Encapsulation of LXR ligand by D-Nap-GFFY hydrogel enhances anti-tumorigenic actions of LXR and removes LXR-induced lipogenesis.
Encapsulation of LXR ligand by D-Nap-GFFY hydrogel enhances anti-tumorigenic actions of LXR and removes LXR-induced lipogenesis.
复制标题
D-Nap-GFFY 水凝胶封装 LXR 配体增强 LXR 的抗肿瘤作用并消除 LXR 诱导的脂肪生成
作者：
Feng K;Ma C;Liu Y;Yang X;Yang Z;Chen Y;Xu T;Yang C;Zhang S;Li Q;Wei Z;Zhao D;Zeng P;Han J;Gao J;Chen Y;Duan Y
背景与目的：肝脏X受体（LXR）被其配体T0901317（T317）激活，可增强干扰素-γ（IFNγ）的产生，从而抑制肿瘤生长。然而，T317诱导的严重高脂血症和脂肪肝限制了其应用。萘乙酸修饰的D-对映体-甘氨酸-苯丙氨酸-苯丙氨酸-酪氨酸（D-Nap-GFFY）可形成可选择性被抗原呈递细胞（APC）摄取的水凝胶。在这项研究中，我们确定了D-Nap-GFFY包封的T317（D-Nap-GFFY-T317）是否可以有效地抑制肿瘤生长，同时对肝脏没有不利的脂肪生成作用。研究方法：我们制备了D-Nap-GFFY-T317水凝胶，并将其皮下注射到IFNγ缺陷型（IFNγ-/-）和野生型（WT）肺癌小鼠中，无论是接种LLC 1细胞还是接种诱导的癌。接受口服T317给药的小鼠用于比较。研究了治疗对肿瘤生长、脂肪生成的影响及其相关机制。结果：与T317口服给药相比，D-Nap-GFFY-T317注射给药能更有效地抑制小鼠LLC 1肿瘤的生长。这种抑制作用依赖于LXR激活的IFNγ在APC中的表达。D-Nap-GFFY-T317增加肿瘤中的M1，同时减少M2型巨噬细胞。与IFNγ表达的激活相关，D-Nap-GFFY-T317增强树突状细胞成熟和向肿瘤中的浸润，增加肿瘤中的CD 3 +/CD 8+细胞，并抑制肿瘤血管生成。类似地，D-Nap-GFFY-T317比T317口服给药更有效地抑制乳腺癌诱导的肺癌的生长。在这两种肿瘤模型中，T317口服给药，而不是D-Nap-GFFY-T317注射，激活肝脂肪生成并诱导脂肪肝。结论：我们的研究表明，D-Nap-GFFY-T317抑制肺肿瘤生长，而对肝脏没有不良影响，表明水凝胶包封的LXR配体可能是一种新的肿瘤治疗方法。
Background and purpose: Activation of liver X receptor (LXR) by its ligand T0901317 (T317) enhances interferon-γ (IFNγ) production to inhibit tumor growth. However, induction of severe hypertriglyceridemia and fatty liver by T317 limits its application. The naphthylacetic acid modified D-enantiomeric-glycine-phenylalanine-phenylalanine-tyrosine (D-Nap-GFFY) can form a nanofiber hydrogel which is selectively taken up by antigen-presenting cells (APCs). In this study, we determined if D-Nap-GFFY-encapsulated T317 (D-Nap-GFFY-T317) can potently inhibit tumor growth while having no adverse lipogenic effects on the liver. Methods: We prepared D-Nap-GFFY-T317 nanofiber hydrogel and subcutaneously injected it into IFNγ deficient (IFNγ-/-) and wild-type (WT) mice with lung carcinoma, either inoculated LLC1 cells or urethane-induced carcinoma. Mice received oral T317 administration were used for comparison. Effects of treatment on tumor growth, lipogenesis and involved mechanisms were investigated. Results: Compared with T317 oral administration, injection of D-Nap-GFFY-T317 more potently inhibited LLC1 tumor growth in mice. The inhibition was dependent on LXR-activated IFNγ expression in APCs. D-Nap-GFFY-T317 increased M1 while reducing M2 type macrophages in tumors. Associated with activation of IFNγ expression, D-Nap-GFFY-T317 enhanced dendritic cell maturation and infiltration into tumors, increased CD3+/CD8+ cells in tumors, and inhibited tumor angiogenesis. Similarly, D-Nap-GFFY-T317 more potently inhibited growth of urethane-induced lung carcinomas than T317 oral administration. In these two tumor models, T317 oral administration, but not D-Nap-GFFY-T317 injection, activated hepatic lipogenesis and induced fatty liver. Conclusion: Our study demonstrates that D-Nap-GFFY-T317 inhibits lung tumor growth without adverse effects on the liver, indicating the hydrogel-encapsulated LXR ligand might be a novel therapy for tumor treatment.