Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.
Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors.
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DOI：
10.1158/0008-5472.can-16-0866
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发表时间：
2017-02-01
期刊：
影响因子：
11.2
通讯作者：
Huang L
中科院分区：
文献类型：
--
作者：
Miao L;Liu Q;Lin CM;Luo C;Wang Y;Liu L;Yin W;Hu S;Kim WY;Huang L
抗癌纳米颗粒（NP）向成纤维细胞的脱靶分布为促结缔组织增生性肿瘤的有效治疗创造了障碍。然而，我们假设这种NP损害可能被利用来靶向肿瘤相关成纤维细胞（TAF）分泌的细胞毒性蛋白的表达作为抗癌策略。在解决这一假设，质粒编码的分泌型肿瘤坏死因子相关因子sTRAIL被加载到脂质包被的鱼精蛋白DNA复合物（LPD），并通过输注给药的人促纤维增生性膀胱癌的小鼠异种移植模型。三个剂量足以产生约70%的TAF作为sTRAIL产生细胞。sTRAIL在TAF附近的肿瘤细胞巢中触发凋亡。此外，由于活化不足，它将残留的成纤维细胞恢复到静止状态，进一步损害肿瘤生长并重塑微环境以有利于第二波纳米治疗。我们证实了这种策略在人胰腺癌原位异种移植模型中的有效性，其中促纤维增生基质是众所周知的治疗性NP递送的主要障碍。总的来说，我们的结果为使用NP修饰TAF作为治疗促纤维增生性癌症的有效策略提供了概念证明。结果为使用纳米颗粒修饰肿瘤相关成纤维细胞作为治疗结缔组织增生性癌症的策略提供了临床前概念证明。
The off-target distribution of anticancer nanoparticles (NP) to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this NP detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes (LPD) and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate ~70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Further, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well-known to be a major barrier to the delivery of therapeutic NP. Collectively, our results offer a proof of concept for the use of NP to modify TAFs as an effective strategy to treat desmoplastic cancers. Results offer a preclinical proof of concept for the use of nanoparticles to modify tumor-associated fibroblasts as a strategy to treat desmoplastic cancers.