Synthesis Of Bismuth-based Photothermal Nanomaterials For Tumor Multimodal Imaging And Thermo-chemotherapy

Photothermal therapy(PTT)is a newly-emerged antitumor therapeutic technique,which mainly utilizes the photothermal conversion capacity of photothermal agents(PTAs)to heat tumors,result ing in local hyperthermia to destroy tumor tissues.Due to the light scattering and absorption effect as well as the inhomogeneous heat distribution upon irradiation,eradicating tumors completely by PTT alone is very difficult.Combining PTT and chemotherapy can remedy the inherent defects of each single-modal therapy and significantly improve antitumor therapeutic efficacy through synergistic thermo-chemotherapy.For an accurate and safe treatment,multimodal imaging techniques are essential to provide diagnostic information and therapeutic monitoring.C urrently,many drawbacks of the developed PTAs have been revealed,such as the sophisticated synthesis and modification,high cost,poor photothermal performance,low biocompatibility,sole function,and lacking drug loading capacity.Therefore,developing novel and high-performance PTAs for multimodal imaging and drug delivery is of great importance to realize precise diagnoses and therapies for tumors.This dissertation has fabricated four kinds of multifunctional bismuth-based PTAs for multimodal imaging,PTT and drug delivery.The main research contents are summarized as follows:To conquer defects(such as instability,lacking biocompatibility and drug loading capacity)of the reported Bi2Se3 nanoplates,drug nancarriers based on Bi2Se3 nanoplates with improved stability is constructed via a successive human serum albumin and polydopamine coating method for efficient loading of doxorubicin(DO X).The nanocarriers show strong N IR absorption,excellent photothermal conversion ability and acid pH-/photothermal-sensitive dual-modal drug releasing property.They can be used not only for X-ray computed topography(C T)and infrared thermal(IRT)imaging,but also for the combination of PTT and chemotherapy to realize thermo-chemotherapy for a significant tumor inhibit ion effect with good biocompatibility.To overcome shortcomings(such as involved multiple modifications and low drug loading capacity)of the Bi2Se3 nanoplate-based nanocarriers,a novel synthetic method for porous Bi2 Se3 nanomaterial is developed.Porous sponge-like Bi2Se3 nanospheres are synthesized via one-step hydrothermal method by utilizing Bi2O3 nanospheres as templates and adding Se source.This method without no complicated modifications is simple and convenient.The nanospheres show excellent storage stability,photothermal conversion ability and cell biocompatibility.They can not only be used for IRT,C T and photoacoustic(PA)triple-modal imaging,but also have a remarkable photothermal inhibit ion effect on tumor cells/tissues.Moreover,their porous structures are successfully utilized to load DO X and improve the drug loading capacity of Bi2Se3 materials,with a loading capacity as high as ~ 19.1%.The drug releasing rate is sensit ive to both acid pH and photothermal effect.The DO X-loaded nanospheres can be used to combine PTT and chemotherapy to realize synergistic thermo-chemotherapy for a more efficie nt tumor suppression.Furthermore,such nanospheres possess excellent biosafety.In addition,by replacing Se with S source,such synthetic method can be expanded to obtain porous Bi2S3 nano-urchins,which also show important potentials for biomedical applications.To solve drawbacks(such as involved toxic synthetic reagents,non-single component,and low CT enhancement efficiency)of the bismuth chalcogenide-based(Bi2Se3 and Bi2 S3)PTAs,a novel mult ifunctional PTA is developed based on pure Bi nanocrystals(NCs).The Bi NCs are first synthesized by a chemical reducing method,and then their sufaces are modified via a layer-by-layer self-assembly technique to obtain polyethylene glycol-coated Bi NCs.The NC s show excellent storage stability and cell biocompatibility,and can not only convert NIR optical energy into heat with a photothermal conversion e fficiency at ~30.1%,but also possess ultrahigh C T enhancement effic iency(~ 60.3 HU·m L/mg),which is much higher than that of bismuth chalcogenide-based materials.The NCs can realize IRT,CT and PA triple-modal imaging.Moreover,utilizing such NCs plus laser irradiation can significantly inhibit tumor growth without obvious in vivo toxicity,showing great potentials for PTT application.To endow the pure Bi-based PTA with drug loading capacity,a novel synthetic method for porous Bi photothermal nanomaterial is developed.Highly porous Bi nanoraspberries(N Rs)are synthesized via a one-step chemical reducing method by utilizing Bi2O3 nanospheres as templates,and then modified with bovine serum albumin to obtain porous Bi N R-based drug nanocarriers.The N Rs can be effectively internalized by tumor cells without noticeable cytotoxicity,and possess strong NIR absorption and excellent photothermal ability,achieving a significant PTT killing effect on tumor cells upon laser irradiation.Due to their porous structure,DOX can be loaded into the N Rs with a loading capacity as high as ~57.8%.The DO X-loaded N Rs exhibit acid pH-/photothermal-sensitive dual-modal drug releasing property,and can realize efficient intracellular drug delivery.PTT and chemotherapy functions of the DO X-loaded N Rs can cooperate in a synergistic manner to realize thermo-chemotherapy,and achieve a much higher tumor inhibit ion efficacy than either monotherapy alone.Moreover,the N Rs show no obvious toxicity in vivo,and thus may have broad application prospects for cancer treatments.