Ferrocene-Containing Functional Polymeric Nanocarriers For Chemodynamic Therapy

Chemodynamic therapy is a novel tumor therapy strategy by utilizing Fenton reaction to produce hydroxyl radical(.OH)for anti-tumor treatment.Compared with chemotherapy,optical therapy and other tumor treatment strategies,chemodynamic therapy has specific advantages such as high selectivity and safety,ignoration of tumor depth,high efficiency of reactive oxygen species generation,no consideration of drug resistance and so on.However,the insufficient concentration of hydrogen peroxide(H2O2)in the tumor microenvironment severely limits the efficacy of chemodynamic therapy.At the same time,chemodynamic therapy cannot inhibit tumor metastasis which makes it difficult to realize clinical transformation.In this work,we increase the H2O2 concentration in situ to ensure the continuous Fenton reaction and improve the efficacy of chemodynamic therapy by nano-delivery strategy.At the same time,we combine chemodynamic therapy with immunotherapy for immune potentiation therapy.This dissertation includes the following three parts:1st Chapter:Relative to normal cells,tumor cells lack adequate capability of reactive oxygen scavenging.Thus,tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue.We constructed an integrated multifunctional polymeric nanoparticle which can selectively improve H2O2 levels in tumor tissue and convert them into more active ·OH by Fenton reaction.First,the diblock copolymers containing polyethylene glycol(PEG)and poly(glutamic acid)modified by ?-cyclodextrin(?-CD)were synthesized.The block copolymer,ferrocenecarboxylic acid hexadecyl ester(DFc),and ascorbyl palmitate(PA)were co-assembled in aqueous solution to obtain stable core-shell micelles through the inclusion complexation between ?-CD moieties in the block copolymer and ferrocene(Fc)groups from DFc.After intravenous injection,the particles achieve significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of H2O2,and subsequently Fenton reaction is catalyzed by Fc groups to produce ·OH to kill cancer cells and suppress tumor growth efficiently.The micellar systems exhibites great potentials toward cancer therapy through synergistic H2O2 production and conversion into hydroxyl radicals specifically in tumor tissue2nd Chapter:Chemodynamic therapy has been proposed to convert tumoral H2O2 into toxic hydroxyl radicals(·OH)via Fenton or Fenton-like reactions for antitumor efficacy,which is frequently limited by low and heterogeneously distributed H2O2 concentrations inside tumor tissues.Herein,we present ferrocene-containing responsive polymersome nanoreactors via loading glucose oxidase(GOD)and hypoxia-activable prodrug tirapazamine(TPZ)in the inner aqueous cavities.After intravenous injection,the polymersome nanoreactors with the optimized nanoparticle size of?100 nm and poly(ethylene glycol)corona facilitate tumor accumulation.The tumor acidic microenvironment can induce the enhancement in permeability of the polymersome membranes to activate the nanoreactors and release the loaded TPZ prodrugs.Tumor oxygen and glucose can enter the polymersome nanoreactors and are transformed into H2O2 under the catalysis of GOD,which are further converted into·OH via Fenton reaction under catalysis of ferrocene moieties.The oxygen consumption can aggravate tumor hypoxia to activate hypoxia-responsive TPZ prodrugs which can produce benzotriazinyl(BTZ)radicals and ·OH.All the produced radicals synergistically kill tumor cells via the amplified CDT and suppress the tumor growth efficiently.Thus,the ferrocene-containing responsive polymersome nanoreactors loading TPZ represent a potent nanoplatform to exert amplified CDT for improved anticancer efficacy3rd Chapter:Stimulator of interferon genes(STING)activation by STING agonists has been recognized as one of important immunotherapy strategies.However,immunosuppressive tumor microenvironment always hinders the therapeutic efficacy of cancer immunotherapy.Herein,we engineer ferrocene-containing polymersome nanoreactors by co-loading glucose oxidase(GOD)and STING agonist,symmetry-linked amidobenzimidazole(DiABZI),for enhanced STING activation and combination chemodynamic-immunotherapy.After intravenous injection,the polymersomes can accumulate in tumor tissues.The tumor acidity-triggered polymersome membrane permeability improvement allows the entrance of tumoral glucose and oxygen for H2O2 production by GOD,which is further transformed into hydroxyl radicals(·OH)under the catalysis of ferrocene moieties.Chemodynamic therapy(CDT)based on ·OH can induce efficient cellular apoptosis and release of fragmented DNA and tumor-associated antigens to promote endogenous STING activation and reverse immunosuppressive tumor microenvironment.Simultaneously,pH-responsive release of DiABZI activates STING pathway to elicit antitumor immune responses.Therefore,DiABZI and CDT synergistically enhance the antitumor immunity via combination chemodynamic-immunotherapy.The primary tumors are completely ablated and the growth of distant tumors that were established after treatment is also suppressed efficiently.The polymersome nanoreactor-mediated chemodynamic-immunotherapy represents a promising treatment strategy toward primary solid and metastatic tumors.