Cyclic RGD-Functionalized closo-Dodecaborate Albumin Conjugates as Integrin Targeting Boron Carriers for Neutron Capture Therapy.,Molecular Pharmaceutics

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Cyclic RGD-Functionalized closo-Dodecaborate Albumin Conjugates as Integrin Targeting Boron Carriers for Neutron Capture Therapy.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-08-26 , DOI: 10.1021/acs.molpharmaceut.0c00478
Kazuki Kawai ₁ , Kai Nishimura ₁ , Satoshi Okada _{1,

2} , Shinichi Sato _{1,

2} , Minoru Suzuki ₃ , Takushi Takata ₃ , Hiroyuki Nakamura _{1,

2}

Affiliation

Cyclic RGD (cRGD) peptide-conjugated boronated albumin was developed to direct toward integrin α_vβ_3, which overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)] and maleimide-conjugated closo-dodecaborate (MID) to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic toward both U87MG and A549 cells. As compared with l-BPA, selective antitumor activity of cRGD-MID-BSA toward U87MG cells overexpressing integrin α_vβ₃ was identified after thermal neutron irradiation. In vivo fluorescence live imaging of Cy5-conjugated cRGD-MID-BSA and MID-BSA revealed that both cRGD-MID-BSA and MID-BSA similarly reached the maximum accumulation during 8–12 h after injection. The selective accumulation and retention of Cy5-cRGD-MID-BSA was more pronounced than Cy5-MID-BSA after 24 h. An in vivo boron neutron capture therapy (BNCT) study revealed that the cRGD peptide ligand combination enhanced accumulation of MID-BSA into tumor cells in U87MG xenograft models. The significant tumor growth suppression was observed in U87MG xenograft models at a dose of 7.5 mg [¹⁰B]/kg after neutron irradiation.

中文翻译：

环状 RGD 功能化的十二硼酸白蛋白结合物作为整合素靶向硼载体，用于中子俘获疗法。

环状 RGD (cRGD) 肽偶联的硼化白蛋白被开发用于针对整合素 α _v β _3，其在许多癌细胞上过表达。℃的逐步偶联[RGDfK（MAL）]和马来酰亚胺缀合的闭合碳-dodecaborate（MID），以牛血清白蛋白（BSA），得到的cRGD-MID-BSA，这是朝向两侧U87MG和A549细胞无细胞毒性。与l- BPA相比，cRGD-MID-BSA 对过表达整合素 α _v β _{3 的}U87MG 细胞的选择性抗肿瘤活性经热中子辐照后鉴定。Cy5 偶联的 cRGD-MID-BSA 和 MID-BSA 的体内荧光实时成像显示，cRGD-MID-BSA 和 MID-BSA 在注射后 8-12 小时内同样达到最大积累。24 小时后，Cy5-cRGD-MID-BSA 的选择性积累和保留比 Cy5-MID-BSA 更明显。一项体内硼中子俘获疗法 (BNCT) 研究表明，在 U87MG 异种移植模型中，cRGD 肽配体组合增强了 MID-BSA 在肿瘤细胞中的积累。在中子照射后，在7.5 mg [ ¹⁰ B]/kg剂量的 U87MG 异种移植模型中观察到显着的肿瘤生长抑制。

更新日期：2020-10-05

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