铁蛋白纳米共轭物引导曲妥珠单抗通过脑内递送，促进小鼠HER2阳性乳腺癌脑转移的抗肿瘤反应。
Ferritin nanoconjugates guide trastuzumab brain delivery to promote an antitumor response in murine HER2+ breast cancer brain metastasis.
发表日期：2023 Sep 19
作者：
Marta Sevieri, Serena Mazzucchelli, Linda Barbieri, Stefania Garbujo, Stephana Carelli, Arianna Bonizzi, Federica Rey, Camilla Recordati, Matteo Recchia, Raffaele Allevi, Leopoldo Sitia, Carlo Morasso, Pietro Zerbi, Davide Prosperi, Fabio Corsi, Marta Truffi
来源：
PHARMACOLOGICAL RESEARCH
摘要：
脑转移（Brain metastasis, BM）是晚期HER2阳性乳腺癌（HER2+breast cancer, BC）患者面临的临床挑战。单克隆抗HER2抗体曲妥珠单抗（Trastuzumab, TZ）提高了BC患者的生存率，但其对中枢神经系统的穿透能力较差，无法治疗脑转移。以前的研究表明，铁蛋白纳米颗粒（HFn）通过与转铁蛋白受体1（Transferrin receptor 1, TfR1）结合可以穿越血脑屏障（Blood brain barrier, BBB）。然而，目前尚未研究HFn是否具有促进TZ经过血脑屏障进入脑部并对抗BC脑转移的有效性。在这里，我们在通过立体定向注射过表达人类HER2的改造BC细胞建立的小鼠BC脑转移模型中，研究了HFn在驱动TZ进入脑部并促进靶向抗肿瘤反应方面的潜力。将HFn与TZ共价结合，得到一个具有HER2和TfR1靶向特异性的纳米共轭物（H-TZ）。H-TZ在腹腔注射后能够有效地将TZ输送到脑部，并触发对癌细胞的稳定靶向。H-TZ与多西他赛联合治疗可显著减少肿瘤的生长，并通过激活巨噬细胞来塑造保护性脑微环境。H-TZ治疗还通过防止药物在心脏中的堆积避免了TZ相关的心脏毒性，并且与多西他赛联合治疗时没有引起其他重大副作用。这些结果在体内证明了H-TZ的药理学潜力，能够与多西他赛联合作用来应对BC脑转移。事实上，通过全身给药，纳米共轭物可以引导TZ在脑中的积累，减少脑转移的生长并限制离靶器官的副作用，因此在处理HER2阳性BC转移到脑部的管理中显示出希望。版权所有©2023 Elsevier Ltd.
Brain metastasis (BM) represents a clinical challenge for patients with advanced HER2+ breast cancer (BC). The monoclonal anti-HER2 antibody trastuzumab (TZ) improves survival of BC patients, but it has low central nervous system penetrance, being ineffective in treating BM. Previous studies showed that ferritin nanoparticles (HFn) may cross the blood brain barrier (BBB) through binding to the transferrin receptor 1 (TfR1). However, whether this has efficacy in promoting the trans-BBB delivery of TZ and combating BC BM was not studied yet. Here, we investigated the potential of HFn to drive TZ brain delivery and promote a targeted antitumor response in a murine model of BC BM established by stereotaxic injection of engineered BC cells overexpressing human HER2. HFn were covalently conjugated with TZ to obtain a nanoconjugate endowed with HER2 and TfR1 targeting specificity (H-TZ). H-TZ efficiently achieved TZ brain delivery upon intraperitoneal injection and triggered stable targeting of cancer cells. Treatment with H-TZ plus docetaxel significantly reduced tumor growth and shaped a protective brain microenvironment by engaging macrophage activation toward cancer cells. H-TZ-based treatment also avoided TZ-associated cardiotoxicity by preventing drug accumulation in the heart and did not induce any other major side effects when combined with docetaxel. These results provided in vivo demonstration of the pharmacological potential of H-TZ, able to tackle BC BM in combination with docetaxel. Indeed, upon systemic administration, the nanoconjugate guides TZ brain accumulation, reduces BM growth and limits side effects in off-target organs, thus showing promise for the management of HER2+ BC metastatic to the brain.Copyright © 2023. Published by Elsevier Ltd.