Fabrication Of Multifunctional Carrier-free Metal-organic Coordination Nanosystems And Their Tumor-targeting Theranostic Studies

Multifunctional nanosystems provide an effective solution for tumor theranostics.However,the cumbersome carrier design,the dramatic differences in the scale-up synthesis,the low drug encapsulation rate,the poor stability,the associated carrier toxicity,and many issues seriously hinder the wide application of nanosystems in biomedicine and even in clinic.Here,to address the aforementioned scientific issues,a series of multifunctional carrier-free metal-organic coordination nanosystems are fabricated by the coordination-driven self-assembly technology via organic small-molecular theranostic agents and functional metal ions as building blocks and systematically discussed their fabrication mechanism,physical and chemical properties,in vitro and in vivo tumor-targeting theranostic effect,as well as biosafety.This paper mainly includes the following four chapters.Chapter 1:we profile the research progress of various multifunctional nanosystems and explain both topic basis and main research contents of this paper.Chapter 2:Recently,chemodynamic therapy(CDT)is still limited in the deficient endogenous H2O2 in tumor microenvironment and the harsh Fenton reaction conditions.In this chapter,dual-acting chemodrug methotrexate(MTX,a specific targeting ligand toward folate(FA)receptors),magnetic resonance(MR)imaging rare-earth GdⅢ,and CDT-1ike agent artesunate(ASA)as functional assemble-building blocks are fabricated into tumor-endogenous FeⅡ-activated and macroscopic MR imaging-monitored self-targeting carrier-free metal-organic coordination nanosystems by coordination-driven self-assembly technology.Such nanosystems with excellent physiological stability,high drug encapsulation rate,and outstanding tumor-targeting effect can be specifically uptaken through tumor cells via FA receptors and then quickly disassembled under the stimuli of lysosomal acidity,resulting in drug burst release.The released ASA can be catalyzed by tumor-specific overexpressed endogenous FeⅡ to generate the high abundance ROS for improving the CDT-like effect,which can exert a synergistic effect with the assistant chemotherapy of MTX.In addition,under guidance of self-targeting,such nanosystems exhibit obvious antitumor effect on FA receptor-overexpressed tumor-bearing nude mice,but have no remarkable toxic side effect on normal cells or tissues.Therefore,MR imaging-monitored self-targeting carrier-free metal-organic coordination nanosystems can not only improve the CDT effect but also provide a new strategy for the synergistic precise theranostics of tumor.Chapter 3:Inhibition of tumor angiogenesis is another idea of tumor therapy.In this chapter,enlightened by the smart transformable self-targeting nanosystems with high tumor-targeting efficiency,tumor penetration,and cellular uptake capacities,dual-acting chemodrug pemetrexed(PEM,a specific targeting ligand toward FA receptors),MR imaging transition-metal FeⅢ,and antiangiogenesis pseudolaric acid B are fabricated into carrier-free metal-organic coordination nanosytems with particle size reduction by coordination-driven supramolecular sequential co-assembly technology.Such nanosystems with good physiological stability and high drug encapsulation rate can decompose into numerous nanosystemes with ultra-small particle size and penetrate into tumor tissues under stimuli of the moderate acidic tumor microenvironment(pH 6.5),and then efficiently internalize into tumor cells through FA-receptor-mediated self-targeting effect.The macroscopic imaging results of both MR and computed tomography show that such nanosystmes possess outstanding self-targeting and tumor penetration effects.Besides,in this chapter,optical coherence tomography angiography and laser speckle microscopic imaging technologies innovatively employ in visually evaluating high efficient antitumor and antiangiogenic effects of nanosystems at the in vivo level.Hence,such nanosystems provide another alternative theranostic strategy for tumor-targeting theranostics.Chapter 4:To minimize the toxic side effect of nanosystems on normal cells or tissues,in this chapter,small-molecular 1,5-dihydroxynaphthalene(DHN)with’switchable toxicity’,Fenton-like agent CuⅡ,and photo/sonosensitizer indocyanine green(ICG)are regarded as functional assemble-building blocks.Programmable carrier-free metal-organic coordination nanosystems with spatiotemporal controllable antitumor effect are fabricated by coordination-driven self-assembly technology,which can be used for both intratumoral synthesis of chemodrug and deep non-invasive tumor therapy of synergistic chemotherapy,sonodynamic therapy,and CDT.Such nanosystems possess excellent physiological stability,high drug encapsulation rate,excellent photoacoustic and near-infrared fluorescence macroscopic imaging characteristics,as well as significant tumor-targeting effect.In addition,after such nanosystems internalization into tumor cells through the endocytic pathway,they will quickly disassemble under the stimuli of lysosomal acidity,leading to drug burst release.The released CuⅡ and ICG can induce Fenton-like and sonosensitive chemical reaction to generate hydroxyl radical(·OH)and singlet oxygen(1O2),respectively.Subsequently,1O2 specifically oxidizes the non-toxic prodrug DHN into the highly toxic chemodrug juglone(HPN).Moreover,in vitro and in vivo experimental results indicate that ·OH,1O2,and HPN can synergistically kill tumor cells and inhibit tumor growth,but have no any toxic side effect on normal cells or tissues.Therefore,such nanosystems provide a new idea for both efficiently non-toxic theranostic tumor and intratumoral selective synthesis of chemodrug.In summary,in this paper,a series of multifunctional carrier-free metal-organic coordination nanosystems have been successfully fabricated based on coordination-driven self-assembly technology.In addition,we systematically evaluate physicochemical properties,in vitro and in vivo performances,and macroscopic or microscopic imaging-monitored multimodal tumor-targeting therapy of such nanosystems.Furthermore,we also innovatively propose non-Fenton reaction-mediated CDT-like,microscopic imaging-monitored the influence of antiangiogenesis agent on tumor microvessels,the synthesis of chemodrug by intratumoral acoustic oxidation,as well as other new technologies and ideas.Therefore,a series of studies in this paper provide a new strategy for targeting theranostics of diseases,especially tumor.