Multi-stimuli Responsive Nanoplatform For Antitumor Therapy

Cancer has already become one of the major diseases,which are hazardous to human health currently.Efficiently eliminating the tumor and minimizing the undesired side-effects are the main challenges for the researchers.Chemotherapy,radiotherapy as well as gene therapy require smart delivery systems to transport the therapeutic agents(drugs,sensitizers and genes)to the lesion sites for enhanced therapeutic outcomes and reduced side-effects.To overcome the various barriers in delivery process,we designed a series of stimuli-responsive nanoplatforms for safe and high-performance tumor cell eradication.Detailed contents are as follows:In Chapter 1,the latest research and main challenges for nanoplatform of various therapeutic methods are introduced,and the design and application of various stimuli-responsive delivery systems are also elaborated.In Chapter 2,a reduction and near infrared(NIR)irradiation dual-responsive gene delivery system has been designed.Electropositive peptide sequence(CKKKKKKC)and nuclear location sequence NLS(CPKKKRKVC)were cross-linked by disulfide bond to obtain pNLS with both gene condensing and nucleus targeting capabilities.After loaded with desired gene,the pNLS/DNA was further decorated with AuNC to form the pNLS/DNA/AuNC complexes via electrostatic interactions.After cellular internalization via the endocytosis pathway,the AuNC could generate ROS and accelerate the endo/lysosomal escape of the pNLS/DNA/AuNC complexes under mild NIR-irradiation.Followed by the GSH induced disulfide bond breakage in cytoplasm,the complexes would release loaded genes and facilitate the subsequent nuclear translocation for enhanced gene transfection.Both endosomal escape and gene transfect capability of the dual-responsive gene delivery nanoplatform have been investigated.In Chapter 3,a reduction-responsive polyethyleneimine-based gene delivery nanoplatform was designed for tumor cell targeting therapy and tracking.Tumor targeting moiety and fluorescent probe were facilely decorated on the nano-complexes of reductive polycations and gene by taking the advantages of host-guest interactions between p-Cyclodextrin and adamantane,a-Cyclodextrin and benzene.Owing to the rich hydroxyl of cyclodextrin,the nanoplatform can inhibit protein adsorption and possess high serum stability.Followed by the cytoplasmic GSH triggered disulfide bond breakage,the complexes would release the loaded genes and facilitate gene transfection.Both in vitro and in vivo results demonstrated that the obtained multifunctional gene delivery system could mediate efficient tumor targeting,fluorescent tracking,gene transfection and possess excellent biocompatibility.In Chapter 4,a tumor microenvironment and NIR irradiation dual-responsive nanoplatform has been designed for combinational chemo-photothermal therapy.According to the in vitro and in vivo results,this stably circulating nanoplatform would deshell and target the tumor cells.Under NIR irradiation,indocyanine green(ICG)-generated hyperthermia would cleave thermal-labile Azo linker and accelerate the release of ICG and DOX in mesoporous silica nanoparticles(MSN).And then the liberated ICG transformed light to cellular hyperthermia for further photothermal therapy,and the liberated DOX diffused to the nuclei for chemotherapy.Integrating the therapeutic processes,the nanoplatform can efficiently suppress tumor growth.In Chapter 5,a pH-responsive size-changeable nanoplatform,which can penetrate the tumor parenchyma,was designed for programmed tumor therapy.Tumor penetrating peptide tLyP-1-modified WS2 quantum dots(WS2-HP)were tethered onto doxorubicin(DOX)-loaded MSN via acid-labile benzoic-imine bonds.tLyP-1 can facilitate the tumor homing.Once located at the mild acidic tumor sites,this nanoplatform can rapidly break into DOX@MSN-NH2 and WS2-HP.The electropositive DOX@MSN-NH2 can mediate efficient chemotherapy on surface tumor cells,while the small-sized high-penetrative WS2-HP can penetrate the tumor parenchyma and accomplish NIR light-triggered photothermal ablation of the deep-seated malignant cells.After killing the tumor cells in different depths via the programmed therapeutic modalities,DOX@MSN-WS2-HP under NIR irradiation would significantly inhibit the solid tumor growth.