Sequential Targeting in Crosslinking Nano-theranostics for Tackling the Multi-barriers of Brain Tumors

• Published in: Advanced materials (Weinheim) 2020-02, Vol.32 (14), p.e1903759-e1903759
• Main Authors: Wu, Hao, Lu, Hongwei, Xiao, Wenwu, Yang, Jinfan, Du, Hongxu, Shen, Yingbin, Qu, Haijing, Jia, Bei, Manna, Suman K, Ramachandran, Mythili, Xue, Xiangdong, Ma, Zhao, Xu, Xiaobao, Wang, Zhongling, He, Yixuan, Lam, Kit S., Zawadzki, Robert J., Li, Yuanpei, Lin, Tzu-Yin
• Format: Article
• Language: English
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.201903759

The efficacy of therapeutics for brain tumors is seriously hampered by multiple drug delivery barriers, including severe destabilizing effects in blood circulation, the blood-brain barrier/blood-brain tumor barrier (BBB/BBTB) and limited tumor uptake. Here we present a S equential T argeting I n C rosslin K ing (STICK) nano-delivery strategy to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK-NPs) could sequentially target BBB/BBTB and brain tumor cells with surface maltobionic acid (MA) and 4-carboxyphenylboronic acid (CBA), respectively, and simultaneously enhance nanoparticle stability with pH-responsive crosslinkages formed by MA and CBA in situ . STICK-NPs exhibited prolonged circulation time (17-fold higher area-under-curve) than free agent, allowing increased opportunities to transpass BBB/BBTB via glucose transporter-mediated transcytosis by MA. Tumor acidic environment then triggered the transformation of STICK-NPs into smaller nanoparticles and revealed secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK-NPs significantly inhibited tumor growth and prolonged the survival time with limited toxicity in mice with aggressive and chemo-resistant diffuse intrinsic pontine glioma. This formulation tackles multiple physiological barriers on-demand with a simple and smart STICK design. Therefore, these features allow STICK-NPs to unleash the potential of brain tumor therapeutics to improve their treatment efficacy.