Cancerous pH-responsive polycarboxybetaine-coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice,Cancer Science

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Cancerous pH-responsive polycarboxybetaine-coated lipid nanoparticle for smart delivery of siRNA against subcutaneous tumor model in mice
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-01 , DOI: 10.1111/cas.15554
Yi-Jung Sung _{1,

2} , Haochen Guo _{1,

2} , Aria Ghasemizadeh _{1,

2} , Xin Shen _{1,

2} , Wanphiwat Chintrakulchai _{1,

2} , Motoaki Kobayashi _{1,

2} , Masahiro Toyoda _{1,

2} , Koichi Ogi ₃ , Junya Michinishi ₃ , Tomoyuki Ohtake ₃ , Makoto Matsui ₁ , Yuto Honda _{1,

2} , Takahiro Nomoto _{1,

2} , Hiroyasu Takemoto _{1,

2} , Yutaka Miura _{1,

2} , Nobuhiro Nishiyama _{1,

2,

4}

Affiliation

Lipid nanoparticles (LNPs) have been commonly used as a vehicle for nucleic acids, such as small interfering RNA (siRNA); the surface modification of LNPs is one of the determinants of their delivery efficiency especially in systemic administration. However, the applications of siRNA-encapsulated LNPs are limited due to a lack effective systems to deliver to solid tumors. Here, we report a smart surface modification using a charge-switchable ethylenediamine-based polycarboxybetaine for enhancing tumor accumulation via interaction with anionic tumorous tissue constituents due to selective switching to cationic charge in response to cancerous acidic pH. Our polycarboxybetaine-modified LNP could enhance cellular uptake in cancerous pH, resulting in facilitated endosomal escape and gene knockdown efficiency. After systemic administration, the polycarboxybetaine-modified LNP accomplished high tumor accumulation in SKOV3-luc and CT 26 subcutaneous tumor models. The siPLK-1-encapsulated LNP thereby accomplished significant tumor growth inhibition. This study demonstrates a promising potential of the pH-responsive polycarboxybetaine as a material for modifying the surface of LNPs for efficient nucleic acid delivery.

中文翻译：

癌症 pH 响应聚羧基甜菜碱包被的脂质纳米颗粒用于针对小鼠皮下肿瘤模型智能递送 siRNA

脂质纳米颗粒 (LNP) 通常用作核酸的载体，例如小干扰 RNA (siRNA)；LNP 的表面改性是其递送效率的决定因素之一，尤其是在系统给药中。然而，由于缺乏有效的递送至实体瘤的系统，siRNA 封装的 LNP 的应用受到限制。在这里，我们报告了一种智能表面修饰，使用基于电荷可切换的乙二胺的聚羧基甜菜碱，通过与阴离子肿瘤组织成分的相互作用来增强肿瘤积累，这是由于响应癌性酸性 pH 而选择性地转换为阳离子电荷。我们的聚羧基甜菜碱修饰的 LNP 可以增强癌性 pH 条件下的细胞摄取，从而促进内体逃逸和基因敲低效率。全身给药后，聚羧基甜菜碱修饰的 LNP 在 SKOV3-luc 和 CT 26 皮下肿瘤模型中实现了高肿瘤积累。siPLK-1 封装的 LNP 从而实现了显着的肿瘤生长抑制。该研究证明了 pH 响应性聚羧基甜菜碱作为修饰 LNP 表面以实现高效核酸递送的材料的巨大潜力。

更新日期：2022-09-01

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