-F127) co-delivering cisplatin (CDDP) and curcumins (Cur) (Hep-F127/CDDP/Cur) has emerged as a notable candidate for temperature-responsive drug delivery. The procedure was based on the entrapment of curcumin into the hydrophobic core of bio-degradable co-polymer Hep-F127 while the hydrophilic drug CDDP subsequently conjugated to the backbone heparin to form the core-shell structure. The copolymer was characterized by Fourier transform infrared (FT-IR) spectrophotometry, Transmission Electron Microscopy (TEM), and Dynamic Light Scattering (DLS), to corroborate the successful synthesis and via HPLC along with AES-ICP to evaluate the high drug loading along with a controllable release from the nano-gels. A well-defined nano-shell with size in the 129.3 ± 3.8 nm size range could enhance higher the efficacy of the conjugated-CDDP to Hep-F127 than that of single doses. Moreover, the considerable amount of dual-drug released from thermosensitive nanogels between different conditions (pH = 7.4 and pH = 5.5) in comparison to CDDP from Hep-F127 partially indicated the significantly anti-proliferative ability of Hep-F127/CDDP/Cur to the MCF-7 cell line. Remarkably, drug testing in a xenograft model elucidates the intricate synergism of co-delivery in suppressing tumor growth, which remedies some of the problems affecting in cancer chemotherapy.

Advances in thermosensitive polymer-grafted platforms for biomedical applications.

Studies on "smart" polymeric material performing environmental stimuli such as temperature, pH, magnetic field, enzyme and photo-sensation have recently paid much attention to practical applications. Among of them, thermo-responsive grafted copolymers, amphiphilic steroids as well as polyester molecules have been utilized in the fabrication of several multifunctional platforms. Indeed, they performed a strikingly functional improvement comparing to some original materials and exhibited a holistic approach for biomedical applications. In case of drug delivery systems (DDS), there has been some successful proof of thermal-responsive grafted platforms on clinical trials such as ThermoDox®, BIND-014, Cynviloq IG-001, Genexol-PM, etc. This review would detail the recent progress and highlights of some temperature-responsive polymer-grafted nanomaterials or hydrogels in the 'smart' DDS that covered from synthetic polymers to nature-driven biomaterials and novel generations of some amphiphilic functional platforms. These approaches could produce several types of smart biomaterials for human health care in future.