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bioRxiv · 10.1101/2020.04.06.027136

Rapamycin-PLGA microspheres induce autophagy and prevent senescence in chondrocytes and exhibit long in vivo residence

Dhanabalan, K. M.·Gupta, V. K.·Agarwal, R.
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Abstract

Osteoarthritis (OA) is a joint disease that results in progressive destruction of articular cartilage and the adjoining subchondral bone. The current treatment is focused on symptomatic relief due to the absence of disease-modifying drugs. The primary cells of the cartilage, chondrocytes, have limited regenerative capacity and when they undergo stress due to trauma or with aging, they senesce or become apoptotic. Autophagy, a cellular homeostasis mechanism has a protective role in OA during stress but gets downregulated in OA. Rapamycin, a potent immunomodulator, has shown promise in OA treatment by autophagy activation and is known to prevent senescence. However, its clinical translation for OA is hampered due to systemic toxicity as high and frequent doses are required. Hence, there is a need to develop suitable delivery carriers that can result in sustained and controlled release of the drug in the joint. In this study, we have fabricated rapamycin encapsulated poly (lactic-co-glycolic acid) (PLGA) based carriers that induced autophagy and prevented cellular senescence in human chondrocytes. The microparticle (MP) delivery system showed sustained release of drug for several weeks. Rapamycin-microparticles protected in-vitro cartilage mimics from degradation, allowing sustained production of sGAG, and demonstrated a prolonged senescence preventive effect in vitro under oxidative and genomic stress conditions. These microparticles also exhibited a long residence time of more than 19 days in the joint after intra-articular injections in murine knee joints. Such particulate systems are a promising candidate for intra-articular delivery of rapamycin for treatment of osteoarthritis. Statement of SignificanceCurrent OA treatment is symptomatic and does not change the disease progression. Many drugs have failed as they are rapidly cleared and are unable to maintain therapeutic concentration in the OA joint. Direct joint administration of drugs using sustained-release systems offer several advantages, which includes increased bioavailability, fewer off-target effects, and lower total drug cost. We have engineered a suitable drug carrier which provides a tunable drug release pattern. This study provides evidence that PLGA encapsulated rapamycin remained potent and prevented OA like changes in chondrocytes under genomic and oxidative stress. The particle formulation also had a longer residence time in the knee joint of mice which can be translated in clinics for intra-articular therapeutic injections for increased patient compliance. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/027136v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1c5901borg.highwire.dtl.DTLVardef@177fa3eorg.highwire.dtl.DTLVardef@1ce2a55org.highwire.dtl.DTLVardef@3d5d6f_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Dhanabalan, K. M., Gupta, V. K., Agarwal, R.. 2020-04-06. Rapamycin-PLGA microspheres induce autophagy and prevent senescence in chondrocytes and exhibit long in vivo residence. https://doi.org/10.1101/2020.04.06.027136

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