Sequential Targeting in Crosslinking Nanotheranostics for Tackling the Multibarriers of Brain Tumors |
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Authors: | Hao Wu Hongwei Lu Wenwu Xiao Jinfan Yang Hongxu Du Yingbin Shen Haijing Qu Bei Jia Suman K Manna Mythili Ramachandran Xiangdong Xue Zhao Ma Xiaobao Xu Zhongling Wang Yixuan He Kit S Lam Robert J Zawadzki Yuanpei Li Tzu-Yin Lin |
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Affiliation: | 1. Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, 95817 USA;2. UC Davis RISE Eye-Pod Laboratory, Department of Cell Biology and Human Anatomy, University of California Davis, Davis, CA, 95616 USA;3. Department of Internal Medicine, School of Medicine, University of California Davis, Sacramento, CA, 95817 USA |
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Abstract: | The efficacy of therapeutics for brain tumors is seriously hampered by multiple barriers to drug delivery, including severe destabilizing effects in the blood circulation, the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB), and limited tumor uptake. Here, a sequential targeting in crosslinking (STICK) nanodelivery strategy is presented to circumvent these important physiological barriers to improve drug delivery to brain tumors. STICK nanoparticles (STICK-NPs) can 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 exhibit prolonged circulation time (17-fold higher area under curve) than the free agent, allowing increased opportunities to transpass the BBB/BBTB via glucose-transporter-mediated transcytosis by MA. The tumor acidic environment then triggers the transformation of the STICK-NPs into smaller nanoparticles and reveals a secondary CBA targeting moiety for deep tumor penetration and enhanced uptake in tumor cells. STICK-NPs significantly inhibit tumor growth and prolong the survival time with limited toxicity in mice with aggressive and chemoresistant 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. |
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Keywords: | blood–brain barrier diffuse intrinsic pontine glioma pH response sequential targeting |
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