Design And Synthesis Of Near-Infrared Light-responsive Nanoplatform And Their Biomedical Applications

With the rapid development of modern biomedicine,nanocarriers have attracted more and more attention due to their advantages such as improving water solubility,reducing side effects and controlling drug release.However,many diseases including tumor or inflammation need treatment at regular time,while most of the polymeric nanocarriers can not deliver the drug to the lesion site.Hence,many researchers began to introduce functional groups that are responsive to external environmental stimuli into the nanocarrier.These controlled drug release systems have become one of the most important research in the field of biological medicine because of its real time control of drug release.Cotrolled drug release mainly includes acid-response,enzyme-response,light-response,magnetic response,thermal response,reduction-response,ultrasonic-response and so on.In all of these response types,light-response have received much attention.On one hand,light have the characteristic of clean,noninvasive and highly efficiency.On the other hand,light-controlled drug release system provides the advantages of a non-contact mode and precise controllability.However,one potential problem in most current photolysis delivery systems is that most light-responsive polymers were sensitive only to ultraviolet?UV?or visible?Vis?light,in which unavoidable cellular damage and shallow penetration depth largely impeded their further application in biomedicine from the viewpoint of clinical applications.Therefore,the development of near-infrared light-responsive nanocarrier can greatly improve the therapeutic effect.This thesis aims to develop near-infrared light-responsive organic functional nanocarriers and their applications in biomedicine.This thesis are divided into four sections:1.Highly efficient two-photon-triggered degradable copolymer nanoaggregates for light-controlled drug releaseWe reported amphiphilic copolymer-based nanoaggregates?NAs?with highly efficient two-photon-triggered degradable properties.In our design,the conventional photo-cleavable species ONB was positioned alternately into the backbone of a?phenylethynyl?benzene?PEB?based polymer.Further,hydrophilic polyethylene glycol?PEG?was grafted onto the side chain of the copolymer to obtain an amphiphilic structure which could self-assemble into NAs.In this case,the PEB fluorophore was used as a two-photon light-harvesting antenna to capture energy and then the electronic excitation was subsequently transferred to ONB,disrupting it under 800 nm irradiation for two photon-triggered photolysis.Compared with single molecules,these copolymer NAs maintained the advantage of a larger TPA cross-section?4.55×10⁷ GM?and a more effective fluorescence resonance energy transfer?FRET?process due to the aggregate conformation of multiple PEB and ONB units.Owing to the large TPA cross-section and highly efficient FRET process,these copolymer NAs showed rapid degradation and successful release of hydrophobic drugs under NIR irradiation which was useful for the photo-degradation of drug carriers.To rule out the other reasons that may cause the degradation,we also synthesized an analogous copolymer without nitro groups in the backbone and then irradiated it under the same conditions.The results showed that they could not degrade after irradiation which indicated that the dissociation of NAs was simply due to the photodegradation of ONB groups.2.Organic/inorganic hybrid nanocarrier for siRNA release and singlet oxygen?¹O₂?generation under NIR light irradiationWe reported the photo-induced charge-variable cationic conjugated polyelectrolyte brushes encapsulating upconversion nanoparticle?UCNP@CCPEB?for promoted siRNA release and collaborative PDT under NIR light irradiation.Conjugated polyelectrolyte?CPE?with conjugated backbone and charged flexible side-chain was employed in virtue of their strong light-harvesting ability,good photostability,and excellent water-solubility.Most importantly,CPE could function as PS for efficient PDT.Since cationic CPE?CCPE?with many positive charges was found to act as a nucleic acid carrier,it was anticipated that CCPE would be a good molecular platform for integrating PS and cationic nanocarrier into one entity.We further introduced a cationic brush structure into CPE because it could not only exhibit outstanding siRNA-loading capacity but also reduce the aggregation of conjugated backbone for enhancing ¹O₂ production.Photodegradable group o-nitrobenzyl?ONB?was introduced into CPE brush?CPEB?by quaternary ammoniation for elevating siRNA release through photo-induced charge variation of the sidechain from cations to zwitterions.Besides,the formed zwitterionic CPEB?ZCPEB?could not only keep avoiding the aggregation of conjugated backbone and retaining primary PDT effects,but also show lower biotoxicity compared to pristine cationic CPEB?CCPEB?.To achieve NIR excitation,upconversion nanoparticle?UCNP?was utilized to couple with CCPEB as it could absorb NIR light and give out emissions ranging from ultraviolet to visible region to activate the CCPEB for efficient PDT and siRNA release simultaneously.In our work,the as-prepared UCNP@CCPEB presented good stability and excellent siRNA-loading capacity?1 mol UCNP@CCPEB to at least 32.5 mol siRNA?.Furthermore,UCNP@CCPEB exhibited good ¹O₂ production and promoted siRNA release?80%?under 980 nm irradiation.3.Organic/inorganic hybrid nanocarrier for siRNA therapy and collaborative photodynamictherapy in vitro and in vivoWe utilized the photo-induced charge-variable conjugated polyelectrolyte brushes encapsulating upconversion nanoparticles?UCNP@CCPEB?for in vitro and in vivo therapy.In vitro and in vivo investigations showed that UCNP@CCPEB/siPlk1 complex had a significant A549 tumor suppression effect under collaborative PDT and siRNA therapy,suggesting a great promise of this system as an efficient nanotherapeutic platform.4.Organic/inorganic hybrid nanocarrier for NO and singlet oxygen?¹O2?generation underNIR light irradiationWe synthesize an organic/inorganic hybrid nanocarrier to realize simultaneous release of NO and¹O₂ under NIR light irradiation.Conjugated polyelectrolyte?CPE?with conjugated backbone and charged flexible side-chain was employed in virtue of their strong light-harvesting ability,good photostability,and excellent water-solubility.Most importantly,CPE could function as PS for efficient PDT.Meantime,photo-responsive group SNO was introduced into CPE brush?CPE-SNO?by quaternary ammoniation for NO release.Compared with single PDT,simultaneous NO and ¹O₂release can enhance the therapeutic effects.To achieve NIR excitation,upconversion nanoparticle?UCNP?was utilized to couple with CCPEB as it could absorb NIR light and give out emissions ranging from ultraviolet to visible region to activate the CCPEB for efficient PDT.Furthermore,we replaced 980 nm excited UCNP with 808 nm excited UCNP to avoid overheat.This nanoparticle can efficiently release NO and ¹O₂ under 808 nm irradiation,suggesting a great promise of this system as an efficient nanotherapeutic platform under hypoxia environment.