| Cancer is one of the world’s leading causes of death.Although many efforts have been made in the cancer research,there is no significant improvement in the five-year survival rate of cancer.Therefore,accurate cancer diagnosis and more effective therapy is urgently needed.Theranostics,integrating diagnostic imaging and therapy into a single system,directly meets the requirements of personalized medicine.However,most of the theranostic agent shave low tumor accumulation ability,short retention time and poor specificity,which greatly limit their biomedical applications.Taking advantages of multiple strategies,we here in develop the gold nanoparticles(AuNPs)-based nanotheranostic agent,SAAN,which can self-assemble in-situ by responding to acidic tumor microenvironment.Two kinds of ligands with different charges arechosen to modify AuNPs surface,aiming to control the size and surface properties of the SAAN under different environments.During the blood circulation,the SAAN presents in the form of ultra small particles with electric neutrality,which significantly extends its circulation time in vivo.Once inside the tumor microenvironment,the lower pH can induce the interaction between different ligands on SAAN surface,making SAAN self-assemble into larger particle with positive charge.Thanks to such large size and positive charge,the self-assembly of SAAN can better take the advantage of the enhanced permeability and retention effect(EPR)of solid tumors to achieve the enhanced retention and high accumulation in the tumor site,which further guarantees the subsequent photoacoustic imaging and image-guided photothermal therapy.The main contents of the thesis are as follows:(1)Gold nanoparticles with different size were synthesized and modified with two kinds of ligands with different charge.The physical and chemical properties of obtained AuNPs were characterized by UV-vis,TEM,DLS,etc.Furthermore,we explored the effects of size and surface ligands on pH responsiveness and plasma coupling of AuNPs.Taking into all these factors,we finally selected the 15 nm spherical AuNPs as the skeleton to fabricate the in-situ self-assembled SAAN in the tumor microenvironment.(2)The performance of photoacoustic imaging and photothermal therapy of SAAN were investigated in vitro.Compared with results under the normal pH,the photoacoustic signal of SAAN was significantly enhanced at pH=6.5,resulting in improved the signal-to-noise ratio(SNR).Then the photothermal effect of SAAN was examined at the solution and cell level.As expected,SAAN did self-assemble at pH=6.5.With decreasing distance between AuNPs,the surface plasma-coupling effect of SAAN was enhanced,which significantly increased photothermal ability of SAAN.Such "OFF-ON" design in response to low pH in the tumor microenvironment not only enhances the SNR of photoacoustic imaging,but also significantly improves photothermal therapeutic effect.(3)Photoacoustic imaging guided photothermal therapy of SAAN were explored in vivo.Compared with the pH-inert Au-PEG probe,the photoacoustic signals of SAAN increased by 17 times,achieving accurate visualization of tumor.Under the guidance of photoacoustic imaging,808 nm laser irradiation made the temperature on the tumor sitereached to 56℃,which is significantly higher than Au-PEG group.Also,SAAN can reduce the damage to the normal tissue and realize specific therapy.Therefore,SAAN is a promising theranostic agent which can achieve effectively photothermal therapy guided by accurately photoacoustic imaging. |
