Extracellular Vesicles Comprising Carborane Prepared by a Host Exchanging Reaction as a Boron Carrier for Boron Neutron Capture Therapy

体内 药物输送 材料科学 碳硼烷 生物物理学 分子 细胞外小泡 纳米技术 化学 组合化学 有机化学 细胞生物学 生物 生物技术
作者
Riku Kawasaki,Ayano Oshige,Nanami Kono,Keita Yamana,Hidetoshi Hirano,Yamato Miura,Ryuji Yorioka,Kaori Bando,Anri Tabata,Naoki Yasukawa,Masahiro Sadakane,Yu Sanada,Minoru Suzuki,Takushi Takata,Yoshinori Sakurai,Hiroki Tanaka,Dilimulati Yimiti,Shigeru Miyaki,Nobuo Adachi,Ryosuke Mizuta,Yoshihiro Sasaki,Kazunari Akiyoshi,Yoshihide Hattori,Mitsunori Kirihata,Takeshi Nagasaki,Atsushi Ikeda
出处
期刊:ACS Applied Materials & Interfaces [American Chemical Society]
卷期号:16 (36): 47137-47149
标识
DOI:10.1021/acsami.4c07650
摘要

With their low immunogenicity and excellent deliverability, extracellular vesicles (EVs) are promising platforms for drug delivery systems. In this study, hydrophobic molecule loading techniques were developed via an exchange reaction based on supramolecular chemistry without using organic solvents that can induce EV disruption and harmful side effects. To demonstrate the availability of an exchanging reaction to prepare drug-loading EVs, hydrophobic boron cluster carborane (CB) was introduced to EVs (CB@EVs), which is expected as a boron agent for boron neutron capture therapy (BNCT). The exchange reaction enabled the encapsulation of CB to EVs without disrupting their structure and forming aggregates. Single-particle analysis revealed that an exchanging reaction can uniformly introduce cargo molecules to EVs, which is advantageous in formulating pharmaceuticals. The performance of CB@EVs as boron agents for BNCT was demonstrated in vitro and in vivo. Compared to L-BPA, a clinically available boron agent, and CB delivered with liposomes, CB@EV systems exhibited the highest BNCT activity in vitro due to their excellent deliverability of cargo molecules via an endocytosis-independent pathway. The system can deeply penetrate 3D cultured spheroids even in the presence of extracellular matrices. The EV-based system could efficiently accumulate in tumor tissues in tumor xenograft model mice with high selectivity, mainly via the enhanced permeation and retention effect, and the deliverability of cargo molecules to tumor tissues in vivo enhanced the therapeutic benefits of BNCT compared to the L-BPA/fructose complex. All of the features of EVs are also advantageous in establishing anticancer agent delivery platforms.
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