Preparation And Multifunctional Antitumor Research Of Novel Network NIR Light-responsive Thermosensitive Hydrogels

Localized drug delivery based on tumor tissue are an effective way to achieve precise treatment of tumors.Injectable smart responsive hydrogels have excellent biocompatibility,and their porous network structure can load chemotherapeutic drugs or new therapeutic agents(such as photothermal/photodynamic reagents,magnetocaloric reagents,genes,antibodies).These drug-loaded hydrogels that can in response to pathological tissue microenvironment or external stimulus changes,such as pH,temperature,enzymes,light,magnetic fields,electric fields,etc.,so as to achieve long-term release and on-demand drug delivery,as well as anti-cancer combined treatment with multiple mechanisms.Therefore,maximum anti-tumor efficacy and minimal systemic toxicity are achieved to ensure patient tolerance while maximizing drug efficacy.In particular,Near Infrared(NIR)light-regulated intelligent in-situ hydrogels benefit from the remote controllability of light,high spatial and temporal precision,and the potential of NIR-driven photothermal therapy or photodynamic therapy for locally combined anti-cancer.These advantages make them a broad application prospect in the field of local cancer treatment.However,the current NIR-responsive intelligent hydrogels themselves lack of the light responsiveness and without antitumor effects,relying on the loaded exogenous NIR photoactive agent,and these phototherapeutic agents generally have a weak interaction with the polymer network of hydrogels,the phototherapy agents are easily to leak out,resulting in a gradually deteriorating therapeutic effects of the hydrogels.In addition,the phototherapeutic reagents are embedded inside the hydrogels and cannot directly response to NIR light,which limits their photothermal conversion efficiency.Therefore,the limited therapeutic effect and low photothermal conversion efficiency(PTCE)are the main problems in the current NIR-responsive intelligent hydrogel systems.In addition,these NIR-responsive intelligent hydrogel systems usually response to the light of NIR-? window,which with a limited penetration depth.Therefore,the development of promising NIR-responsive intelligent hydrogels with the inherent light-responsive framework as well as the NIR-? responsiveness for the combined treatment of deep tumors has theoretical significance and practical clinical value.In view of the above analysis,this thesis based on the multifunctional conjugated polymers,the NIR-I responsive and NIR-? responsive hydrophilic conjugated polymers were obtained by chemical grafting or physical entanglement coating,respectively.And then they were used as the backbone or the building units to construct framework NIR-responsive thermosensitive hydrogel by a mild supramolecular host-guest self-assembly.Benefiting from the NIR absorption properties and photothermal conversion effects of the conjugated polymer backbones,these as-prepared multifunctional intelligent hydrogels can be used not only as an in-situ drug controlled release carrier,but also as a highly efficient phototherapy reagent.The application of these novel hydrogels loaded with chemotherapeutic drugs or photodynamic reagents in localized delivery,intelligent controlled release and multi-mechanical combined anti-tumor therapy were studied.The main contents of this thesis are as follows:1.Network NIR-responsive thermosensitive hydrogel(PPG-peg5k/?-CD)for doxorubicin controlled release and synergistic chemo-photothermal therapyA novel poly(N-phenylglycine,PPG)containing a large number of carboxyl group modifiable sites was synthesized by chemical oxidative polymerization of N-phenylglycine monomer using ammonium persulfate as oxidant.The polymer chain of PPG is composed of alternated benzene rings and anthracene rings linking with imine bone,this conjugated structure is similar to polyaniline.Furthermore,a PEG-modified water-soluble conjugated polymer backbone(PPG-peg5k)was obtained through the amide condensation between the amino groups on methoxypolyethylene glycol ammonia(MW:5000,mPEG-NH₂)and the carboxyl groups on PPG.The strong NIR absorption and NIR-responsive photothermal heating effect of PPG-peg5k were confirmed by UV test and 808 nm laser excitation.Following,a network NIR-responsive thermosensitive hydrogel(PPG-peg5k/?-CD)was formed by host-guest assembly cross-linking between?-cyclodextrin(?-CD)and PPG-peg5k,and it was used for NIR-triggered on-demand delivery and combined chemo-photothermal therapy.Benefit from the conjugated polymer backbone can directly absorb NIR light and convert it into thermal energy,endue the PPG-peg5k/?