The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer.
The targetable nanoparticle BAF312@cRGD-CaP-NP represses tumor growth and angiogenesis by downregulating the S1PR1/P-STAT3/VEGFA axis in triple-negative breast cancer.
复制标题
靶向纳米颗粒 BAF312@cRGD-CaP-NP 通过下调三阴性乳腺癌中的 S1PR1/P-STAT3/VEGFA 轴来抑制肿瘤生长和血管生成
DOI：
10.1186/s12951-021-00904-6
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发表时间：
2021-05-31
影响因子：
10.2
通讯作者：
Duan Y
中科院分区：
文献类型：
--
作者：
Gong K;Jiao J;Xu C;Dong Y;Li D;He D;Zhao D;Yu J;Sun Y;Zhang W;Bai M;Duan Y
背景
过表达的血管内皮生长因子A(VEGFA)和磷酸化信号转导和转录激活子3(P-STAT3)可导致乳腺癌(BRCA)，特别是三阴性乳腺癌(TNBC)的肿瘤生长和血管生成不受限制。因此，迫切需要新的治疗策略。
结果
我们发现鞘氨醇1磷酸受体1(S1PR1)可以调节P-STAT3/VEGFA。数据库显示，S1PR1在BRCA中高表达，导致患者预后不良。阻断S1PR1的表达可通过影响S1PR1/P-STAT3/VEGFA轴抑制人乳腺癌细胞(MCF-7和MDA-MB-231)的生长，抑制人脐静脉内皮细胞(HUVECs)的血管生成。Siponimod(BAF312)是S1PR1的选择性拮抗剂，在体外通过下调S1PR1/P-STAT3/VEGFA轴抑制肿瘤生长和血管生成。我们制备了pH敏感、肿瘤靶向的壳核结构纳米粒子，其中亲水性的环状精氨酸-甘氨酸-天冬氨酸(CRGD)修饰的PEG2000形成壳层，疏水的DSPE形成核心，帽(钙离子和磷酸根离子)吸附在壳层上；纳米粒子被用来传递BAF312(BAF312@cRGD-Cap-NPs)。纳米粒的大小为109.9±1.002 nm，−为10.6±0.056 mV。BAF312的掺入效率为81.4%。结果证实BAF312@cRGD-Cap-NP可通过下调S1PR1/P-STAT3/VEGFA轴，显著抑制肿瘤的生长和血管生成。
结论
我们的数据表明，BAF312@cRGD-CAP-NPs通过下调S1PR1/P-STAT3/VEGFA轴，在治疗BRCA，特别是TNBC方面发挥了重要作用。
图形摘要
Background
Overexpressed vascular endothelial growth factor A (VEGFA) and phosphorylated signal transducer and activator of transcription 3 (P-STAT3) cause unrestricted tumor growth and angiogenesis of breast cancer (BRCA), especially triple-negative breast cancer (TNBC). Hence, novel treatment strategy is urgently needed.
Results
We found sphingosine 1 phosphate receptor 1 (S1PR1) can regulate P-STAT3/VEGFA. Database showed S1PR1 is highly expressed in BRCA and causes the poor prognosis of patients. Interrupting the expression of S1PR1 could inhibit the growth of human breast cancer cells (MCF-7 and MDA-MB-231) and suppress the angiogenesis of human umbilical vein endothelial cells (HUVECs) via affecting S1PR1/P-STAT3/VEGFA axis. Siponimod (BAF312) is a selective antagonist of S1PR1, which inhibits tumor growth and angiogenesis in vitro by downregulating the S1PR1/P-STAT3/VEGFA axis. We prepared pH-sensitive and tumor-targeted shell-core structure nanoparticles, in which hydrophilic PEG2000 modified with the cyclic Arg-Gly-Asp (cRGD) formed the shell, hydrophobic DSPE formed the core, and CaP (calcium and phosphate ions) was adsorbed onto the shell; the nanoparticles were used to deliver BAF312 (BAF312@cRGD-CaP-NPs). The size and potential of the nanoparticles were 109.9 ± 1.002 nm and − 10.6 ± 0.056 mV. The incorporation efficacy for BAF312 was 81.4%. Results confirmed BAF312@cRGD-CaP-NP could dramatically inhibit tumor growth and angiogenesis in vitro and in MDA-MB-231 tumor-bearing mice via downregulating the S1PR1/P-STAT3/VEGFA axis.
Conclusions
Our data suggest a potent role for BAF312@cRGD-CaP-NPs in treating BRCA, especially TNBC by downregulating the S1PR1/P-STAT3/VEGFA axis.
Graphic abstract
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