Key Laboratory for Advanced Materials, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, People's Republic of China.
Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.
Int J Nanomedicine. 2019 May 31;14:4029-4044. doi: 10.2147/IJN.S201688. eCollection 2019.
As well as functioning as a ligand that is selectively internalized by cells overexpressing human epidermal growth factor receptor-2 (HER2), HApt can exert cytotoxic effects by inducing cross-linking and subsequent translocation of HER2 to cytoplasmic vesicles, such downregulation of HER2 inhibits cell proliferation and induces apoptosis. We aimed to exploit the potential of HApt as both a targeting agent and antagonist to maximize the efficacy of mesoporous silica nanoparticle (MSN)-based drug release systems for HER2-positive breast cancer. We fabricated novel HApt aptamer-functionalized pH-sensitive β-cyclodextrin (β-CD)-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (termed MSN-BM/CD-HApt@DOX) for targeted delivery and selective targeting of HER2-positive cells. MSN-functionalized benzimidazole (MSN-BM) was used to load and achieve pH stimuli-responsive release of the chemotherapeutic agent doxorubicin (DOX). β-cyclodextrin was introduced as a gatekeeper for encapsulated DOX and HApt as a selective HER2-targeting moiety and biotherapeutic agent. Physical and chemical characterizations (FT-IR, XRD, TEM and BET) confirmed successful construction of MSN-BM/CD-HApt@DOX nanoparticles. In vitro release assays verified pH-sensitive DOX release. MSN-BM/CD-HApt@DOX (relative DOX concentration, 3.6 μg/mL) underwent HER2-mediated endocytosis and was more cytotoxic to HER2-positive SKBR3 cells than HER2-negative MCF7 cells. MSN-BM/CD-HApt@DOX also exhibited better uptake and stronger growth inhibition in SKBR3 cells than the control MSN-BM/CD-NCApt@DOX functionalized with a scrambled nucleotide sequence on CD. Overall, intracellular delivery of DOX and the biotherapeutic agent HApt resulted in synergistic cytotoxic effects in HER2-positive cancer cells in comparison to either DOX or HApt alone. MSN-BM/CD-HApt@DOX enables HER2-mediated targeting and biotherapeutic effects as well as pH-responsive DOX drug release, resulting in synergistic cytotoxic effects in HER2-overexpressing cells in vitro. This novel nanocarrier could potentially enable specific targeting to improve the efficacy of chemotherapy for HER2-positive cancer.
作为一种选择性地被人表皮生长因子受体 2（HER2）过表达细胞内化的配体，HApt 可以通过诱导 HER2 交联和随后向细胞质小泡转移来发挥细胞毒性作用，这种 HER2 的下调抑制细胞增殖并诱导细胞凋亡。我们旨在利用 HApt 作为靶向剂和拮抗剂的潜力，最大限度地提高基于介孔硅纳米粒子（MSN）的药物释放系统对 HER2 阳性乳腺癌的疗效。我们制备了新型的 HApt 适体功能化的 pH 敏感β-环糊精（β-CD）封端阿霉素（DOX）负载介孔硅纳米粒子（称为 MSN-BM/CD-HApt@DOX），用于 HER2 阳性细胞的靶向递药和选择性靶向。MSN 功能化苯并咪唑（MSN-BM）用于负载并实现化疗药物阿霉素（DOX）的 pH 刺激响应释放。β-环糊精被引入作为封装的 DOX 的门控，而 HApt 作为选择性 HER2 靶向部分和生物治疗剂。物理化学特性（FT-IR、XRD、TEM 和 BET）证实了 MSN-BM/CD-HApt@DOX 纳米粒子的成功构建。体外释放实验验证了 pH 敏感的 DOX 释放。MSN-BM/CD-HApt@DOX（相对 DOX 浓度为 3.6μg/mL）经历了 HER2 介导的内吞作用，对 HER2 阳性 SKBR3 细胞的细胞毒性比 HER2 阴性 MCF7 细胞更强。MSN-BM/CD-HApt@DOX 对 SKBR3 细胞的摄取和生长抑制作用也强于用 CD 上的乱序核苷酸序列功能化的对照 MSN-BM/CD-NCApt@DOX。总体而言，与 DOX 或 HApt 单独使用相比，DOX 和生物治疗剂 HApt 的细胞内递药导致 HER2 阳性癌细胞的协同细胞毒性作用。MSN-BM/CD-HApt@DOX 能够实现 HER2 介导的靶向和生物治疗作用以及 pH 响应的 DOX 药物释放，从而在体外对 HER2 过表达细胞产生协同细胞毒性作用。这种新型纳米载体有可能实现特异性靶向，以提高 HER2 阳性癌症的化疗疗效。
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