The Construction Of Intelligent Nanomaterials For Cancer Therapy

Cancer has become a serious threat to human health due to its high mortality and low cure rates.However,the common clinical treatments including mainly surgery,radiation therapy and chemotherapy are often restricted from poor selectivity and serious damage to normal cells and healthy tissues.Therefore,achieving passive and/or positive targeting cancer therapy is of great importance.Recently,nanomedicine has received intensive attention.Typically,nanoparticles(NPs)possess tunable size,good biocompatibility and easy modification,highlighting a great potential in drug delivery.In the regard of the passive targeting,NPs can accumulate in the tumor site through the enhanced permeability and retention(EPR)effect of tumor.Moreover,by decorating with targeting molecules,NPs can also realize active drug delivery.In this dissertation,we developed several intelligent nanocarriers to achieve targeted drug delivery and on-demand drug release.And the main content is summaried as follows:1.A Targeted DNAzyme-Nanocomposite Probe Equipped with Built-in Zn2+ Arsenal for Combined Treatment of Gene Regulation and Drug DeliveryDNAzymes have been extensively used as catalytic nucleic acids in the design of sensing platforms.However,their potentials as intelligent drug carriers for responsive drug release in gene therapy and chemotherapy were rarely explored.Therefore,we report a dual-functional probe(GNPs-ES-Dox/ZnO)composed of gold nanoparticles(GNPs),catalytic Zn2+dependent DNAzyme,anticancer drug doxorubicin(Dox),targeted AS 1411 aptamer and acid-decomposable ZnO quantum dots(ZnO QDs)to achieve intracellular gene regulation and drug delivery in a controlled manner.By means of aptamer-guided targeting and receptor-mediated endocytosis,the probes were specifically internalized into the HeLa cells and trapped in the acidic endo-/lysosomes,where the ZnO QDs as the built-in Zn2+ arsenal were promptly dissolved to offer Zn2+,leading to the activation of DNAzyme to cleave the substrate strands,and subsequent drug release.Meanwhile,as designed,one part of the cleaved substrate,hybridized with the overexpressed miR-21 in the target cells,thereby declining its intracellular level.Taken together,the down-regulation of miR-21 has a synergistic effect with Dox to efficiently eradicate the cancer cells.Thus,the favorable biocompatibility,cancer cell specificity and combined treatment make the probe promising for therapy of multidrug-resistant cancer and in vivo application.2.Acid-Degradable Gadolinium-Based Nanoscale Coordination Polymer:A Potential Platform for Targeted Drug Delivery and Potential MR ImagingDuring conventional chemotherapy for cancer,nonspecific drug distribution,which causes serious side effects in normal tissues,is a serious limitation.Thus,it is desirable to develop a tumor or intracellular microenvironment-responsive nanosystem for targeted and on-demand drug release.In the present study,we engineered an intelligent pH-activatable nanosystem,in which a gadolinium-doxorubicin-loaded nanoscale coordination polymer(Gd-Dox NCPs)was the core and hyaluronic acid was the targeting shell.Taking advantage of CD44 receptormediated recognition,the nanoparticles were internalized selectively into HeLa cells,and trapped within acidic compartments where the fluorescence of Dox recovered,along with the acid dismantling of the Gd NCPs,allowing real-time monitoring of drug release.In vitro experiments also showed that the Gd NCPs present enhanced T1 signals after acid-triggered degradation,suggesting their potential use as contrast agents for magnetic resonance imaging.Such nanocarriers,which feature high biodegradation,selective targeting ability,and rapid response to stimulus,demonstrated enhanced therapeutic efficacy in targeted cancer cells and"turned on" T1 in vitro,showing great promise for diagnosis and treatment.3.In Situ Assembly of Large Pore Silica-MnO2 Nanoparticles as pH-/H2O2-Responsive Nanocarriers for Oxygen-Elevated Photodynamic Therapy and Potential MR Imaging The low selectivity and poor photostability of currently available photosensitizer seriously hinders the therapeutic effect of O2-dependent photodynamic therapy(PDT)and restricts its potential applications in clinical treatment.Herein,cancer cell-specific,endogenous H+/H2O2-activated,and O2 self-sufficient nanocomplexes are engineered for efficient cancer therapy.The nanoparticles(NPs)are constructed utilizing large pore silica NPs(LPMSNs)as substrates for in situ MnO2 growth and as nanocarriers for photosensitizers loading,and further functionalized with tumor targeting AS 1411 aptamers.Upon selectively taken up by cancer cells,massive O2 and Mn2+ ions are generated arising from the endogenous H+/H2O2triggered disintegration of MnO2.The continuous O2 generation can greatly improve the O2dependent PDT efficiency.In vitro experiments show that the response to H+/H2O2 also enhances T1-weighted MR signals,which is benefited from the liberation of Mn2+ions that enable the largest access of Mn2+to water molecules.Such NPs with good biocompatibility and rapid response to intracellular H+/H2O2,have demonstrated improved therapeutic effect in targeted cancer cells and activated MR signals in vitro,providing a promising strategy to alleviate the tumor hypoxia for guided and effective PDT.4.PEGylation of UiO-66 Nanoparticles for Combined Photodynamic and HypoxiaActivated TherapyThe PDT outcomes are often discounted by inadequate O2 level in tumor site.In order to efficiently eradicate cancer cells,AQ4N,a bioreductive prodrug which will become quite toxic under hypoxic condition is utilized to combine PDT.Under hypoxic condition,AQ4N will undergoes enzymatic reduction to become toxic AQ4 by endogenous enzyme.And the produced AQ4 is a topoisomerase II inhibitor which will affect the DNA replication,inhibit cell proliferation and induce cell death.As triggered by laser irradiation,PDT will generate severe hypoxia which will fully trigger the cytotoxicity of AQ4N to achieve combined photodynamic therapy and chemotherapy.Herein,photosensitizer(HPPH)functionalized UiO-66 metal-organic framework(MOF)NPs,which feature biodegradation and high porosity,are selected as nanocarriers for AQ4N payload.The further PEG decoration helps to(?)improve the stability of the NPs;(?)prolong the blood-circulation time of the NPs and(?)eliminate nonspecific uptake by healthy tissues.During drug delivery,the NPs are stable with minimal prodrug release.Upon reaching tumor site and trapped within cancer cell,AQ4N will be promptly released in the presence of the extra high phosphates concentration in intracellular fluid.Meantime,chemotherapy is activated by virtue of PDT induced tumor hypoxia,thus achieving enhanced therapeutic efficiency compared to PDT.