The Role Of D-Nap-GFFY Hydrogel In Antitumorigenic Actions Of LXR Ligand

Background and objective:Lung carcinoma is the cancer with the highest morbidity and mortality in the world,and lung adenocarcinoma is the most common type.Although great progress has been made in both basic research and clinic treatment,the current clinical treatment for lung adenocarcinoma is still very limited.We previously reported that activation of liver X receptor(LXR)by ligand,such as T0901317(T317),can enhance expression of interferon-?(IFN?),thereby exerting anti-tumorigenic effect.However,activation of LXR can also induce lipid synthesis gene expression,leading to excessive accumulation of lipids in the liver and hypercholesterolemia,which limits the clinical application of LXR agonists.D-Nap-GFFY hydrogel is a polypeptide composed of D-enantiomeric amino acids modified by naphthylacetic acid,which can be specifically phagocytized by antigen-presenting cells(APCs),such as dendritic cells and macrophages,and enhance immune response.D-Nap-GFFY has the advantage and potential to become a drug carrier.In this study,we used D-Nap-GFFY-encapsulated T317 delivery system(D-Nap-GFFY-T317)and injected it subcutaneously in mice to explore the effect of D-Nap-GFFY-T317 on inhibiting lung carcinoma and avoiding side effects of hepatic lipogenesis.Methods:We initially prepared D-Nap-GFFY hydrogel in PBS,characterized its physical properties,and determined its degradation in the presence of protease.We then prepared D-Nap-GFFY-T317 and determined the release of T317 from D-Nap-GFFY-T317 both in vivo and in vitro.To determine the effect of D-Nap-GFFY-T317 on tumorigenesis,C57BL/6J mice and IFN?knockout mice with C57BL/6J background were selected to establish the xenograft model by subcutaneous injection of lung adenocarcinoma tumor cell,LLC1 cells,or the orthotopic lung cancer model by intraperitoneal injection of urethane.Mice in each model received oral administration of T317 or subcutaneous injection of D-Nap-GFFY-T317,followed by determination of tumor growth and lipogenesis in the liver.Results:D-Nap-GFFY-T317 formed a stable colloid with even distribution of T317.D-Nap-GFFY-T317 was selectively taken up by APCs,particularly by macrophages,not by hepatocytes.The release of T317 depends on the degradation of D-Nap-GFFY by action of intracellular protease.Therefore,compared with oral administration of T317,the circulating T317 in mice was much lower by s.c.injection of D-Nap-GFFY-T317.In mice with lung carcinoma,D-Nap-GFFY-T317demonstrated better anti-tumorigenic effect than oral T317.Mechanistically,D-Nap-GFFY-T317 promoted IFN?expression in APCs,increased the number of M1 type macrophages in tumors in an IFN?-dependent manner,while reduced the number of M2 type macrophages.It also enhanced maturation and infiltration of dentritic cells(DCs),increased the number of CD3~+CD8~+T cells in tumors,and inhibited angiogenesis in tumors in an IFN?-dependent manner.In addition,compared with oral T317,s.c.injection of D-Nap-GFFY-T317 removed activation of lipogenic genes in the liver,thereby eliminating the side effects of fatty liver and hypertriglyceridemia caused by oral T317.Furthermore,we determined that uptake of D-Nap-GFFY-T317 by macrophages was mediated by scavenger receptor type A(SR-A).Conclusion:D-Nap-GFFY-T317 can be selectively taken up by DCs and macrophages.The released T317 from D-Nap-GFFY-T317 activates IFN?expression,thereby inhibiting lung tumor growth without side effect of hepatic lipogenesis.Our study suggests that D-Nap-GFFY-T317 might be a new strategy for tumor treatment.