Albumin-stabilized manganese-based nanocomposites with sensitive tumor microenvironment responsivity and their application for efficient SiRNA delivery in brain tumors
Albumin-stabilized manganese-based nanocomposites with sensitive tumor microenvironment responsivity and their application for efficient SiRNA delivery in brain tumors
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具有敏感肿瘤微环境响应性的白蛋白稳定锰基纳米复合材料及其在脑肿瘤中高效 SiRNA 递送的应用
DOI：
10.1039/c9tb02341k
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发表时间：
2020
影响因子：
7
通讯作者：
Zhang Weiguo
中科院分区：
文献类型：
--
作者：
Xu Kai;Zhao Zhenghuan;Zhang Junfeng;Xue Wei;Tong Haipeng;Liu Heng;Zhang Weiguo
基于Mn（IV）的纳米颗粒（NP）在改善肿瘤氧合（缺氧）和减少肿瘤区域中的内源性过氧化氢和酸性方面是有效的。然而，常规Mn（IV）基NP的优化还原条件通常报道为pH ≤ 6.5，而肿瘤微环境（TME）的通常pH范围为6.5-7.0。但在弱酸性环境中成像性能不理想，限制了其在肿瘤诊断中的进一步应用。在这项研究中，Mn（III）被引入到纳米平台中，因为它在弱酸性环境中被还原成Mn（II）。以精氨酸-甘氨酸-天冬氨酸（Arg-Gly-Asp，RGD）修饰的牛血清白蛋白（bovine serum albumin，BSA）为稳定剂和支架材料，制备了尺寸合适、稳定性好、生物相容性好的Mn（III）和Mn（IV）纳米复合材料（RGD-BMnNPs）。由于Mn（III）在弱酸性环境中的固有反质子化反应，所制备的NPs在体外pH 6.5-6.9下显示出明显的对比增强，以及在胶质母细胞瘤（U87 MG）原位模型中肿瘤区域内的灵敏和快速的T1加权成像性能。此外，这些NP可用于有效的siRNA递送。它们在该过程中显示出上级优势，包括增加肿瘤摄取、改善肿瘤积聚和通过调节TME增强治疗效果。这些新型白蛋白稳定的锰基纳米颗粒与有效的药物递送能力相结合，具有作为智能治疗诊断剂用于进一步临床转化的巨大潜力。
Mn(IV)-Based nanoparticles (NPs) are effective in improving tumor oxygenation (hypoxia) and reducing endogenous hydrogen peroxide and acidity in the tumor region. However, the optimized reduction conditions of conventional Mn(IV)-based NPs are generally reported at pH ≤ 6.5, while the usual pH range of the tumor microenvironment (TME) is 6.5–7.0. The dissatisfactory imaging performance in the weakly acidic environment may limit their further application in tumor diagnosis. In this study, Mn(III) was introduced in a nanoplatform, because it is reduced into Mn(II) in weakly acidic environments. Arg-Gly-Asp (RGD) peptide-decorated bovine serum albumin (BSA) was employed as the stabilizer and scaffold to fabricate Mn(III)- and Mn(IV)-integrated nanocomposites (RGD-BMnNPs) with suitable size, good stability, and excellent biocompatibility. The as-prepared NPs showed clear contrast enhancement at pH 6.5–6.9 in vitro as well as sensitive and rapid T1-weighted imaging performance within the tumor region in a glioblastoma (U87MG) orthotopic model, owing to the intrinsic disproportionation reaction of Mn(III) in the weakly acidic environment. In addition, these NPs could be used for efficient siRNA delivery. They showed superior advantages in this process, including increased tumour uptake, improved tumor accumulation and enhanced therapeutic effects with the modulation of the TME. These novel albumin-stabilized manganese-based NPs combined with efficient drug delivery capacity hold great potential to serve as intelligent theranostic agents for further clinical translation.