High Targeting Nanoplatform For Enhanced Photothermal And Chemotherapy Efficiency In Breast Cancer

Nanomedicine has been an unprecedented expansion with the development for various desease including cancer.Nanopartilce is the most important part of the nanomedicine,the unique biological properties of the nanoparticles given their small size and large suface area-to-volume ratio and small volume,which allow them to carry drugs and bind to compounds such as small molecule DNA,RNA,proteins,resulting in their modified surface chemical properties.Furthermore,the tunable size,shape,and surface characteristics also allow the nanoparticles have high stability,high hydrophilic features.The targeting ability is the most important feature of the nanoparticles,with modified receptor or ligand,which can efficiently navigate the nanoparticles through the complex in vivo environment,resulting in increased intracellular trafficking,and sustained release of drug payload.These advantages make nanoparticles potentially superior to conventional cancer therapies with higher therapeutic efficiency.This theis highlights the high targeting ability of the nanoplatform for combination therapies for breast cancer,mainly including the following three aspects:Part Ⅰ:The assembly and in vitro characteristics of nanoscale flexible Mo S2 embeded human serume albumin hollow nanocapsulesNanomaterials mediated nanomedicine provides multiple imaging and combination therapeutic methods for tumor diagnosis and treatment.Human serume albumin(HSA)is natural protein in human body,which has the advantages of no immunogenicity,long blood circulation time,and tumor targeting,which is the ideal material for tumor treatment.Herein,Mo S2 embedded human serum albumin hollow nanocapsules(denoted Mo S2/HSA)are successfully prepared via a hard-core-assisted layer-by-layer coating approach.During the preparation,the300 nm Si O2 are coated with Mo S2 nanospheres via electrostatic interaction,following by coatinh HSA on the surfaces of the Mo S2 modified Si O2 by using poly(ethylene imine)and glutaraldehyde as crosslinking agents.When the Si O2cores are etched away,the hollow Mo S2/HSA nanocapsules are obtained.The fabricated hollow Mo S2/HSA nanocapsules possess an uniform size(280 nm),a larger hollow cavity,a low Young’s modulus(E_Y,222±20 MPa),excellent photothermal conversion ability,and a high doxorubicin(DOX)loading capacity(27 wt%)(Mo S2/HSA-DOX).The in vitro and in vivo experiments show that the biocompatibility of the Mo S2/HSA hollow nanocapsules is excellent,and the Mo S2/HSA hollow nanocapsules can significantly enhanced cellular uptake against the stiffer ones via targeting to the high expressed gp60 receptor in tumor.In the p H7.4 PBS solution,the release rate of DOX is 5.9%,while under the acid condition(p H4.0)and laser irradiation(2 W/cm~2),the DOX release rate significantly increase up to 48.2%.The acid and laser responsive drug release characteristic make these flexible Mo S2/HSA hollow nanocapsules an excellent chemotherapeutic agent.Furthermore,under the laser irradiation for 10 min(2W/cm~2),the Mo S2(100μg)can convert the laser into heat,with the increasing tempreture up to 68.7℃,which allow to kill the cancer cells with the cell viability of 12.3%via photothermal therapy.Therefore,the flexible Mo S2/HSA nanoplatforms potentially play an important role to effectively ablate breast cancer via synergistic photothermal and chemotherapy.Part Ⅱ:The in vivio tumor targeting and synergistic therapeutic efficiency of nanoscale flexible Mo S2 embeded human serume albumin hollow nanocapsulesThe flexible Mo S2/HSA hollow nanocapsules are obtained by using hard-core-assisted layer-by-layer coating approach.These flexible Mo S2/HSA hollow nanocapsules exhibit a long circulation profile,with the half-life time of 9.2 h,mean residence time of 170.9 h,blood area under the curve of 109 mg/m L*h,and clearance of 0.18 m L/h*kg.The breast tumor bearing mice model show that the flexible Mo S2/HSA hollow nanocapsules have higher tumor accumulation(27%)than their solid counterparts.Under the conditions of tumor acid environment and laser irradiation,the flexible Mo S2/HSA hollow nanocapsules dramatically release DOX for chemotherapy.In the same time,the Mo S2 converts the laser into heat for photothermal therapy after laser irradiation.In vivo experiments of breast tumor bearing mice further demonstrate that the Mo S2/HSA-based nanoplatforms effectively ablate breast cancer cells via synergistic photothermal therapy and chemotherapy.Considering the excellent properties,it is believed that the flexible Mo S2/HSA nanoplatforms open a new window for the elasticity and tumor targeting properties,as well as provide strong support and evidence for effective high targeting and combination therapy in breast cancer.Part Ⅲ:Disulfiram-Gold-Nanorod Integrate for Effective Tumor Targeting and Photothermal-Chemical Synergistic TherapyHerein,we successfully construct a gold nanorods with disulfiram integrates(denoted Au-DSF)nanoplatform for high tumor targeting and combination therapy.The Au nanorods are stabilized with thiol group-terminated PEG and then modified with DSF via thiol-gold bonds.The Au-DSF integrates possess a uniform length(70 nm),excellent photothermal conversion ability,and a high DSF loading content(23.2%),and glutathione-,acid-,and laser-responsive release properties.In addition,the Au-DSF integrates show significantly enhanced cellular uptake by chelating to the high intracellular concentrations of copper(Cu)to form DSF/Cu complex.The in vitro experiment show that the cellular uptake of Au-DSF integrates significantly increase,suggesting the Au-DSF integrates had high tumor targeting ability.Furthermore,after co-incubated with Au-DSF integrates for 24 h,the reactive singlet oxygen(ROS)is deteted,and the amount of ROS significantly increase,the over-produced ROS cause abundant cells apoptosis.Therefore,the Au-DSF integrates can effectively kill cancer cells by producing ROS for chemotherapy.Importantly,the Au-DSF integrates can convert the laser into heat and cause local high tempreture under the laser irradiation.The in vitro experiment show that the Au-DSF integrates and laser irradiation effectively kill cancer cells with only 2.3%cell viability,suggesting the Au-DSF integrates and laser facilitate photothermal and chemotherapy for high efficiency cancer treatment.The in vivo experiment show that the Au-DSF integrates exhibit a long circulation profile,with the half-life time of 8.0 h,mean residence time of 28.4 h,high blood area under the curve of 36.8 mg/m L*h,and clearance of 0.5 m L/h*kg.The breast tumor bearing mice model show that the Au-DSF integrates had higher tumor accumulation(12%)due to the targeting ability of DSF to the abundance of Cu ions in the tumor site.In vivo experiments show that the Au-DSF integrates dramatically decreased tumor size via photothermal therapy and chemotherapy.Hematoxylin-eosin and TUNEL staining show that the Au-DSF integrates induce necrotic and apoptotic for cancer cells.The high therapeutic efficiency of the Au-DSF integrates for breast cancer is further demonstrated by the reduced elasticity on ultrasound elastography,and no perfusion of the contrast agent on contrast-enhanced ultrasound imaging in tumors.This work gives advantages for sophistication of nanomedicine by incorporating active targeting,multidrug combinations,and synergistic therapeutics for cancer treatment,which is of great importance for its clinical translation.