Construction Of Aggregation Induced Emission Luminogens-based Multi-modular Probe And Its Application In Organelle Targeted Delivery And Therapy

Cancer is increasingly becoming a major factor threatening human health.In order to prolong the survival time of patients with malignant tumors,clinical research on advanced therapeutic methods,such as photothermal therapy,photodynamic therapy and gene therapy,is being rapidly advanced.Due to the complex tumor microenvironment,the above-mentioned therapeutic drugs often suffer from insufficient accumulation in tumor tissues,low efficiency of cell internalization,off-target effects of drugs and other problems,which ultimately lead to unsatisfactory therapeutic effects.As the main factor hindering cancer treatment,complex biological barriers are being widely concerned by researchers.The modular strategy has been recognized by researchers because it can make the probes functionally diverse and can effectively overcome multiple biological barriers.In addition,organelle-targeting strategies can help drugs intervene in tumors at the molecular level to alleviate off-target effects,and are widely used in tumor enhancement therapy.Therefore,the construction of organelle targeting therapy probes based on modular strategies has great application potential in tumor enhancement therapy.In this thesis,aggregation-induced emission luminogens（AIEgen）and peptides are mainly used to construct multi-module probes that overcome biological barriers,which was used to enhance the effect of subcellular delivery and thus enhance tumor therapy.This thesis is mainly divided into the following five parts:The first part systematically reviews the role of modular strategies in overcoming biological barriers and the application of organelle-targeting strategies in enhancing tumor therapy.The second part is the design and synthesis of AIEgens:（1）Py TPA based on triphenylamine derivatives was designed and synthesized,which has various advantages,such as convenient click reaction site for module connection,low self-toxicity,strong aggregation induced luminescence performance,and good photodynamic performance.It is planned to be used as the delivery fluorescent tracker and therapeutics of targeted organelles.（2）AIE-N₃ based on tetraphenylethylene derivatives was designed and synthesized,which has good aggregation-induced luminescent properties and photodynamic properties.Because it contains two positively charged pyridinium salt groups,it has good mitochondrial targeting ability.At the same time,the end of AIE-N₃is connected with two click reaction sites for convenient module connection,which can asymmetrically modify two functional modules.It is planned to explore the impact of the modular connection mode of the mitochondria-targeted multi-module probe on its targeting specificity and therapeutic effect.The third part is the design and synthesis of multi-module probe with tunable membrane affinity and its application in overcoming the membrane barrier.Cell membrane transport is the first and crucial step for bioprobes to realize the diagnosis,imaging,and therapy in cells.However,during this transport,there is a trade-off between anchoring and internalization steps,which will seriously affect the membrane transport efficiency.In the past,because the interaction between probes and cell membrane is constant,this challenge is hard to solve.Here,we proposed a strategy to regulate the membrane affinity of multi-module probes that enabled probe to have strong affinity during cell membrane anchoring and weak affinity during internalization.Specifically,a multi-module probe defined as LK-M-NA was constructed,which consisted of three main parts,membrane-anchoringα-helix peptide（LK）,anchoring regulator（M）,and therapeutic module（NA）.With theα-helix module,LK-M-NA was able to rapidly anchor on the cell membrane and the binding energy was-1450.90 kcal/mol.However,after pericellular cleavage by the highly active matrix metalloproteinase-2,LK could be removed due to the breakage of M and the binding energy reduced to-869.95 kcal/mol.Thus,the internalization restriction caused by high affinity was relieved.Owing to the alterable affinity,the membrane transport efficiency of LK-M-NA increased to 14.58%,well addressing the trade-off problem.The fourth part is the design and synthesis of multi-module probes with different spatial arrangement of modules and investigation of their specificity and toxicity.To overcome a series of challenges in tumor therapy,modular-agent probes（MAPs）comprised of various functional modules have been proposed.Researchers have tried to optimize the MAPs by exploiting the new modules or increasing the numbers of module,while neglecting the configuration of various modules.Here,we focus on the different spatial arrangements of existing modules.By utilizing a tetraphenylethylene（TPE）derivative with stereochemical structure and dual modifiable end-group sites as small molecule scaffold,two MAPs with same modular agents（module T for enhancing the internalization of MAPs by tumor cells and module M for causing mitochondrial dysfunction）but different spatial arrangements（on the one side,TM-AIE,and two sides,T-AIE-M,of the molecule scaffold）are designed.T-AIE-M with larger RGD binding angle performed higher specificity,while TM-AIE characterizing longerα-helix structure displayed superior toxicity.This significant phenomenon could guide the design of MAPs in the future and also open a window for the renaissance of existing MAPs.The fifth part mainly describes the main conclusions of this thesis and looks forward to the application prospect of modularization probe targeting organelles in tumor therapy.The future of modular probes for other biomedical applications is also prospected.