Bio-inspired Synthesis Of High-performance Nanoprobes For Tumor Diagnosis And Therapy

Objective:(1)Tf-ICG nanoprobe: Targeting theranostic nanoprobes play a vital role in bioimaging and therapy in vivo,and give profound significance for the development of precision medicine with minimized systematic effects.The biosafety of theranostic nanoprobes also attracts increasing attention.Although plenty of nanoprobes with excellent imaging abilities,effective therapeutic effects and remarkable targeting abilities are available,the ambiguous toxicity of non-biodegradable components has highly hindered their application in clinical therapy.In addition,tedious synthetic procedures,the necessity for toxic reagents,harsh reaction conditions and large energy consumption in most of the traditional methods have also limited the large-scale and environmentally-friendly production of the nanoprobes with high reproducibility.So,the design of a smart strategy for the fabrication of theranostic nanoprobes with excellent active targeting ability and impressive biocompatibility in a facile and green way is highly desired.(2)BSA-CuS nanoprobe: Photothermal therapy as a physical therapeutic approach has greatly attracted research interest due to its negligible systemic effects.Among the various photothermal agents,CuS nanoparticles have been widely used due to their easy preparation,low cost,high stability and strong absorption in the NIR region.However,the ambiguous biotoxicity of CuS nanoparticles limited their bio-application.So it is highly desirable to develop biocompatible CuS photothermal agents with the potential of clinical translation.Subjects and Methods:(1)Tf-ICG nanoprobe: We reported a green and facile strategy to synthesize an active targeting theranostic nanoprobe with intrinsic biosafety and active targeting ability for near-infrared(NIR)fluorescent imaging and photothermal therapy.The nanoprobe was fabricated by simply mixing transferrin(Tf)and indocyanine green(ICG)in aqueous solution under stirring at room temperature.Tf,as a human-inherent tumor targeting ligand,was employed as a smart scaffold to load ICG,and FDA approved ICG was used as a theranostic agent.The application of free ICG suffers from non-specific binding to proteins,self-aggregation in physiological solutions and rapid elimination from the body.The hydrophobic interaction between the hydrophobic binding pockets of Tf and amphiphilic ICG enables their selfassembly to produce Tf-ICG nanoparticles.(2)BSA-CuS nanoprobe: We reported a simple synthetic route to construct biocompatible albumin-directed CuS photothermal agents.The BSA-CuS nanoparticles were prepared via mimicking biomineralization processes.In a typical procedure,Cu(NO3)2 was added to BSA solution under magnetic stirring,resulting in a blue mixture.After quickly adding NaOH,the mixture turned to purple.Then Na2 S was added,and the color of the solution turned to brick red immediately.The solution was further processed at 90°C for 0.5 h,and the color turned to dark green,indicating the formation of BSA-CuS nanoparticles.Results:(1)Tf-ICG nanoprobe: We have shown the fabrication of an efficient theranostic nanoprobe with intrinsic biocompatibility and targeting ability for NIR fluorescence imaging and photothermal therapy of tumors.A green and facile strategy for loading ICG on Tf was proposed based on the hydrophobic interaction-mediated self-assembly of Tf and ICG by simple mixing in aqueous solution without the need of any toxic reagents or tough synthetic conditions.The novel theranostic nanoprobe offered uniform size,excellent water solubility and colloidal stability,favorable biocompatibility and impressive active targeting theranostic effects in vitro and in vivo.(2)BSA-CuS nanoprobe: We reported a novel strategy to synthesize biocompatible CuS nanoparticles for in vivo PTT using BSA as the template due to its commercial availability,low cost and good biocompatibility.More importantly,the protein-directed synthesis has advantages in the aspects of excellent colloidal stability and good biocompatibility since it is an inherent biomacromolecule in living organisms.The low cytotoxicity and negligible toxicity in vivo were proven by MTT assays,biochemical analysis of blood and weight monitoring.The tumor cells treated with the nanoparticles under irradiation were effectively damaged.Furthermore,the tumor of the mice treated with BSA-CuS nanoparticles was removed by laser rradiation with a low power density in a short irradiation time without causing any obvious systemic damage.Conclusion:(1)Tf-ICG nanoprobe: This work presents the simplest method for the fabrication of active targeting theranostic agents;and also the first example of active targeting theranostic agents synthesized using green reagents and procedures.The proposed method opens a new way for the fabrication of biocompatible and targeting nanoprobes using a green and facile strategy,and could be easily extended to construct other nanoprobes for the diagnosis and treatment of malignant tumors using other functional proteins and FDA approved small organic molecules.(2)BSA-CuS nanoprobe: A novel strategy for the synthesis of CuS nanoparticles was developed using BSA as the template,and the excellent biocompatibility and efficient photothermal therapy effects of BSA-CuS nanoparticles show great potential as an ideal photothermal agent for cancer treatment.The proposed BSA-CuS nanoparticles with excellent biocompatibility and favorable photothermal therapy efficacy will open a new way for the fabrication of high-performance and biosafe photothermal therapy nanoagents.