Preparation Of Activatable Photoacoustic Detection/Imaging Systems And Their Applications

In medicine,biomarkers are measurable indicators of the severity or presence of some disease state;they encompass a wide variety of molecules,such as enzymes,metabolites,nucleic acids,and etc.They are often assayed and evaluated for diagnosing specific diseases,in which specific biomarkers are consistently presented at abnormal concentrations.As a noninvasive imaging method,photoacoustic?PA?imaging,which is a hybrid imaging technique realized by detecting ultrasound waves following light absorption,can provide images for a region up to several centimeters in depth and offer a resolution down to 100?m.Furthermore,three-dimensional?3D?PA imaging can be realized by utilizing photoacoustic tomography?PAT?technology,which is especially suitable for precisely locating the focus of disease via detecting disease-specific biomarkers.For the contrast agents,the activatable ones capable of responding to specific biological stimuli and generating strong photoacoustic signals are particularly desirable,because they can achieve high sensitivity detection and allow for real-time tracking of dynamic processes.Hence,developing activatable photoacoustic contrast agents,which can quickly respond to the activity change of the corresponding disease biomarkers and thereby provide temporal and 3-D spatial information of the disease focuses,is of great significance.In this study,three kinds of activatable photoacoustic contrast systems were designed and prepared for detecting or monitoring drug-induced liver injury and cancer metastasis.First,an ALP-activated turn-on photoacoustic system was developed.A near infrared?NIR?chromophore?C₁X-OH?was synthesized by incorporating an indole group onto the xanthene structure;and then the ALP recognition element?phosphate group?was attached onto the chromophore to offord the“turn-on”photoacoustic contrast agent?C₁X-OR₁?.Under the catalysis of ALP,the electron-withdrawing phosphate?R₁?in C₁X-OR₁ can be hydrolyzed to the electron-donating group hydroxyl,thereby turning the contrast agent into its activated form?C₁X-OH?with a red-shifted absorption band and PA intensity enhancement at 684 nm.Thus the imaging of drug-induced liver injury and liver rehabilitation via responding to hepatic ALP activity was realized.Next,a Gal-activated turn-on photoacoustic agent was prepared.Compared with C₁X-OH,a more red-shifted near infrared?NIR?chromophore?C₂X-OH?was synthesized by replacing the indole group with a benzindole group,and then the Gal recognition element?galactose group?was attached onto the chromophore to give the“turn-on”photoacoustic contrast agent?C₂X-OR₂?.Under the catalysis of Gal,the weak electron-donating galactose?R₂?in C₂X-OR₂ can be hydrolyzed into the strong electron-donating group hydroxyl,thereby turning the contrast agent into its activated form?C₂X-OH?with a red-shifted absorption band and PA intensity enhancement at 703 nm.Hence the imaging of the metastasized tumors of ovarian cancer in abdominal cavity via responding to abdominal GAL level was achieved.Finally,a HAase-activated turn-on photoacoustic system was developed.A positively-charged tricyanofuran-containing heptamethine?TCHM?chromophore was synthesized and a negatively-charged hyaluronan was hydrophobically modified by introducing acetate groups into the polysaccharide.They are allowed to form nanoparticles TCHM@HA by electrostatic interactions to achieve the“turn-on”photoacoustic detection of HAase.The high HAase level in tumors can quickly disintegrate the photoacoustic system,and correspondingly induce deaggregation of TCHM and eventually generate enhanced PA signals,thereby producing temporal and 3D spatial information of the breast cancer metastasis to lungs.This study may help to promote the photoacoustic tomography technology to play even more significant roles in a variety of disease diagnoses with the help of activatable photoacoustic contrast agents.