Performance Regulation And Cancer Theranostic Application Of Perylene Imide-Based Photothermal Agents

As an efficient and non-invasive cancer treatment,photothermal therapy(PTT)has received wide attention.PTT mainly relies on photothermal agents to achieve good therapeutic results.Comparing to inorganic photothermal agents,organic photothermal agents are highly biocompatible and biodegradable,thus showing more promise.Nevertheless,organic photothermal agents also share some disadvantages such as poor photothermal and thermal stabilities,which greatly limit their applications.Perylene imide,a class of organic fluorescent dye with high stability,high molar extinction coefficient and adjustable photophysical property,has been extensively studied in the fields including fluorescence imaging,drug delivery,photodynamic therapy,and so on.Due to the electron-deficient characteristic of imide group,perylene imide-based photothermal agents can be constructed by introducing electron-donors such as organic amines.Because of the strong electronic push-pull effects,these photothermal agents display red-shifted absorption.Simultaneously,the twisted intramolecular charge transfer quenches the fluorescence and thus render these photothermal agents good photothermal performance.However,there are still many critical problems for perylene imide-based photothermal agents that hinder their further applications:(1)The absorption wavelengths are still too short to meet the demand;(2)The photothermal conversion efficiencies(PCE)are relatively low;(3)They lack responsiveness toward the tumor microenvironment,thus prone to causing damage to normal tissue.To solve these problems,herein,we use chemical modification and self-assembly to regulate the performance of perylene imide-based photothermal agents:Firstly,by changing the substituents and self-assembly conditions,the self-assembly behaviors of perylenediimide(PDI)photothermal agents were well regulated,giving rise to the J-aggregate photothermal agent with red-shifted absorption.Secondly,PDI anions were confirmed to have high photothermal conversion capacity.Further,through chemical modification and self-assembly,a basic intra-particle microenvironment was created,which successfully regulated the p H responsiveness of PDI anion and lowered its p K_a.Thus,a novel PDI anion-based photothermal agent with superb photothermal performance and high stability was developed.Lastly,based on a perylene monoimide(PMI)photothermal agent,a glutathione(GSH)-responsive photothermal prodrug was obtained.Further,regulation of the photothermal property was successfully achieved in tumor,enhancing the tumor selectivity of PTT.The main studies of this paper are as follows:1.Based on the amino-substituted PDI,we detailedly studied the influences of the substituent groups and assembly conditions on the formation of J-aggregate,and thus successfully regulated the self-assembly behavior.Then,a J-aggregate photothermal agent(PJ NPs)was successfully constructed,with 93 nm red shift compare to the precursor molecule.PJ NPs exhibited an average size of 129 nm,a good stability under room temperature and a PCE of 40.7%.Under laser irradiation of 808 nm,PJ NPs could effectively kill cancer cells,showing good prospects in antitumor applications.2.PDI anions obtained by deprotonation of hydroxyl PDI exhibit strong push-pull electron effects and red-shifted absorptions,which are potential photothermal molecules.This study confirmed that the PDI anion(PDI-O~-)have excellent photothermal ability with a PCE higher than that of amine substituted PDI.However,due to their intrinsic p H responsiveness,these PDI anions can only stabilize under basic conditions.In order to regulate their p H responsiveness and construct PDI anion-based photothermal agent that can stabilize under neutral p H,a hydroxylated PDI(PDI-A)with tertiary amine and polyethylene glycol(PEG)substituents is synthesized,which can transform into PDI anion through deprotonation.With PEG offering hydrophilicity,PDI-As can assemble into PDI-A NPs with an average size of81 nm,in which the abundant tertiary amines create basic intra-particle microenvironments.The p K_aof PDI-A NPs was as low as 6.6,demonstrating that the regulation of p H responsiveness was achieved through the construction of basic intra-particle microenvironment.PDI-A NPs showed green color in deionized water and permitted near-infrared(NIR)absorption and a high PCE up to 62%,higher than those of most reported PDI-based photothermal agents.Upon light irradiation,the heat generated by PDI-A NPs induced obvious elimination of cancer cells.The in vivo experiments showed that PDI-A NPs effectively inhibited the tumor growth through photoacoustic-guided PTT.The cellular level and in vivo experiments confirmed the good biocompatibility of PDI-A NPs.3.A responsive PMI photothermal agent was constructed,based on which regulations of photothermal property and particle size were achieved by utilizing the tumor microenvironment.Firstly,the PMI-based photothermal agent(NHP)was abtained with a high PCE of 52%.Secondly,NHP was covalently linked with the chemotherapeutic drug chlorambucil(Chl)to get the prodrug CP.CP was further co-assembled with DSPE-m PEG2000 to obtain the prodrug nanoparticle(CP NPs)with an average particle size of 62nm.CP NPs showed significant responsiveness to GSH:before response,CP NPs exhibited an absorption peaking at 490 nm and little absorbance,photothermal effect and fluorescence emission in NIR region;after response,the photothermal molecule NHP and Chl were released,leading to a 110 nm red shift of absorption peak,switching on the NIR photothermal and fluorescence imaging function.Moreover,the response caused aggregation of NHP molecules and size increasing of nanoparticles.In vivo experiments showed that the photothermal ability and drug release of CP NPs were successfully activated through response toward tumor microenvironment,and eventually,the tumor growth was effectively inhibited.Moreover,the released NHP was found to retain in tumor for a long time due to the response-caused size increasing,achieving long-term and high-contrast NIR fluorescence imaging of tumor.In this way,the regulations of photothermal properties and molecular aggregation were achieved in vivo,allowing improved tumor selectivity of PTT and synergetic NIR fluorescence imaging and therapy of tumor.