Synthesis And Application Of Multifunctional Response Nanocarrier In Multimodal Synergistic Cancer Therapy

In recent years,the application of nanotechnology in the field of cancer has increased exponentially.In particular,nanoparticles provide an opportunity to design and adjust the effects that other types of treatment can't achieve,and show a promising as a new generation of cancer treatment.In the treatment of cancer,targeted treatment,in which only cancer cells are killed and normal cells are not injured,has become increasingly desirable.The introduction of nanoparticles has brought new materials and approaches for cancer targeted therapy.These nanoparticles also have the functions of imaging guidance and early diagnosis.It is still an urgent problem that nanoparticles targeted to in the lesion and combine various treatments to improve the cure rate of tumor.Futhermore,as the diversity and complexity of tumor,a single treatment method is difficult to achieve the desired effect.In this paper,multifunctional nanocarriers with exogenous stimulation and tumor microenvironment response were constructed for tumor diagnosis and multimodal combination therapy.The main findings are summarized as follows:(1)The targeted chemo-photothermal synergistic therapy and photoacoustic/CT imaging of tumor were achieved by one novel multifunctional nanoprobe(GMS/DOX@SLB-FA),it was composed of gold nanostar core and doxorubicin(DOX)loading mesoporous silica shell(GMS),which was coated with folic acid(FA)modified thermosensitive supported lipid bilayer(FA-SLB)as gatekeeper.The multifunctional probe had perfect dispersion and stability;2.1 nm mesoporous pore and 208 nm hydration particle sizes were obtained.In vitro studies indicated that drug-loading probe had excellent ability of controlling release of DOX with 71.98±2.52% cumulative release after laser irradiation,which was significantly higher than that of unirradiation control group.A survival rate of 72.75±4.37% of He La cells at 57.75 ?g/m L probe also demonstrated the low cytotoxicity of the targeted probe.Both in vitro and in vivo results showed that the probe could achieve targeted photoacoustic imaging of tumor due to the fact that FA modified probe could specifically recognize the overexpressed FA receptors on tumor cells;meanwhile,the probe could also achieve the chemo-photothermal synergistic therapy of tumor through controlling the drug release from mesoporous channels by near infrared laser.Therefore,the probe had great potential in the early diagnosis and treatment of cancer.(2)A biomimetic nanoplatform was designed with dual p H/ultrasound response,homologous targeting and low phototoxicity for combined nitric oxide(NO)gas therapy with SDT.This nanoplatform is composed of zeolite imidazole framework-8 material embedded with nitrosoglutathione(GSNO)and chlorin e6(Ce6)by one-step encapsulation,and then wrapped by homologous tumor cell membrane.In vitro and in vivo experiments indicate that the biomimetic nanoplatform has excellent biocompatibility and shows higher retention in tumor by homologous targeting.Importantly,it can sustainably release the encapsulated drug in acidic tumor microenvironment and accelerate degradation by ultrasound(US).Furthermore,NO released from GSNO and reactive oxygen species generated by Ce6,which are both triggered by US,react with each other to produce highly reactive peroxynitrite to inhibit the growth of tumor.Moreover,by repeated US irradiation,the tumor hypoxia can be relieved for a much-longer term,resulting in an effective gas-sonodynamic combined treatment.This study fully utilizes the advantages of US,providing a new strategy for high-performance cancer therapy.(3)A smart biodegradable drug delivery nanoplatform with mitochondrial-targeted ability,p H-responsive drug release and enzyme-like catalytic function is designed.This efficient ROS-generating platform uses ultrasound with deeper penetration capability as excitation source for combined chemotherapy and sonodynamic therapy(SDT)of tumor.In vitro experiments show that the nanoplatform can co-load Ce6 and DOX and be degraded in slight acid environment,and the DOX release rate is 63.91±1.67 %.In vivo experiments show that the nanoplatform has extremely biosafety and can be enriched in tumor site and excluded from body after 24 h.More significantly,after combined treatment,the tumors are eliminated and the mice still survive healthily without recurrence after 60 d.This is because not only it can achieve mitochondrial targeting and use platinum particle to increase oxygen content in TME to enhance the effect of SDT,but also it can use weak acidic TME to accelerate drug release to achieve the combination of chemotherapy and SDT.The probe provides a new strategy for designing ROS-based nanoplatform for the treatment of malignant tumor.In summary,this paper mainly constructs multifunctional probes with imaging and combine various treatments methods,and at the same time uses external laser or ultrasonic irradiation and special microenvironment of tumor tissue to achieve drug controlled release.It provides a new strategy and basis for the exploration of multimodal combined therapy.