The Design,Synthesis Of Multifunctional Targeted Nanoparticles Based On Copper/Bismuth And Their Applications In Cancer Therapy

Nowadays,the serious environmental pollution,increased of human expectancy life and changes of lifestyle induced a high incidence of cancer ever before.China,as a populous country,has the highest morbidity and mortality of malignant cancer.The main treatment approaches are still operation,radiotherapy and chemotherapy.It is still difficult to attain satisfactory therapeutic effect only by these methods.The early diagnosis,precise and personalized treatment of tumors play a key role in the effective treatment of tumors.According to the characteristics of overexpressing and rapidly proliferating special receptors in tumor site,abnormal distribution of capillaries,hypoxia and high acidity.We designed nanocarriers that can actively target tumor,microenvironment responsed to reduce side effects of drugs.The copper and bismuth based nanomaterials have special advantages in photothermal treatment due to their special absorption peaks in the near infrared region,high photothermal conversion efficiency,facile preparation and abundant raw materials in the world.At the same time,Bi-based nanomaterials can be employed as theranostic platforms because of the large atomic number and high X-ray attenuation coefficient.This dissertation focuses on designing and constructing of multifunctional targeted copper-based and bismuth-based nanomaterials and their application in the treatment of tumors,including the following four parts:(1)In vivotargeted photothermal chemotherapy for breast cancer by multifunctional Cu39S28hollow nanopeanutsHere,unique Cu39S28 hollow nanopeanuts(HNPs)were synthesized via a facile one-step method.The formation mechanism was investigated by different reaction times through XRS,XRD and TEM results.The as-synthesized Cu39S28 HNPs exhibit outstanding photothermal conversion efficiency(41.1%)and drug storage capacity(DOX,99.5%).At the same time,the DOX drug loading nanocomposites have shown great sensitive response of release to either pH value or near infrared ray(NIR).In particular,the folic acid(FA)can easily conjugate with the synthesized Cu39S28 HNPs without further modification to get a targeted effect.The FA modified Cu39S28 HNPs showed an efficiently targeting effect in vitro and could considerably enhance the tumor-targeting effect more than 10 times in vivo.Moreover,the synthetical hyperthermia and drug release from Cu39S28 HNPs when under 808 nm laser could significantly improve the therapeutic efficacy compared with photothermal or chemotherapy alone both in vitro and in vivo.The histological studies in main organs also proved the well biocompatibility,while the tumor sites were in seriously destruction due to the accumulation of the nanocomposites and the combined photothermal chemo therapy effect.Therefore,the multi-functional nanocomposites can be excellent antitumor agents for their superb therapy effect in breast cancer.(2)Highly Efficient NIR-Triggered Drug Release from a Theranostic Platform for Osteosarcoma Imaging and Photothermal-Chemotherapy Using Actively Targeted Bismuth Sulfide@Mesoporous Silica NanoparticlesHerein,a smart NIR responsiveand osteosarcoma targeted theranostic platform was established.First,the CTAB-Bi2S3 was prepared as precursor and then formed Bi2S3@MSN by a template method.Moreover,the Bi2S3@MSN NPs were further modified with arginine-glycine-aspartic acid(RGD)peptide(c(RGDyC))through NHS-PEG-Mal linker.The as-synthesized NPs exhibited outstanding photothermal conversion(36.62%),ultrahigh drug loading(doxorubicin(DOX),99.85%)and an excellent X-ray CT contrast value(1.28 times higher than iobitridol).Notably,the NPs hold promising advantages for tumor treatment such as highly NIR-triggered drug release(even at an ultralow power density of 0.3 W cm-2),efficient active targeting and excellent real-time CT imaging at the tumor site.The synergistic photothermal-chemotherapy of the RGD-Bi2S3@MSN/DOX significantly ablated the highly malignant osteosarcoma.We further proves that the superior combined killing effect is achieved by enhancing the mitochondrial apoptosis pathway.Hence,the smart RGD-Bi2S3@MSN/DOX theranostic platform is a promising candidate for future applications in CT monitoring and synergistic treatment of malignant tumors.(3)Actively Targeted Deep-Tissue Imaging and Photothermal-Chemo Therapy of Breast Cancer by Antibody-Functionalized Drug-Loaded X-ray-Responsive Bismuth Sulfide@Mesoporous Silica Core-Shell NanoparticlesA theranostic platform combining synergistic therapy and real-time imaging attracts enormous attention but still faces great challenges,such as tedious modifications and lack of efficient accumulation in tumor.Here,we developed a novel type of theranostic agent,bismuth sulfide@mesoporous silica(Bi2S3@mPS)core/shell nanoparticles(NPs),for targeted image-guided therapy of human epidermal growth factor receptor-2(HER-2)positive breast cancer.To generate such NPs,polyvinylpyrrolidone decorated rod-like Bi2S3 NPs were chemically encapsulated with a mesoporous silica(mPS)layer and loaded with an anticancer drug,doxorubicin.The resultant NPs were then chemically conjugated with trastuzumab(Tam,a monoclonal antibody targeting HER-2 overexpressed breast cancer cells)to form Tam-Bi2S3@mPS NPs.By in vitro and in vivo studies,we demonstrated that the Tam-Bi2S3@mPS bear multiple desired features for cancer theranostics,including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation(with a bismuth content in tumor being?16 times that of non-targeted group).They can simultaneously serve both as an excellent contrast enhancement probe(due to the presence of strong X-ray-attenuating bismuth element)for computed tomography(CT)deep-tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermal-chemo therapy.(4)A targeted yolk-like Gd hybridized Bi theranostic nanoplatform for in vivo multimodal imaging and photothemal-chemotherapyIn order to establish a multi-imaging nanomaterial with clinical significance,and make up for the shortcomings of single imaging in practical applications.Herein,we designed a multifunctional yolk-like gadolinium(Gd)-hybridized bismuth(Bi)nanocomposites(mNPs)system for dual CT and MRI contrast imaging and photothermal-chemotherapy.The delicate mNPs was fabricated by silica-coated bismuth nanoparitcles with loading citrate-Gd complexes for tracing,and further silica coatings for better biocompatibility,reduced Gd3+leakage and further modification.The specific MCF-7 targeted peptide(AR)was conjugated with the mNPs by a disulfide bond linker.After loading with doxorubicin(DOX),the resultant AR-mNPs/DOX presented a glutathione(GSH)and NIR irradiation responsive drug release.Specially,the AR-mNPs/DOX could selectively accumulated in MCF-7 tumor cells and thoroughly ablate tumors under NIR irradiation(808 nm,1 W/cm2)via a combined photothermal-chemotherapy effect both in vitro and in vivo.Simultaneously,the AR modified mNPs possess ultrahigh efficiency for enhanced CT/MRI contrast imaging and extra-long tumor retention time(7 days).Thus,the precise dual-modal(CT and MRI)imaging and synergistic photothemal-chemotherapy of the AR-mNPs make them promising candidates in breast cancer diagnosis and treatment.