-CD gel with excellent photothermal conversion efficiency(?=52.62%)and enhanced photothermal stability.At the same time,the mild host-guest self-assembly as the stimulus switch enabled photothermal-driven and reversible gel-sol thermosensitive transition and shear-thinning injectability.The upper critical solution temperature(UCST=45⁵2 ?)located in the range of suitable for photothermal therapy(PTT).Therefore,it had the ability to trigger drug release via gel-sol transition for synergistic treatment while in PTT.The photothermal-induced gel-sol transformation enabled remote controlled release of the model drug Doxorubicin(DOX).In addition,the PPG-peg5k/?-CD-mediated chemo-photothermal therapy not only effectively induced 4T1 cell death in vitro,but also can effectively eliminate 4T1 breast cancer after one-time intratumoral injection following with repeated treatment with low-power NIR light(0.15 W cm^-2).As a versatile hydrogel system,PPG-peg5k/?-CD with both the NIR-responsive photothermal backbone and the reversible thermosensitive phase transition provided a new intelligent platform for photo-controlled drug delivery and combined photothermal anticancer therapy.2.Network NIR-response thermosensitive hydrogel(PPG-peg4k/?-CD)for controlled release indocyanine green and combined phototherm-photodynamic therapyIndocyanine green(ICG)is a versatile diagnostic reagent that has the abilities of photothermal,photodynamic and NIR fluorescence imaging.However,its disabilities of photothermal instability,short plasma half-life and lack of targeting capacity limit its usage.Based on the above work,poly(N-phenylglycine)was firstly esterified condensed with polyethylene glycol(MW:4000,PEG)to obtain a water-soluble conjugated polymer network(PPG-peg4k).Next,a network NIR-responsive thermosensitive hydrogel(PPG-peg4k/?-CD)was constructed by supramolecular self-assembly between PPG-peg4k and cyclodextrin for stabilizing ICG and high-efficiency photothermal/photodynamic combination anti-tumor therapy.The conjugated polymer backbone in PPG-peg4k/?-CD can stabilize the aromatic phototherapy agent(ICG)through?-?stacking interactions,improving its stability and effectively avoiding undesirable leakage during non-NIR treatment.Additionally,the PPG backbone can directly convert NIR light into heat and induced local hyperthermia for enhanced photothermal effects.The synthesized PPG-peg4k/?-CD exhibited a reversible and easily adjustable gel-sol upper critical solution temperature(UCST=43-50 ?).The on/off release of the ICG can be remotely controlled by NIR photothermal induced gel-sol transition.In vitro and in vivo anti-tumor experiments demonstrated that ICG-loaded PPG-peg4k/?-CD hydrogel not only effectively induced 4T1 cancer cell death,but also can completely photoablation of most 4T1 breast cancers through one-time intratumoral injection following with repeated combination photothermal/photodynamic therapy under the low-dose 808 nm laser(0.14W cm^-2).In addition,combined phototherapy can completely kill cancer cells avoiding tumor recurrence,which is better than alone phototherapy alone(PTT)or alone photodynamic therapy(PDT).3.NIR-? responsive thermosensitive hydrogel(PPG@peg6k/?-CD)for light-controlled cisplatin release and chemo-photothermal therapyThe NIR-? region has deeper tissue penetrating ability and better laser tolerance than the NIR-? region,and the synthesis of NIR-? responsive intelligent hydrogel system is significant.Firstly,the water-soluble doped conjugated polymer composite nanoparticle(PPG@peg6k)with NIR-? region light absorption was obtained through in-situ polymerization of N-phenylglycine in the presence of acidic mediums and polyethylene glycol(MW:6000,PEG).Following,a NIR-? responsive thermosensitive hydrogel was further prepared by the self-assembly between?-cyclodextrin and PPG@peg6k.Since the building units(PPG@peg6k)of hydrogels themselves absorbed NIR-? region light and mediated photo-thermal conversion,it has a stable and highly efficient photothermal effect.Under the NIR-? laser irradiation of 1064 nm,the local photothermal effect can not only effectively kill the highly invasive triple negative breast cancer(TNBC),but also trigger the thermosensitive gel-sol transition to mediate the controlled release of cisplatin,resulting in reduced off-target toxicity of cisplatin and chemo-photothermal enhanced anti-tumor activity.This work not only provides a novel and versatile platform for NIR-? light-controlled cisplatin release and chemo-photothermal therapy,but also offers a promising strategy for rational design of NIR-? responsive hydrogel for interventional invasiveness cancer.