Smart Bioresponsive Optical Theranostic Agents

Optical theranostic agents have been widely used in clinical practice because light is ease production,noninvasive nature,adjustable intensity and wavelength,and finely controllable spacetime.Most of currently developed optical theranostic agents are “always-on”agents that continuously emit signal regardless of whether they reach target sites,causing low target-to-background ratio and serious side-effect of theranostic.Recent research has showed that physiological environment of the normal tissues are obviously different from the pathological microenvironment of diseased tissues.The pathological microenvironment is important biomarker for different kinds of disease,such as cancer,inflammation and cardiovascular disese.Thus,pathological microenvironment-responsive optical theranostic agents,which pristinely stay in the “off” state and uncage theranostic signals(“on” state)in responding to pathological parameters(i.e.,irregular pH,redox,or enzyme),receive increasing attention.Such pathological microenvironment-responsive optical theranostic agents exhibit higher target-specificity than traditional “always-on” optical theranostic agents.However,there are still some drawbacks in the structure design and applications for the existing pathological microenvironment-responsive optical theranostic agents: 1.Currently reported pathological microenvironment-responsive probes are ambiguous to identify complex and dynamic pathological environment in vivo and may potentially pose the issue of nonspecific activation and even cause ‘false positive' result.2.Currently reported optical theranostic agents are seriously limited to the shallow tissue-penetration of external photoexcitation.Therefore,we aim to develop novel pathological microenvironment-responsive optical theranostic agents with good optical property,ultrahigh specific activation and deeper tissue-penetration of depth.The thesis can be divided into three sections:1.Diketopyrrolopyrrole-based semiconducting polymer nanoparticles for in vivo second near-infrared window imaging and image-guided tumor surgeryA diketopyrrolopyrrole-based semiconducting polymer nanoparticle(PDFT1032)as a NIR-?(Near infrared window ?,1,000-1,700 nm)fluorescent probe has been developed.It shows high photostability,favorable absorption peak at 809 nm,large Stokes shift of 223 nm,outstanding biocompatibility and minimal in vivo toxicity.More importantly,the versatile use of PDFT1032 for several important biomedical applications in NIR-? window have been demonstrated,including NIR? optical imaging of tumor on subcutaneous osteosarcoma model,assessing of vascular embolization therapy of tumor,and NIR-? image-guided orthotopic tumor surgery and sentinel lymph node biopsy(SLNB)with high spatial and temporal resolution.Overall,excellent biocompatibility,favorable hydrophilicity,and desirable chemical and optical properties render the semiconducting polymer nanoparticle PDFT1032 a highly promise NIR-? imaging probe with a potential of being widely applicable in clinical imaging and surgical treatment of malignancy.2.Organic Semiconducting macromolecule probe with Redox-Activatable NIR-? Fluorescence for In Vivo Real-time Monitoring drug-toxicityDrug toxicity is one of the most common concern for the majority of modern medicine.1 The liver,as the central role of transforming and clearing of exogenous and endogenous xenobiotics in human body,is often the most affected organ,and its failure can result in mortality.For a marketing license of drug applications,drug-induced hepatotoxicity is a critical rejection factor.Drug toxicity is one of the most common concern for the majority of modern medicine.The liver,as the central role of transforming and clearing of exogenous and endogenous xenobiotics in human body,is often the most affected organ,and its failure can result in mortality.For a marketing license of drug applications,drug-induced hepatotoxicity is a critical rejection factor.Thus,innovative preclinical screening methods for drug-induced hepatotoxicity holds great promise for reducing hepatotoxicity,improving patient safety,and raising therapeutic effect.An activatable organic semiconducting macromolecular probe that specifically turns on its second near-infrared window fluorescence upon nitric oxide(NO)stimuli was developed for in vivo in-situ,real-time and high spatial resolution mapping dosedependent drug-induced hepatotoxicity.3.‘Dual lock-and-key'-controlled nanoprobes for ultrahigh specific fluorescence imaging in the second near-infrared windowFluorescence imaging in the second near-infrared window(NIR-?,1.0-1.7 ?m)is a new technique which permits visualization of deep anatomical features with unprecedented spatial resolution.Although attractive,effectively suppressing the interference signal of background is still an enormous challenge for obtaining target-specific NIR-? imaging in the complex and dynamic physiological environments.Herein we develop dual-pathological parameters cooperatively activatable NIR-? fluorescence nanoprobes(HISSNPs)whereby hyaluronic acid chains and disulphide bonds act as the ‘double locks' to lock the fluorescence-quenched aggregation state of NIR-? fluorescence dyes for performing ultrahigh specific imaging of tumor in vivo.The fluorescence can be lighted up efficiently only when the ‘double locks' are opened by reacting with the ‘dual smart keys'(overexpressed hyaluronidase and thiols in tumor)simultaneously.In vivo NIR-? imaging shows that they reduce non-specific activitation and achieve ultralow background fluorescence,which is 10.6-fold lower than single-parameter activatable probes(HINPs)in liver at 15 h post-injection.Consequently,‘dual lock-and-key'-controlled HISSNPs exhibit 5-fold higher tumor-to-normal tissue ratio than ‘single lock-and-key'-controlled HINPs at 24 h post-injection,attractively realizing ultrahigh specificity of tumor imaging.To our best knowledge,this is first try to implement ultralow background interference with the participation of multiple pathological parameters in NIR-? fluorescence imaging.