Novel Rylene-based Photothermal Nanomedicine For Theranostic Of Cancer

The rylene colorant family possessing unique optical property are one of the most important chromophores in dyestuff chemistry.In recent decades,NIR-absorbing perylene diimides(PDI),terrylene diimides(TDI)and higher quaterrylene diimides(QDI)can be efficiently synthesized by extending theπ-conjugation in a longitudinal manner,and they exhibit a prominent extinction coefficient(ε≈105 M-1cm-1)in the targeted near-infrared(NIR,λ=650-1100 nm)region.We considered that the radiative decay of the excitation would drop off and the non-radiative relaxation(vibrational relaxation)channel would be dominant in photophysics relaxation,especially in the rylene aggregates in a bio-environment.Vibrational relaxation induced photothermal effect of organic dyes have been widely applied in light-based thermal therapy.NIR organic chromophores have been developed as photothermal agents in photodiagnosis and phototherapy of diseases,especially cancer.Correspondingly,various NIR-absorbing nanomaterials have been widely exploited as photothermal agents(PTAs)to enhance photothermal therapy(PTT).However,current organic PTAs such as ICG and IR820 suffered from poor photostability,which leads to the unstability of the nanostructures and limited photothermal conversion efficiencies.These challenges may lead to potential bio-toxicity and reduced therapeutic effect.Therefore,it is highly desirable to develop organic PTAs as novel nanomedicine with robust nanostructure and considerable photothermal conversion efficiency for safe pre-clinical PTT applications.To our knowledge,the photothermal effect of rylene derivatives especially TDI and QDI and their further applications in PTT haven’t been reported yet.In this article,we designed and prepared a series of water soluble rylene-based macromolecules as NIR-absorbing PTAs.Through self-assembling,rylene-based photothermal nanomedicines(RNMs)were prepared and applied in cancer theranostic.First,through introducing the electron donation groups to PDI or extending the π conjugation of PDI,three rylene cores with NIR absorption were obtained.To overcome the poor biocompatibility of the hydrophobic rylene chromophores,polyethylene glycol(PEG)or polyacrylic acid(PAA)shells were introduced to rylene cores via chemical modification such as esterification reactions and atom transfer radical polymerization(ATRP),resulting in water-soluble macromolecules.The molecular structures were characterized by NMR,GPC and MALDI-TOF-MS.The as-synthesized macromolecule were self-assembled into RNMs with hydrophilic corona and aggregated rylene chromophores inside.The well-defined nanostructures were determined by transmission electron microscopy(TEM)and DLS(dynamic light scattering).The self-assembled RNMs performed good water solubility,low biotoxicity and potential in vivo photothermal ability.Secondly,the optical property and photothermal ability were investigated.With the extension of the π-conjugation,RNMs exhibited bathochromic shift,showing strong absorption at 630 nm(PDI),690 nm(TDI)and 780 nm(QDI),respectively.Under laser irradiation,the solution of RNMs exhibited significant temperature rise.The factors such as theπ-conjugation and substituent in bay position could directly affect the photothermal conversion efficiency.Besides,RNMs were ultrastable after repeated laser irradiation for several times.Thirdly,photoacoustic imaging(PAI)with high spatial resolution were achieved and the photoacoustic spectrum,tumor location/outline as well as pharmacokinetics in tumor tissue were obtained.Thus,the RNMs were potential photoacoustic contrast agents for tumor diagnostic.Finally,the RNMs showed low dark cytotoxicity and high light cytotoxicity in vitro and in vivo.By evaluating the tumor volume,mass,pathological examination,we confirmed the rylene-based photothermal nanomedicines could cure the cancer in vivo.The splanchnic pathology and hematologic values of the mice were unchanged after nanomedicine treatment,indicating the good biocompatibility of rylene-based photothermal nanomedicines.The as-prepared rylene-based photothermal nanomedicines showed several advantageous features,including(1)controllable nanostructure and excellent biocompatibility;(2)robust photostability under laser irradiation;(3)intrinsic theranostic property with high photothermal conversion efficiency.With these excellent features,the RNMs were successfully exploited as PTAs for efficient PAI guided cancer PTT without long-term biotoxicity in vivo.This investigation not only paves the way towards the development of high-performance RNMs for personalized PTT,but also enriches the class of PTA species,thus providing more choices in future cancer therapy.