Novel Nanoplatforms For Biological Imaging And Antitumor Therapy

Real-time monitoring of the concentration and distribution of disease markers in cells is significant for early diagnosis,prevention and inmediate treatment of disease.Currently,the major imaging technologies include optical imaging and magnetic resonance imaging.Among them,fluorescence imaging technology based on fluorescent probe shows high sensitivity,spatial-temporal resolution imaging and almost nondestructive to cells,which is a powerful tool for monitoring disease markers in live cells.However,the existing one-photon fluorescent probes have shortcomings such as photobleaching,shallow penetration depth and intracellular self-fluorescence interference.Notably,two-photon fluorescence imaging is a technique that incorporates two-photon laser as the excitation.Due to the longer excitation wavelength,two-photon fluorescence can achieve deeper tissues penetration depth,reduced photo-damage,and lower background fluorescence interference.Therefore,two-photon fluorescent probes are more suitable for the study of complex biological systems.Nanotechnology is a revolutionary development in science and engineering in recent years.Nanomaterials have been widely used in catalysis,energy,biological imaging and drug delivery due to their unique size dependence.Nano-sensors and nano-theranostics have been rapidly developed.The nanomaterials that are commonly used to construct nanoprobes and nanotheranostics include gold nanoparticles,metal organic frameworks(MOFs),coordination polymer nanomaterials,etc.,which have high membrane penetration capacity,excellent biocompatibility and large loading capacity.Therefore,nanoprobes constructed by combining imaging technology and nanotechnology have a broad potential application in the study of complex biological systems.Due to the biological instability and insufficient imaging effect of the existing fluorescent probe,as well as the complicated synthesis and low loading capacity of nanotheranostics,in this paper,by using the advantages of the imaging technology and nanomaterials,a series nanoprobes and nanotheranostics were developed for imaging in complex biological systems and effective anti-tumor treatment.The major contents are as follows:1)In chapter 2,to solve the problems of traditional function nucleic acid-gold nanoparticles-based single photon fluorescent probe,we combine two-photon fluorescent molecules with the deoxyribozyme(8-17DNAzyme)-gold nanoparticle system to obtain a two-photon fluorescent nanoprobe for Zn²⁺imaging.The nanoprobe has a high two-photon absorption cross section and good selectivity to Zn²⁺.The nanoprobe was applied to the imaging of Zn²⁺in living cells and mouse tissue slices,and the results were satisfactory.The design of the nanoprobe is universal and c an be used to develop advanced fluorescent probes for biosensors and biomedical imaging.2)In chapter 3,based on the size adjustability,good biological compatibility and biological degradation of metal-organic frameworks(MOFs),a two-photon metal-organic framework(TP-MOF)imaging platform was synthesized using PCN-58 as the building block by the method of post-synthetic modification for imaging of zinc ions in the living cells and tissues.The nanoprobe shows low background signal.After being endocytosed by cells,in the presence of zinc ions,the nanoprobe exhibites enhanced fluorescence under the light radiation.This synthetic strategy provides a general idea for the design of probes of various target molecules in complex biological systems.3)The imbalance of hydrogen sulfide in the body is related to a variety of diseases,such as hypertension and myocardial ischemia.Therefore,it is of great significance to study the distribution of hydrogen sulfide in living organisms.However,most of the sensing probe are based on organic molecular probes,which shows limited application in cellular imaging due to the false positive signals.In chapter 4,based on the design proposed in the previous chapter,we construct a two-photon fluorescent nanoprobe based on metal organic frameworks for imaging hydrogen sulfide in living cells and tissues.After endocytosed by cells,in the presence of hydrogen sulfide,the nanoprobe shows fluorescent signal recovery.The nanoprobe shows better detection performance than that of the mesoporous silicon based nanoprobe.In addition,under the condition of cell lysate,this probe has better anti-interference ability than organic small-molecule probe,which provides a better platform for detecting hydrogen sulfide in complex systems.4)MOFs is widely used in biomedical imaging and drug delivery due to its size adjustability,good biocompatibility and biodegradability.However,the application of MOFs-based nanocarriers has been limited by some disadvantages,such as low load ing efficiency and complex construction steps.An ideal drug carrier usually shows the advantages of high drug loading rate,good biocompatibility and controlled drug release behavior.In chapter 5,we developed an“one-pot”method for constructing FU-Mn metallodrug nanotheranostics(Mn-FU),through a facile coordination self-assembly strategy.Compared with other drug delivery systems,higher loading efficiency of FU(47.7 wt%)was achieved,by embedding FU as bridging ligands into such metal-drug coordinated nanotheranostics.After proper surface modification,Mn-FU was able to accumulate into the tumor site,which significantly improved the utilization rate of FU.Notably,Mn-FU exhibited ultra-sensitive release of FU and Mn²⁺within acidic tumor microenvironment,resulting in high selectivity toward cancer cells,so as to reduce the unwanted toxicity toward normal tissues.Moreover,the accompanying release of Mn²⁺produced gradually elevated MRI contrast and the responsive MRI signal was correlated with the release of FU,which could achieve MRI correlated drug release,being beneficial for evaluating therapeutic outcomes.Thereby,Mn-FU could effectively amplify the combined chemo-radio therapeutic outcomes,with synergistic antitumor efficacy,and reduce the toxic side effects.