| The concept of aggregation-induced emission（AIE）provides an effective solution to overcome the aggregation-caused quenching（ACQ）effect of conventional organic fluorescent materials,which is booming in the field of life science and health.The design and synthesis of AIE-active amphiphilic copolymers could enhance the fluorescence emission intensity of materials via self-assemble,and elegantly overcome the shortcoming of fluorescence quenching behavior of traditional ACQ chromophores in aqueous environment,and finally optimized the properties of organic-luminescent-based drug delivery system（DDS）.Moreover,various functional components,such as targeting and responsive units could be facilely introduced in AIE-active polymeric DDS during fabrication process to achieve multifunctionality.Taken advantage of the difference between normal and pathological tissues（redox/oxidative stress levels,enzyme expression,and p H,etc.）,the design of responsive DDS offers new idea for further improving drug efficacy and achieving precision therapy.However,responsive DDS still faces challenges such as complex synthetic routes,low drug loading capacity,premature leakage and burst release.Besides,most of AIE-active polymeric DDS developed so far are focused on limited types of anticancer drugs,such as DOX and PTX.More possibilities and combinations should be explored to further expand the application of AIE-active polymers and exploit their potentiality in cancer therapy.According to the characteristic differences between tumor microenvironment（TME）and normal tissues,amphiphilic polymers with AIE activity were synthesized through the selection of different linkers for fabricating sustained and controlled release nano-DDS.The AIEgens containing active hydroxyl groups were selected as the key research objects.On the one hand,in terms of molecular design,the fluorescent nanocarriers with TEM responsiveness were constructed by introducing responsive groups to form dynamic bonds with the drug（bortezomib,BTZ）or to achieve responsive breakage of the polymer backbone;on the other hand,the photosensitive properties of AIEgens were thoroughly investigated,and the combination of chemo-photodynamic therapy was carried out to further enhance the anticancer activity of the DDS.The main research results are as follows:1.Hexachlorocyclotriphosphonitrile（HCCP）was selected as the linker,and the inorganic-organic crosslinked DDS was constructed by one-step sonication with hydrophobic block AIEgen（QM-OH）and hydrophilic block PEG-NH2.On the one hand,the participation of AIE-active molecules endowed the polymer with good fluorescence cell imaging performance;on the other hand,this highly crosslinked amphiphilic system possessed strong drug loading capacity,realizing the construction of multifunctional DDS.In addition,the P-O bond in polyphosphazene polymer is susceptible to hydrolytic breakage,so the nanoparticles have the potential to be biodegradable in vivo.Due to the different swelling ratios of the drug loading micelles in acid TME and normal physiological environment,the release of BTZ exhibited a significant p H dependence.Unfortunately,the cumulative release rate of BTZ was significantly faster under p H=7.4 than in acidic condition,suggesting that this AIE cross-linked system is suitable for oral colon-targeted drug delivery with limited scope for development.2.In order to improve the release behavior of BTZ,a DDS containing catechol moieties with AIE feature was constructed.1,2,4,5-cyclohexanetetracarboxylic dianhydride（CHTAD）was selected as the linker to construct the amphiphilic polymer backbone with AIEgen（TPA-OH）and m PEG5k-OH under mild reaction conditions.Then,the side chains of the polymer were modified with dopamine.The obtained drug carrier can form p H-sensitive boronic ester with the boronic acid group in BTZ,aiming to overcome the shortcomings,such as low DLC（wt%）,easy leakage in physiological environment,slow drug release in tumor cells and so on.Compared with QM-HCCP-PEG DDS,this DDS（TPA-CHTAD-PEG-DA）not only improved the DLC（wt%）,but also realized p H-responsive release in the acid TME.Thereby,the drug could be enriched at the tumor site,exhibiting strong toxicity to cancer cells.Meanwhile,the AIE-active TPA-OH was involved in the construction of the DDS,which endowed the polymer with excellent fluorescent properties.3.Due to the introduction of the triphenylamine（TPA）moiety,TPA-OH showed excellent photosensitivity and photodynamic therapy（PDT）efficacy in addition to good fluorescence properties.However,because of the antioxidation capacity of catechol structure in TPA-CHTAD-PEG-DA,the photodynamic property of photosensitizer（PS）was serious inhibited.Based on this,in order to fully make use of the photosensitivity of TPA-OH,N,N-bis（2-hydroxyethyl）ethylenediamine was utilized to modify the polymer side chains instead of dopamine.The obtained polymer TCP-DEA contains a series of diethanolamine groups（DEA）and has high drug loading capacity.The diethanolamine（DEA）group can form p H-sensitive boronic ester with BTZ,while the N atom could form intramolecular coordination bond with the B atom,thereby building a more stable internal boron-nitrogen coordinated boronic ester（IBNCB）.Comparing with the TPA-CHTAD-PEG-DA DDS,this DDS improved the DLC（wt%）and realized p H-responsive slow/controlled release of BTZ.Moreover,TPA-OH is mainly a type I photosensitizer that is more adaptable to the anoxic TME,thus accomplishing highly efficient chemo-photodynamic combination therapy and improving the anti-cancer efficiency.4.The selection of the main chain block of TCP-DEA drug delivery system was continued,and the reactive oxygen species（ROS）reactive groups were added to construct a ROS-responsive DDS.High level of ROS is one of the characteristics of TME.Herein,a self-amplified chain-shattering cinnamaldehyde（CA）-derived poly（thioacetal）DDS（TPA-CA-PEG）was designed and constructed,including ROS-responsive thioacetal（TA）and ROS-generating agent CA.Firstly,endogenous ROS was used as triggering agent to facilitates chain cleavage of TA with the release of CA,which in turn produces more ROS through mitochondrial dysfunction,resulting in an exponential polymer degradation cascade.The amphiphilic copolymer was used to carry the anti-cancer drug BTZ through non-covalent bond interaction,combing the chemotherapy and PDT to improve the efficiency of cancer treatment.5.Based on the above study of amphiphilic DDSs with AIE feature,AIE PS TPA-1OH with stronger fluorescence imaging ability and photosensitivity was synthesized to build a p H/GSH dual-responsive DDS（TPA-SS-DEA）.Overexpression of glutathione（GSH）is another typical feature of TME.Taking advantage of this difference from normal tissues,disulfide bond capable of reacting with GSH was introduced into the main chain to achieve GSH-responsive polymer cleavage.The intermediate hydrophobic chain was first synthesized using disulfide-bonded monomers with CHTAD.Subsequently,the water-soluble AIE-active probe TPA-1OH and hydrophilic block PEG2k-OH were utilized for capping,which endowed the polymer with good biocompatibility,excellent PDT performance,and superior fluorescence imaging ability.Finally,the side chain was modified with DEA groups to carry the drug BTZ,and the DLC（wt%）was increased to 19.8%.TPA-1OH was mainly a type I PS and showed significant PDT efficiency under photoexcitation within200 s.The polymer was also characterized with great high PDT performance.At cellular level,the drug-loaded micelles combined with chemo-photodynamic therapy demonstrated excellent lethality to tumor cells.In conclusion,this thesis focuses on the development of sustained and controlled release nano-DDSs with AIE activity.Starting from the design of amphiphilic polymer molecules,the nano-DDSs with excellent DLC（wt%）,controlled-release capabilities and photosensitivity were preferred through the different choices and combinations of linkers,AIE-active molecules and responsive moieties.These DDSs enable combined chemo-photodynamic therapy and improve the anticancer effect of the DDSs.The design and development of these DDSs have important implications for the construction of function-oriented biomaterials in the future. |
