Basic Investigation On Anti-tumor Drug Delivery System Based On Multi-stimuli Responsive Mesoporous Nanomaterials

The nanomedicines integrate with the characteristics including tumor targeting effect,high efficiency and low toxicity,controlled drug release behavior,which provide new insights into multimodality theranostic applications in cancer treatments.New therapeutic models based on nanomaterials such as photothermal therapy,photodynamic therapy and magnetic hyperhermia therapy,also open exciting opportunities for tumor therapy.The drug delivery systems based on physical responsive nanomaterials with surface gatekeeper modification have been developed for drug targeted delivery,intelligent controlled release and tumor multi-mechanism theranosics.In this study,we constructed a various of anti-tumor drug delivery system based on multi-stimuli responsive mesoporous nanoplatforms.The main contents are as follows:1.Tumor-targeted and multi-stimuli responsive drug delivery system for near-infrared light induced chemo-phototherapy and photoacoustic tomographyThe doxorubicin(DOX)as the chemotherapeutic agent is accompanied by low accumulation in tumor and drug resistance,which limited its therapeutic index.In this study,we constructed a tumor-targeted and multi-stimuli responsive drug delivery system for near-infrared light induced chemo-phototherapy and photoacoustic tomography.Hollow mesoporous copper sulfide nanoparticles(HMCu2-xS NPs,0<x<1),a rising star in near infrared(NIR)resonant materials,could generate heat and cytotoxic reactive oxygen species(ROS)for photothermal therapy(PTT),photodynamic therapy(PDT)and photoacoustic tomography(PAT)under NIR irradiation.On account of their unique hollow porous structure,HMCu2-xS NPs easily served as nanocarriers in which small DOX molecules could be loaded as guest molecules inside the pores in doses sufficient for high therapeutic efficacy.The outer surface of HMCu2-xS NPs was capped with multifunctional hyaluronic acid(HA)simultaneously as smart gatekeeper as well as tumor targeting moiety,which was responsible for minimizing premature drug release and tumor targeting effeciency.In vitro drug release experiment showed that the coated HA could be degraded by intracellular lysosomal enzyme hyaluronidase(Hyal-1),which facilitated DOX release.After that,the acidic micro-environment of tumor cell and external NIR stimulus could trigger more release of DOX from nanoparticles.Reasonably,tumor intracellular tunable drug release with spatial/temporal resolution opened up new possibilities for a more sophisticated on-demand cargo delivery and enhanced antitumor efficacy.In vitro studies,the nanoplatform(DOX/HMCu2-xS-HA)pinpointed MCF-7 cells via CD44 receptor-mediated endocytosis pathway.Additionally,PAT imaging results showed that HMCu2-xS-HA exhibited highest photoacoustic signals in tumor site at 3 h post-injection.Therefore,HMCu2-xS NPs could serve as a powerful contrast agent for PAT to guide chemo-phototherapy by visualizing the tumor site/size/morphology.In vivo anti-tumor efficacy assay showed that the synergistic combination of chemo-phototherapy offered by DOX/HMCu2-xS-HA under NIR irradiation reduced V/V0 as low as 0.94 ± 0.11,showing a substantial therapeutic effect.2.An intelligent NIR-responsive chelate copper-based anticancer nanoplatform for synergistic tumor targeted chemo-phototherapyThe chelate copper-based anticancer drug bleomycin(BLM)is usually believed to bind metal ions especially Cu(Ⅱ)in the presence of O2 to form BLM-Cu(Ⅰ)-O2,the"activated BLM" for DNA cleavage.Under NIR irradiation,a leakage of a small quantity of copper ions containing Cu(Ⅰ)and Cu(Ⅱ)from HMCu2-xS NPs(0<x<1)took place since the solubility product constant Ksp of Cu2-xS NPs increased along with photo-hyperthermia.Thus,it might be a great idea to load BLM into HMCu2-xS NPs to realize the formation of BLM-Cu(Ⅱ),which offered an intelligent NIR-responsive chelate copper-based anticancer nanoplatform for synergistic tumor targeted chemo-phototherapy.The biocompatible phase-changing material,L-menthol(LM),could instantaneously transform from its liquid state to a solid phase below its Tm(43 ℃),entrapping BLM in the solid LM and acting as a gatekeeper to realize "zero premature release".Herein,BLM and LM co-loaded HMCu2-xS NPs with surface folic acid(FA)modification were formulated to construct an intelligent NIR-responsive nanoplatform.With the tumor targeting ability of the folate receptor(FR)-positive,FA-HMCu2-xS/BLM/LM could pinpoint tumor cells efficiently.Under NIR irradiation,the photohyperthermia and ROS generation induced by FA-HMCu2-xS resulted in the endo/lysosomal disruption and redistribution of guest molecules from the endosomal compartment to the cytoplasm for further delivery.In vivo anti-tumor efficacy assay showed that FA-HMCu2-xS/BLM/LM under NIR irradiation reduced V/V0 as low as 0.35 ± 0.12,showing a substantial therapeutic effect.More importantly,it so happened that NIR-responsive BLM release and copper ion(Cu(I)and Cu(Ⅱ))leakage from FA-HMCu2-xS occurred simultaneously upon photoexcitation,followed by the generation of the "activated BLM",which further initiated the Cu-dependent BLM-mediated DNA strand scission.Therefore,FA-HMCu2-xS/BLM/LM herein has offered an intelligent NIR-responsive chelate copper-based anticancer nanoplatform for synergistic tumor targeted chemo-phototherapy in a coordinated way.With this delicate design,such a versatile all-in-one drug delivery platform would pave the way for more effective nanotherapeutics in biomedical fields.3.pH/ultrasound dual-responsive drug delivery system for ultrasound imaging-guided therapeutic inertial cavitation and sonodynamic therapyIn this study,we found that mesoporous calcium carbonate nanoparticles(MCC NPs)showed the pH/ultrasound dual-responsive instantaneous decomposition behaviors.Based on these desirable properties,we developed a pH/ultrasound dual-responsive drug delivery system,which was based on mesoporous calcium carbonate(MCC)nanoparticles by loading sonosensitizer(hematoporphyrin monomethyl ether,HMME)and modifying surface hyaluronic acid(HA).After pinpointing the tumor regions via CD44 receptor-mediated endocytosis pathway,HMME/MCC-HA decomposed instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound(US)irradiation,concurrently accompanying with CO2 generation and HMME release with spatial/temporal resolution.Subsequently,multiple factors including increased osmotic pressure led to the endo/lysosomal disruption and redistribution of nanoplatform from endosomal to cytoplasm for further delivery.In vivo anti-tumor efficacy assay showed that HMME/MCC-HA under NIR irradiation reduced V/V0 as low as 0.87 ± 0.13,showing a substantial therapeutic effect.On the one hand,the CO2 bubbling and bursting effect under US stimulus resulted in cavitation-mediated irreversible cell necrosis,as well as the blood vessel destruction to further occlude the blood supply,providing a "bystander effect".On the other hand,US activated ROS generation of HMME targeted the apoptotic pathways for effective SDT effect.Reasonably,it was undoubtedly logical that HMME/MCC-HA exploited the merits of synergistic combination of therapeutic inertial cavitation and sonodynamic therapy(SDT)simultaneously,resulting in antitumor effects with multi-mechanisms.More importantly,absences of targeting effect and two local stimulations(acidity and US irradiation)in normal tissues,would significantly avoid the potential side effect.Moreover,the echogenic property of CO2 made the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions.Based on the above findings,such all-in-one drug delivery platform of HMME/MCC-HA highlighted possibilities of advancing cancer theranostics in biomedical fields.