Studies On Design,Fabrication And Application Of Smart Enzyme-responsive Theranostics Nanoprobes

As one of the great threats to human health,cancer kills millions of people every year.Therefore,precise treatment of cancer is particularly important.With the rapid development of nanoscience,the application of nanomaterials in the field of biomedicine has received much attention.Nanomedicine provides a new strategy for precise cancer diagnosis and treatment,which helps to improve clinical treatment efficiency and reduce side effects.Due to the structural diversity,adjustable physicochemical properties,and easy functional modification,nanomaterials can be used as drug carriers,imaging contrast agents and therapeutic agents for research of cancer diagnosis and treatment.As a visual tool,imaging is significant for the early diagnosis and guidance of cancer treatment.Each imaging mode has its own unique advantages,but it also has inherent defects,and it is difficult to achieve the desired therapeutic effect with single treatment.The construction of multifunctional nanomaterials provides new ideas for the design of theranostic probes and synergistic therapeutic nanoplatform under the guidance of multimodal imaging,which can improve the accuracy of diagnosis and treatment.For cancer treatment,phototherapy greatly improves the selectivity of treatment because light,as an external stimulus,can be easily operated.However,the problem of imaging depth,the autofluorescence and the phototoxicity of non-specific activation of photosensitizers still severely restrict their clinical application in the accurate diagnosis and treatment of cancer.The development of stimuli-responsive system provides a good solution to the problem.Tumor tissue has a microenvironment different from normal tissue.The designs of intelligent nanomaterials often rely on their ability to respond to the intrinsic stimuli in tumor site,thereby producing activatable imaging signals/intratumoral release of payloads used to enhanced imaging contrast or therapy efficacy for precise diagnosis and treatment.Therefore,in this paper,we mainly focus on the design and synthesis of stimuli-responsive smart nanoprobes and their application in cancer diagnosis and treatment.The results indicate that the nanoprobe can specifically respond to the tumor marker MMP2,thereby performing activatable fluorescence imaging to light up cancer cells,localize tumor precisely and achieving highly selective photodynamic therapy?PDT?,photothermal therapy?PTT?and controlled drug release.The smart nanoprobe enables precise targeted synergistic therapy guided by fluorescence imaging.This paper is mainly divided into the following three parts:Chapter 1:A brief introduction to the application of nanomaterials in the diagnosis and treatment of cancer.Chapter 2:Activatable Smart Nanoprobe for Sensitive Endogenous MMP2 Detection and Fluorescence Imaging Guided PhototherapiesIn this study,we develop a MMP2-activatable theranostic nanoprobe with linking Pyropheophorbide-a?PPa?to the surface of AuNRs through MMP2 substrate peptide,which can be used for selective imaging and controlled PDT to cancer cells.The photosensitizer is silenced at normal tissue during the circulation owing to fluorescence resonance energy transfer?FRET?effect but can be activated by over-expressed MMP2when the nanoprobe reaches tumor site,restoring the fluorescence of PPa and ¹O₂generation for selective PDT.The restored fluorescence can be used to quantitatively detect MMP2 and light up cancer cells,further guiding the synergistic activated PDT/PTT for highly efficient and special killing cancer cells.The nanoprobe has great potential in vivo tumor localization and inhibition applications.The work provides a promising approach for designing efficient tumor microenvironment-responsive theranostic probes.Chapter 3:Smart MMP2-Responsive Nanoprobe for Activatable Fluorescence Imaging-Guided Local Triple-Combination Therapy with Single LightHerein,a smart theranostic nanoprobe composed of hollow gold nanospheres?HAuNs?,photosensitizer?PPa?,a matrix metalloproteinase 2?MMP2?substrate peptide linker,and doxorubicin?DOX?is designed.The fluorescence and ¹O₂generation of PPa are inhibited by HAuNs through FRET,avoiding phototoxicity to normal tissues during circulation.While,the PPa can be efficiently activated in tumor for selective fluorescence imaging and photodynamic therapy due to MMP2-triggered peptide cleavable.HAuNs can generate photo-thermal effects based on plasmon resonance absorption under photoexcitation,thereby preforming PTT.And the synergistic treatment of activated PDT,PTT,and controlled DOX release are achieved with single light by adjusting the wall thickness of HAuNs.Importantly,the restored fluorescence can be used to detect MMP2 activity,locate tumor in vivo,further to guide local triple-combination therapy?PDT/PTT/chemotherapy?.Besides,under the guidance of activatable fluorescence,the local triple-combination therapy provides the best therapeutic effects with notable reduced nonspecific toxicity of PS and DOX.This study helps to provides approach for the future development of precision cancer theranostics.