Construction Of Organic Nanomaterials Based On Aggregation-induced Emission And Their Applications In Imaging-guided Enhanced Phototherapy

For centuries,cancer has become one of the main culprits that endanger human health and life.Traditional cancer treatments mainly include surgery,radiotherapy and chemotherapy.However,in many cases,surgery is hard to totally remove the whole cancer cells,while both chemotherapy and radiotherapy may cause serious side effects on normal cells.Recently,phototherapy,including photothermal therapy（PTT）and photodynamic therapy（PDT）,has attracted widespread attention owing to its high-efficiency,non-invasive light conversion,desirable tumor targeting and minimal side effects.However,most of the reported phototherapy materials are mainly composed of gold nanoparticles,transition metal chalcogenides,carbon nanotubes and other inorganic nanomaterials,and commercial dyes such as porphyrin-,chlorin e6,cyanine-based dyes,etc.Generally,they often face long-term toxicity,non-degradability and the troublesome aggregation-caused quenching（ACQ）phenomenon during their applications,which will greatly limit their development in cancer treatments.In addition,most of the reported phototherapy systems lack certain targeting ability or low conversion efficiency of phototherapy agents（PAs）,leading to poor therapeutic effects and increasing the risk of tumor recurrence and metastasis.Nevertheless,the organic nanomaterials with aggregation-induced emission（AIE）characteristics can not only bypass the toxicity problems caused by inorganic nanomaterials and overcome the ACQ effect induced by traditional commercial dyes,but also enhance the phototherapy effect through modification or PAs structure design,so they are generally regarded as one of the most promising bio-nanomaterials.In this paper,through peptides modification and PAs structure design,three novel AIE fluorogens（AIEgens）-active organic nanomaterials have been constructed for exploring their applications in imaging-guided enhanced phototherapy.Thus obtained AIE-active organic nanomaterials have good biocompatibility,superior AIE imaging and enhanced cancer cells ablation effects,which provide new strategies for the construction of novel functional AIE-active organic nanomaterials in cancer treatment.Generally speaking,the specific research results of this paper are as follows:（1）Based on the nano-coprecipitation method,we co-encapsulated AIE fluorogens（AIEgens）（TPA-BDTO,T）and the first near-infrared（NIR）（NIR-I）（700-900nm）absorbing semiconductor polymer（SPs）（PDPPP,P）with maleimide terminated amphiphilic polymer(DSPE-PEG₂₀₀₀-Mal,D),and then further modified with the targeting peptides R（RGDFGGRRRRC）via“click”reaction.Thus,such dual PTT nanomaterial（termed as DTPR）was fabricated.Thus obtained DTPR could form spherical nanoparticles by self-assembly with a diameter of about 44nm.When DTPR was irradiated with an 808nm laser,the NIR fluorescence of T could be partially transformed into heat through the fluorescence resonance energy transfer（FRET）between T and P,coupling with the heat generated by the photothermal agent P itself,achieving image-guided dual PTT.Furthermore,the photothermal conversion efficiency of DTPR reached 60.3%（dual PTT）,much higher than its intrinsic of 31.5%（single PTT）,which was further demonstrated by the more severe photothermal ablation of cancer cells with an 808nm laser in vivo and vitro.Therefore,DTPR successfully achieved a single 808nm laser excitated image-guided dual PTT for thermal ablation of cancer cells,which is considered to be one of the most promising treatment methods for image-guided PTT.（2）In order to further improve treatment efficiency and achieve precise treatment,based on the nano-coprecipitation method,we use maleimide terminated amphiphilic polymer D to co-encapsulate AIE fluorogens（AIEgens）（TPATPE-BDTO,T）and the second NIR（NIR-II）（1000-1700nm）absorbing SPs（PBQ,P）,and then further conjugated with peptide R₉（RGDRRRRRRRRRC）,thus DTPR₉ nanoassemblies were obtained.DTPR₉ could specifically anchored on the cell membrane and retained on the cell membrane for more than 8h.Upon irradiation of a 1064nm laser,DTPR₉ with high NIR-II photothermal conversion efficiency（η=70.4%）could directly destroy the cell membrane through the generated hyperthermia in situ,thus leading to the death of cancer cells.Additionly,AIEgens fluorescence on the damaged cell membrane was transferred from the cell membrane to the nucleus,which could be used to self-report the therapeutic effect and avoid overtreatment.the translocation of AIE fluorescence from damaged cell membrane could be used to self-report the therapeutic effect.This cell-membrane-anchored nano-assembly opens up a novel avenue to overcome the difficulties of low therapeutic efficiency and serious potential side effects in NIR-II PTT.（3）Based on π-linker engineering,three novel AIEgens with D-π-A structure,namely BtM,ThM and NaM,were developped and prepared by adjusting their structures.Thus prepared three AIEgens all showed good photostability,high molar absorption coefficient,and their emission edges were extended to NIR region,which could be used as photosensitizers（PS）and imaging agents.It was found that the energy gap(?E_ST)of NaM was the smallest due to the good separation of the highest occupied molecular orbital（HOMO）and lowest unoccupied molecular orbital（LUMO）.Then,we obtained BtM,ThM and NaM nanoparticles（NPs）by encapsulating AIEgens with the help of amphiphilic polymer DSPE-m PEG₃₀₀₀（Dm）.When under white light irradiation,NaM NPs possessed the highest singlet oxygen（¹O₂）yield,which was about 3 times that of the reference Rose Bengal（RB）.In addition,MTT,live and dead cells staining experiments showed that NaM NPs was significantly better than BTM and ThM NPs in killing cancer cells.Hence,NaM NPs could successfully photodynamic ablation of cancer cells and has great potential in photodynamic therapy of superficial diseases.