Abstract��OBJECTIVE To synthesize low molecular weight chitosan-acetylcysteine (LMWC-NAC) conjugate and investigate its renal targeting profile and the rapeutic effects in model mice with acute kidney injury (AKI).METHODS NAC was conjugated to LMWC by EDC/NHS reaction and the LMWC-NAC conjugate was identified by 1H-NMR. The cellular uptake of LMWC-NAC conjugate and megalin receptor involved in this process was investigated in vitro. In addition, the tissue distribution of ICG-labelled LMWC-NAC conjugate was investigated in nude mice. AKI were induced by LPS intraperitoneal injection (20 mg��kg-1).The parameters including Scr, BUN, inflammatory factors (TNF-�� and IL-1��),and oxidative stress (MDA) were determined and renal histology was observed.RESULTS LMWC-NAC conjugate was successfully synthesized by the amide interaction.The in vitro studies demonstrated that the uptake of LMWC-NAC conjugate was mediated by the megalin receptor on HK-2 cells, and the tissue distribution experiment indicated that LMWC-NAC conjugate was mainly accumulated in the kidney.LMWC-NAC conjugate significantly suppressed Scr, BUN, inflammatory factors and oxidative stress (P<0.01) and improved kidney injury. CONCLUSION LMWC-NAC conjugate showed good renal targeting profile and effect in recovering renal functions, which indicates the potential of LMWC-NAC conjugate as a safe and efficient drug delivery system for the treatment of AKI.
ELBINI DHOUIB I, JALLOULI M, ANNABI A, et al. A minireview on N-acetylcysteine: an old drug with new approaches [J]. Life Sci, 2016, 151:359-363.
GONG Y Q, XU S Z, HUANG T L, et al. Meta-analysis of N-acetylcysteine on prevention of contrast-induced nephropathy [J]. Chin J Nephrol(�л����ಡ��־), 2012, 28(12): 927-932.
TARIQ M, MORAIS C, SOBKI S, et al. N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats [J]. Nephrol Dial Transplant, 1999, 14(4):923-929.
NITESCU N I, RICKSTEN S E, MARCUSSEN N, et al. N-acetylcysteine attenuates kidney injury in rats subjected to renal ischaemia-reperfusion [J]. Nephrol Dial Transplant, 2006, 21(5):1240-1247.
ZYOUD S H, AWANG R, SULAIMAN S A, et al. Relationship between serum acetaminophen concentration and N-acetylcysteine-induced adverse drug reactions [J]. Basic Clin Pharmacol Toxicol, 2010, 107(3):718-723.
GAO S, HEIN S, DAGNAS-HANSEN F, et al. Megalin-mediated specific uptake of chitosan/siRNA nanoparticles in mouse kidney proximal tubule epithelial cells enables AQP1 gene silencing [J]. Theranostics, 2014, 4(10):1039-1051.
YUAN Z X, ZHANG Z R, ZHU D, et al. Specific renal uptake of randomly 50% N-acetylated low molecular weight chitosan [J]. Mol Pharm, 2009, 6(1):305-314.
YUAN Z X, LI J J, ZHU D, et al. Enhanced accumulation of low-molecular-weight chitosan in kidneys: a study on the influence of N-acetylation of chitosan on the renal targeting [J]. J Drug Target, 2011, 19(7):540-541.
LEELAHAVANICHKUL A, YASUDA H, DOI K, et al. Methyl-2-acetamidoacrylate, anethyl pyruvate analog, decreases sepsis-induced acute kidney injury in mice [J]. Am J Physiol Renal Physiol, 2008, 295(6):1825-1835.
SUH S H, LEE K E, KIM I J, et al. Alpha-lipoic acid attenuates lipopolysaccharide-induced kidney injury [J]. Clin Exp Nephrol, 2015, 19(1):82-91.
YANG L. Mechanisms of injury and repair of acute kidney injury [J]. Chin J Kidney Dis Invest, 2013, 2:120-124.
WEISBORD S D, PALEVSKY P M. Contrast-associated acute kidney injury [J]. Crit Care Clin, 2015, 31(4):725-735.
ANDRADE K Q, MOURA F A, SANTOS J M, et al. Oxidative stress and inflammation in hepatic diseases: therapeutic possibilities of N-acetylcysteine [J]. Int J Mol Sci, 2015, 16(12):30269-30308.
DOLMAN M E, HAMSEN S, STOM G, et al. Drug targeting to the kidney: advances in the active targeting of therapeutics to proximal tubular cells [J]. Adv Drug Deliv Rev, 2010, 62(14):1344-1357.