Construction Of NIR Responsive Nanocomposite Hydrogel System And Its Anti-Tumor Properties

Malignant tumor is an important disease threatening human health,and its clinical treatment is mostly surgical excision.However,some metastatic lesions cannot be treated with surgery,so the development of new therapeutic methods to effectively ablate malignant tumors has become the focus of researchers.It is found that there are not only tumor cells but also tumor blood vessels in tumor tissue.The abundant tumor blood vessels serve as the transport channel of nutrients,which promotes the rapid growth of malignant tumors.If it can block nutrient delivery and prevent angiogenesis,it is expected to fundamentally achieve tumor ablation.Since 1971,Harvard University professor Volkman has proposed the theory of cutting off the blood vessels of tumors and starving them to death.This "vasoblocking therapy" uses various methods to starve cancer cells by blocking their supply of nutrients.The main strategies include:inhibiting the formation of new blood vessels;Blocking the blood transfusion and oxygen supply function of tumor vessels by embolization;Inhibit the metabolic process of tumor cells.At present,many tumor angiogenesis inhibitors have been applied clinically,such as Sorafenib,Sunitinib,Apatinib,etc.However,as an oral small-molecule drug,vascular inhibitors have poor water solubility,which leads to low gastrointestinal absorption efficiency and affects the therapeutic effect.Many vascular embolic agents,such as gels,magnesium silicide nanoparticles and carbon dioxide gas,can be effective in a short time.However,tumors have strong mutation ability and adaptability,and the efficacy of single blocking therapy is not ideal,so it is difficult to achieve excellent anti-tumor effects through the use of vascular embolic agents.Therefore,there is still a need to develop a novel synergistic therapy strategy of vascular occlusion to achieve the desired tumor therapeutic effect.As a kind of emerging biomaterial,hydrogels,especially intelligent response hydrogels,show great prospects in biomedical applications because of their excellent biocompatibility and excellent drug delivery ability.The poor mechanical strength of traditional thermosensitive gel severely limits its biological application.The appearance of nanocomposite hydrogels can effectively solve the problem of insufficient mechanical stress of traditional hydrogels,and the mechanical properties can be significantly enhanced at low nanomaterials content.The research shows that Layered Double Hydroxide(LDHs),as a two-dimensional nanomaterial with rich hydrogen bonds,is promising to construct nanocomposite hydrogels by weaving three-dimensional networks.Based on the above research ideas,we synthesized a new type of nearinfrared response injectable nanocomposite hydrogel,which can realize the controlled release of near-infrared light response drugs and make the gel shrink and squeeze blood vessels through the enhancement of photothermal effect,blocking the supply of nutrients and realizing the precise treatment of tumors.The research content and relevant results of this paper are as follows:1.Near-infrared response nanocomposite hydrogels with enhanced mechanical properties were prepared by using nano enhancement effectMonolayers of MgAl-LDH nanosheets were synthesized by simple coprecipitate.Then,Mg2+and Al3+ were substituted by Cu2+,and CuS nanodots were grown in situ on MgAl-LDH laminate after simple vulcanization.Subsequently,we conjured SOR(vascular inhibitor that blocks neovascularization targeting VEGF)on the surface of LDH-CuS by intermolecular force(electrostatic attraction).Finally,nanocomposite hydrogel SOR@LDH-CuS/PNIPAAm(SOR@L/P)was prepared by free radical polymerization.Through a series of structural characterization methods,such as TEM,SEM,XRD,XPS,UV,etc.,the successful synthesis of nanocomposite hydrogels has been proved.Based on the excellent absorption capacity of LDHCuS in the NIR region,we demonstrated through photothermal tests that LDHCuS and nanocomposite hydrogel SOR@L/P also showed excellent nearinfrared response performance,and the cumulative drug release could reach 80%under three near-infrared illuminations.We also tested the mechanical and rheological properties of SOR@L/P with different contents of LDH-CuS,proving that the addition of nanomaterials can increase the cross-linking sites of hydrogels and improve the mechanical properties by 3-4 times.The above experimental results prove that SOR@L/P nanocomposite hydrogel synthesized by us can achieve near-infrared controlled release of SOR,and is expected to block blood supply by squeezing tumor vessels through gel contraction,so as to conduct tumor therapy under the action of double vascular occlusion.2.Study on the anti-tumor effect of NIR response nanocomposite hydrogel system in vivo and in vitroIn vitro vasoconstriction experiments and in vivo blood flow imaging have shown that the nano-enhanced hydrogel can block the delivery of blood and nutrients to tumor sites.Then,the biocompatibility of L/P gel materials against three cancer cells(Hela,4T1 and HepG2)was evaluated.The survival rate of L/P gel materials was more than 95%at high LDH-CuS concentration,which proved the excellent biocompatibility of the gel materials.Then HepG2 cells were used to verify the cytotoxicity of SOR@L/P.The cell survival rate in the SOR@L/P+NIR group decreased significantly,only 13%,much lower than that in the control group.The results of MTT,PI/CA live and dead cell double staining and flow cytometry analysis was consistent with the above experimental results,proving that SOR@L/P has excellent antitumor properties.Finally,in vivo studies were conducted on HepG2 tumorbearing mice,and fluorescence imaging results showed that hydrogel could be retained in tumor sites for a long time,proving the stability of the gel and providing experimental basis for precision therapy of tumors.Subsequently,the mice were randomly grouped as follows:(1)PBS,(2)L/P,(3)L/P+NIR(4)SOR,(5)SOR@L/P,(6)SOR@L/P+NIR.By monitoring the tumor growth of mice,it is proved that SOR@L/P has good therapeutic effect on tumor under 1064 nm laser irradiation,and greatly improves the survival rate of mice.In summary,we prepared a near-infrared response nanocomposite hydrogel SOR@L/P anti-tumor system,which enhanced the retention time of drugs in tumors,and under NIR irradiation,gel contraction could be achieved to block blood vessels,and drug release could be achieved.