Non-small cell lung cancer (NSCLC) brain metastases present a significant treatment challenge due to limited drug delivery efficiency and severe adverse reactions. In this study, we address these challenges by designing a “on/off” switchable crosslinked paclitaxel (PTX) nanocarrier, BPM-PD, with novel ultra-pH-sensitive linkages (pH 6.8 to 6.5). BPM-PD demonstrates a distinct “on/off” switchable release of the anti-cancer drug paclitaxel (PTX) in response to the acidic extratumoral microenvironment. The “off” state of BPM-PD@PTX effectively prevents premature drug release in the blood circulation, blood-brain barrier (BBB)/blood-tumor barrier (BTB), and normal brain tissue, surpassing the clinical PTX-nanoformulation (nab-PTX). Meanwhile, the “on” state facilitates precise delivery to NSCLC brain metastases cells. Compared to nab-PTX, BPM-PD@PTX demonstrates improved therapeutic efficacy with a reduced tumor area (only 14.6%) and extended survival duration, while mitigating adverse reactions (over 83.7%) in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), offering a promising approach for the treatment of NSCLC brain metastases. The precise molecular switch also helped to increase the PTX maximum tolerated dose from 25 mg/kg to 45 mg/kg This research contributes to the field of cancer therapeutics and has significant implications for improving the clinical outcomes of NSCLC patients.

中文翻译：

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“开/关”可切换的交联 PTX 纳米制剂，与 nab-PTX 相比，可提高 NSCLC 脑转移的精确递送并抑制不良反应

由于有限的药物输送效率和严重的不良反应，非小细胞肺癌（NSCLC）脑转移提出了重大的治疗挑战。在本研究中，我们通过设计一种“开/关”可切换的交联紫杉醇 (PTX) 纳米载体 BPM-PD 来应对这些挑战，该载体具有新颖的超 pH 敏感连接（pH 6.8 至 6.5）。 BPM-PD 表现出抗癌药物紫杉醇 (PTX) 响应酸性瘤外微环境的独特“开/关”可切换释放。 BPM-PD@PTX的“关闭”状态有效防止药物在血液循环、血脑屏障（BBB）/血肿瘤屏障（BTB）和正常脑组织中过早释放，优于临床PTX纳米制剂（NAB）。 -PTX）。同时，“开启”状态有利于精确递送至 NSCLC 脑转移细胞。与nab-PTX相比，BPM-PD@PTX显示出更高的治疗效果，减少了肿瘤面积（仅14.6％）并延长了生存时间，同时减轻了天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）的不良反应（超过83.7％） ），为非小细胞肺癌脑转移的治疗提供了一种有前途的方法。精确的分子开关还有助于将 PTX 最大耐受剂量从 25 mg/kg 提高到 45 mg/kg。这项研究为癌症治疗领域做出了贡献，对改善 NSCLC 患者的临床结果具有重要意义。