| Hepatocellular carcinoma(HCC)is a great threat to human health due to its high rates of death,metastasis and recurrence.Chemotherapy is the most common treatment strategy for the cancer,the non-selective distribution and limited drug penetration in tumors,however,causing serious toxic side effects and limited in vivo antitumor efficacy.The emergence of nanoparticulate drug delivery systems holds promise to address these problems,which can improve drug accumulation to the tumor site via the enhanced permeability and retention(EPR)effects.In addition,it can also reduce the toxicity of drugs in normal tissues.Herein,we have developed a cascade tumor therapeutic nanoplatform consisting of docosahexaenoic acid(DHA)and nicorandil(NI),namely DNP,to specifically produced cytotoxic agents in tumor cells.In addition to directly killing tumor cells,DNP can dilate tumor blood vessels and increase the intratumoral oxidative stress levels.The DHA was able to generate lipid peroxides in a radical chain reaction under the stimulation of endogenous H2O2,resulting in intracellular extensive accumulation of reactive oxygen species(ROS).Meanwhile,NI produced nitric oxide(NO)in response to overexpressed glutathione(GSH)in tumors.Notably,the two functional species further reacted in situ to form reactive nitrogen species(RNS),exacerbating tumor cells death.In addition,the released NO induces vasodilation in tumor site,leading to tumor hypoxia alleviation and increased deep tumor penetration of nanoparticles.In contrast,DNP barely generate ROS and NO in normal cells with low redox level,it has relatively little impact on normal cells,which guarantees security of normal cells to some extents.The major research contents of this paper are shown as follows:Preparation and characterization of liposomes.The DHA and NI co-loaded liposomes(DNP)were prepared by thin-film hydration method,DNP was observed by transmission electron microscope(TEM)to be well-dispersed,uniformly spherical nanoparticles.The particle size of DNP was about 171.1 nm,and the zeta potential was-50 mV,it also displayed good stability under the physiological conditions and storage environment.In addition,DNP produced ROS and NO in response to redox environment in tumor cells specifically.In vitro functional antitumor capacity of liposomes.We have applied the hepatocellular carcinoma cells HepG2 and normal liver cells LO2 models for specific cytotoxicity and functional studies.The results indicated the efficient internalization of DNP by HepG2 cells.Cytotoxic ROS,NO,and RNS produced by DNP could kill tumor cells,moreover,the cytotoxic effects of DNP was inhibited by the RNS scavenger(Uric acid).However,DNP did only generate low or no ROS and NO in LO2 cells,indicating the selective cytotoxicity of DNP.Furthermore,DNP could elevate the levels tumor oxidative stress and alleviate tumor hypoxia by inhibiting Glutathione peroxidase 4 and hypoxia-inducible factor-1α,.In vivo functional antitumor capacity of liposomes.we have established HCC patient-derived xenograft(PDX)mode on BALB/c nude mice to investigate the antitumor capacity of DNP in primary tumors.The results show that DNP can effectively reach the tumor site and responsively produce RNS for antitumor therapy.In addition,the released NO can dilate blood vessels,which increased the blood flow and oxygen perfusion in tumor site,especially deep tumors,and relieve the hypoxic state of the tumor.In addition,due to the enhanced EPR effect mediated by NO,increasing the accumulation and penetration of Doxorubicin in tumor site,presenting the best antitumor efficacy.The tissue sections of major organs and blood biochemistry analysis suggested the good biocompatibility and safety of DNP.In summary,here we have developed a cascade therapy nanoplatform for tumor cascade therapy with tumor-specific killing,hypoxia alleviation and enhanced intratumoral delivery efficiency of chemotherapy drugs,which provides ideas and strategies for the development of antitumor nanomedicines. |
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