Peptide-Targeted High-Density Lipoprotein Nanoparticles for Combinatorial Treatment against Metastatic Breast Cancer.
Peptide-Targeted High-Density Lipoprotein Nanoparticles for Combinatorial Treatment against Metastatic Breast Cancer.
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用于治疗转移性乳腺癌的肽靶向高密度脂蛋白纳米颗粒。
DOI：
10.1021/acsami.1c02074
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发表时间：
2021-07
影响因子：
9.5
通讯作者：
Qiu Zeng
中科院分区：
文献类型：
--
作者：
Chuli Jiang;Biyun Teng;Yuan Guo;Fenghe Li;Zhe Wang;Xingyue Wang;Yu Zhao;Qiu Zeng
音刺猬（SHH）信号通路在三阴性乳腺癌（TNBC）中表现出异常激活，其中它调节与肿瘤转移相关的几种恶性表型。GANT 61是SHH信号通路的抑制剂，当与常规化疗联合治疗转移性TNBC时，可能会提供希望。然而，生物利用度差和明显的脱靶毒性限制了其临床应用。为了解决这些限制，我们设计了一种肽功能化的双靶向递送系统，其将紫杉醇和GANT 61封装在tLyP-1肽修饰的重构高密度脂蛋白纳米颗粒（tLyP-1-rHDL-PTX/GANT 61 NP）中，用于转移性TNBC治疗。纳米颗粒表面修饰的载脂蛋白A-1和tLyP-1肽使递送系统能够通过与过表达的清道夫受体B I型和神经纤毛蛋白-1受体结合而靶向肿瘤细胞。此外，tLyP-1肽还使纳米颗粒能够深入肿瘤渗透，进一步促进紫杉醇和GANT 61的递送。在MDA-MB-231、BT-549肿瘤细胞及其3D肿瘤球体中观察到纳米颗粒的细胞摄取增加。一系列体外实验表明，GANT 61能够抑制与转移相关的关键肿瘤细胞活性，包括血管生成、迁移、侵袭和干性。由于更有效的药物给药，GANT 61的转移抑制效率被双靶向tLyP-1-rHDL递送系统显著增强。同时，与药物溶液相比，通过双靶向tLyP-1-rHDL纳米颗粒共递送紫杉醇和GANT 61显示出上级的破坏肿瘤细胞增殖和诱导肿瘤细胞凋亡的效率。在自发转移性乳腺癌NCG小鼠模型中，tLyP-1-rHDL-PTX/GANT 61纳米粒表现出高度的肿瘤特异性分布，显著抑制原发肿瘤生长，显著减少肺转移，且无明显毒副作用。目前的工作表明，结合SHH信号通路抑制和化疗辅助肽功能化靶向tLyP-1-rHDL纳米颗粒可能提供一个有前途的策略转移性TNBC治疗。
The sonic hedgehog (SHH) signaling pathway exhibits aberrant activation in triple-negative breast cancer (TNBC), wherein it regulates several malignant phenotypes related to tumor metastasis. GANT61, an inhibitor of the SHH signaling pathway, may offer promise when administered in combination with conventional chemotherapy to treat metastatic TNBC. However, poor bioavailability and substantial off-target toxicity limit its clinical application. To address these limitations, we designed a peptide-functionalized dual-targeting delivery system encapsulating paclitaxel and GANT61 in tLyP-1 peptide-modified reconstituted high-density lipoprotein nanoparticle (tLyP-1-rHDL-PTX/GANT61 NP) for metastatic TNBC treatment. The apolipoprotein A-1 and tLyP-1 peptide modified on the surface of nanoparticles enable the delivery system to target tumor cells by binding to the overexpressed scavenger receptor B type I and neuropilin-1 receptor. Moreover, the tLyP-1 peptide also enables the deep tumor penetration of nanoparticles further facilitating paclitaxel and GANT61 delivery. Increased cellular uptake of the nanoparticles was observed in both MDA-MB-231, BT-549 tumor cells, and their 3D tumor spheroids. A series of in vitro experiments reveal that GANT61 was able to suppress key metastasis-related tumor cell activities including angiogenesis, migration, invasion, and stemness. Owing to more effective drug administration, the metastasis suppression efficiency of GANT61 was significantly enhanced by the dual-targeting tLyP-1-rHDL delivery system. Meanwhile, the codelivery of paclitaxel and GANT61 by dual-targeting tLyP-1-rHDL nanoparticles demonstrated superior efficiency of disrupting proliferation and inducing apoptosis in tumor cells compared with drug solutions. In a spontaneous metastasis breast cancer NCG mice model, the tLyP-1-rHDL-PTX/GANT61 nanoparticles exhibited highly tumor-specific distribution and result in significant inhibition of the primary tumor growth and dramatic reduction of lung metastasis without obvious side effects. The present work suggests that a combination of the SHH signaling pathway suppression and chemotherapy assisted by peptide-functionalized targeting tLyP-1-rHDL nanoparticles may provide a promising strategy for metastatic TNBC treatment.
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DOI：
10.1093/annonc/mdy201
发表时间：
2018-08-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Yardley DA;Coleman R;Conte P;Cortes J;Brufsky A;Shtivelband M;Young R;Bengala C;Ali H;Eakel J;Schneeweiss A;de la Cruz-Merino L;Wilks S;O'Shaughnessy J;Glück S;Li H;Miller J;Barton D;Harbeck N;tnAcity investigators
通讯作者：
tnAcity investigators
影响因子：
9.5
作者：
Rodriguez-Quijada, Cristina;de Puig, Helena;Hamad-Schifferli, Kimberly
通讯作者：
Hamad-Schifferli, Kimberly
肿瘤微环境产生的酸度驱动局部侵袭。
影响因子：
11.2
作者：
Estrella V;Chen T;Lloyd M;Wojtkowiak J;Cornnell HH;Ibrahim-Hashim A;Bailey K;Balagurunathan Y;Rothberg JM;Sloane BF;Johnson J;Gatenby RA;Gillies RJ
通讯作者：
Gillies RJ
DOI：
10.1080/14756366.2017.1419221
发表时间：
2018-12
影响因子：
5.6
作者：
Calcaterra A;Iovine V;Botta B;Quaglio D;D'Acquarica I;Ciogli A;Iazzetti A;Alfonsi R;Lospinoso Severini L;Infante P;Di Marcotullio L;Mori M;Ghirga F
通讯作者：
Ghirga F
影响因子：
3.3
作者：
Weaver BA
通讯作者：
Weaver BA