Abstract：
BACKGROUND: Triple-negative breast cancer (TNBC) represents the most aggressive subtype of breast cancer with an extremely dismal prognosis and few treatment options. As a desmoplastic tumor, TNBC tumor cells are girdled by stroma composed of cancer-associated fibroblasts (CAFs) and their secreted stromal components. The rapidly proliferating tumor cells, together with the tumor stroma, exert additional solid tissue pressure on tumor vasculature and surrounding tissues, severely obstructing therapeutic agent from deep intratumoral penetration, and resulting in tumor metastasis and treatment resistance.
OBJECTIVE: Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop.
RESULTS: Herein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis.
CONCLUSIONS: Systematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.
OBJECTIVE: Fucoxanthin (FX), a xanthophyll carotenoid abundant in marine algae, has attracted widespread attention as a promising alternative candidate for tumor prevention and treatment. Twist is a pivotal regulator of epithelial to mesenchymal transition, and its depletion has proven to sensitize antitumor drugs, inhibit metastasis, reduce CAFs activation and the following interstitial deposition, and increase tumor perfusion. The nanodrug delivery system co-encapsulating FX and nucleic acid drug Twist siRNA (siTwist) was expected to form a potent anti-TNBC therapeutic cyclical feedback loop.
RESULTS: Herein, our studies constituted a novel self-assembled polymer nanomedicine (siTwist/FX@HES-CH) based on the amino-modified hydroxyethyl starch (HES-NH2) grafted with hydrophobic segment cholesterol (CH). The MTT assay, flow cytometry apoptosis analysis, transwell assay, western blot, and 3D multicellular tumor spheroids growth inhibition assay all showed that siTwist/FX@HES-CH could kill tumor cells and inhibit their metastasis in a synergistic manner. The in vivo anti-TNBC efficacy was demonstrated that siTwist/FX@HES-CH remodeled tumor microenvironment, facilitated interstitial barrier crossing, killed tumor cells synergistically, drastically reduced TNBC orthotopic tumor burden and inhibited lung metastasis.
CONCLUSIONS: Systematic studies revealed that this dual-functional nanomedicine that targets both tumor cells and tumor microenvironment significantly alleviates TNBC orthotopic tumor burden and inhibits lung metastasis, establishing a new paradigm for TNBC therapy.
摘要：
背景：三阴性乳腺癌（TNBC）是最具侵袭性的乳腺癌亚型，其预后极其糟糕，治疗选择很少。作为促纤维增生性肿瘤，TNBC肿瘤细胞被由癌症相关成纤维细胞（CAF）及其分泌的基质成分组成的基质包围。迅速增殖的肿瘤细胞，连同肿瘤间质，对肿瘤血管和周围组织施加额外的实体组织压力，严重阻碍治疗剂的深度肿瘤内渗透，并导致肿瘤转移和治疗耐药。
目的：岩藻黄质（FX），一种富含海洋藻类的叶黄素类胡萝卜素，作为肿瘤预防和治疗的一种有希望的替代候选药物，引起了广泛的关注。Twist是上皮细胞向间充质转化的关键调节因子,它的消耗已被证明会使抗肿瘤药物敏感，抑制转移，减少CAFs活化和随后的间隙沉积，增加肿瘤灌注。预期共包封FX和核酸药物TwistsiRNA(siTwist)的纳米药物递送系统形成有效的抗TNBC治疗性循环反馈回路。
结果：这里，我们的研究构成了一种新型的自组装聚合物纳米药物（siTwist/FX@HES-CH）基于氨基改性羟乙基淀粉（HES-NH2）接枝疏水链段胆固醇（CH）。MTT法,流式细胞术细胞凋亡分析，transwell分析，westernblot,和3D多细胞肿瘤球体生长抑制实验均表明siTwist/FX@HES-CH可以协同杀死肿瘤细胞并抑制其转移。体内抗TNBC功效证明siTwist/FX@HES-CH重塑了肿瘤微环境，促进间质屏障穿越，协同杀死肿瘤细胞，显著降低TNBC原位肿瘤负荷并抑制肺转移。
结论：系统研究表明，这种靶向肿瘤细胞和肿瘤微环境的双功能纳米药物可显着减轻TNBC原位肿瘤负荷并抑制肺转移，建立TNBC治疗的新范式。
目的：岩藻黄质（FX），一种富含海洋藻类的叶黄素类胡萝卜素，作为肿瘤预防和治疗的一种有希望的替代候选药物，引起了广泛的关注。Twist是上皮细胞向间充质转化的关键调节因子,它的消耗已被证明会使抗肿瘤药物敏感，抑制转移，减少CAFs活化和随后的间隙沉积，增加肿瘤灌注。预期共包封FX和核酸药物TwistsiRNA(siTwist)的纳米药物递送系统形成有效的抗TNBC治疗性循环反馈回路。
结果：这里，我们的研究构成了一种新型的自组装聚合物纳米药物（siTwist/FX@HES-CH）基于氨基改性羟乙基淀粉（HES-NH2）接枝疏水链段胆固醇（CH）。MTT法,流式细胞术细胞凋亡分析，transwell分析，westernblot,和3D多细胞肿瘤球体生长抑制实验均表明siTwist/FX@HES-CH可以协同杀死肿瘤细胞并抑制其转移。体内抗TNBC功效证明siTwist/FX@HES-CH重塑了肿瘤微环境，促进间质屏障穿越，协同杀死肿瘤细胞，显著降低TNBC原位肿瘤负荷并抑制肺转移。
结论：系统研究表明，这种靶向肿瘤细胞和肿瘤微环境的双功能纳米药物可显着减轻TNBC原位肿瘤负荷并抑制肺转移，建立TNBC治疗的新范式。
