Construction Of Photothermal-immunotherapeutic Vector And Its Antitumor Application

Cancer is one of the leading causes of human death due to its low cure rate.One of the main reasons for the low cure rate of cancer is that it is difficult to diagnose at an early stage,and most cancers are already in the advanced stages when they are discovered.A major feature of cancer during this period is that cancer cells infiltrate from the primary site to the surrounding tissues,or metastasize to the distal tissue through lymphatic and blood circulation.These characteristics lead to the inability to implement effective surgical treatment for cancer patients;the toxic side effects of chemoradiotherapy on the body and the resistance to tumorigenesis also make traditional treatments difficult to achieve the desired results.Therefore,it is very necessary to explore an effective treatment for the metastases.A therapeutic vector that is effective in combining photothermal ablation with immunotherapy for advanced metastases was constructed in this study.We chose Hollow gold nanospheres(HAuNS)with strong surface plasmon resonance to eradicate the primary tumor cells with its near-infrared photothermal ablation(PTA)effect.Simultaneously an anti-PD-1 peptide(APP)was introduced to block the combination of PD-1 receptor on the surface of T lymphocytes with its PD-L1/L2 ligand on the surface of tumor cells.Then the host CD8 T cells were restarted to effectively eliminate the diffuse tumor cells in vivo and the immune escape of the tumor cells was reduced.In order to achieve the simultaneous elimination effect on the primary and metastatic tumor cells,we co-loaded HAuNS and APP with a clinically safe,biodegradable polymer material-polylactic acid-glycolic acid copolymer(poly(lactic-co-glycolic)Acid,PLGA).We firstly prepared the HAuNs and APP co-loaded nanoparticles(AA@PN)with hydrophobization modified HAuNS and APP through single solvent emulsification evaporation.Then,investigating the in vitro release behavior of APP in nanoparticles.The results confirmed that APP was pulsed in the nanoparticles under the 808 nm Near-infrared light(NIR).After intratumoral injection of the nanoparticles and NIR irradiation on the tumor site,HAuNS exerted therapeutic effect of PTA,killing most of the primary tumor cells of the mouse and triggering the release of some APP from the nanoparticles,rapidly increasing the systemic drug concentration level.Subsequently,with the slow degradation of PLGA materials,the drug is gradually released,which can help to achieve a long term blocking effect of immune checkpoint and restart the body's immune system,thus removing the distal tumor cells and remaining primary tumor cells.During the experiment,we further found that the number of immune cells in tumor tissues and spleen tissues of mice treated with photothermal ablation alone increased significantly compared with the control group,and the level of related immune factors also increased.These phenomena indicate that simple photothermal therapy also has effect of improving host immune function.To better exploit the photothermal-mediated immune effect,we introduced the Toll-like receptor agonist,CpG adjuvant.It is desirable to have a multiple immunotherapeutic strategy that triggers a systemic immune response based on photothermal ablation of local tumors.This treatment strategy combines the use of photothermal,immunoadjuvant and PD-1 inhibitors,and has the advantages of low toxicity,high efficiency,and ease of use.By establishing lung metastasis models of mouse CT26 and 4T1 tumor,we investigated the therapeutic effect of AA@PN with the help of CpG.At the same time,through the treatment of tumor recurrence model and postoperative tumor rechallenged model,it is found that the nanoparticle has a tumor vaccine-like effect and can induce more long-lasting memory immune cells in the body.In summary,from the perspective of pharmacy,this paper designed a therapeutic vector combining photothermal ablation with immunotherapy for the metastatic tumor in mice,and further proved that the therapeutic vector can effectively inhibit the growth of the metastatic tumors and also has a good inhibitory effect on the postoperative recurrence of the tumor,confirming its potential as a tumor vaccine.It provides a feasible idea for the treatment of clinical metastases.