“On/off”-switchable crosslinked PTX-nanoformulation with improved precise delivery for NSCLC brain metastases and restrained adverse reaction over nab-PTX

• Published in: Biomaterials Vol. 307; p. 122537
• Main Authors: Li, Shuaijun, Meng, Caiting, Hao, Qian, Zhou, Ruina, Dai, Luyao, Guo, Yucheng, Zhao, Sitong, Zhou, Xin, Lou, Chunju, Xu, Ji, Xu, Peng, Yang, Jinfan, Ding, Yifan, Lv, Yanni, Han, Shengli, Li, Shuai, Li, Jing, Kang, Huafeng, Xiao, Zhengtao, Tan, Mingqian, Ma, Xiaobin, Wu, Hao
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 01.06.2024
• Subjects: Antineoplastic Agents - therapeutic use; Brain Neoplasms - drug therapy; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Humans; Improved delivery efficiency; Lung Neoplasms - drug therapy; NSCLC brain metastases; Paclitaxel - therapeutic use; Restrained adverse reaction; Switchable crosslinking; Tumor Microenvironment; Ultra-pH-sensitive linkages; Switchable crosslinking; Improved delivery efficiency; NSCLC brain metastases; Ultra-pH-sensitive linkages; Restrained adverse reaction
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2024.122537

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.