Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, PR China; Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore.
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, PR China.
Biomaterials. 2014 Sep;35(27):7951-62. doi: 10.1016/j.biomaterials.2014.05.058. Epub 2014 Jun 13.
In this study, a type of intracellular redox-triggered hollow mesoporous silica nanoreservoirs (HMSNs) with tumor specificity was developed in order to deliver anticancer drug (i.e., doxorubicin (DOX)) to the target tumor cells with high therapeutic efficiency and reduced side effects. Firstly, adamantanamine was grafted onto the orifices of HMSNs using a redox-cleavable disulfide bond as an intermediate linker. Subsequently, a synthetic functional molecule, lactobionic acid-grafted-β-cyclodextrin (β-CD-LA), was immobilized on the surface of HMSNs through specific complexation with the adamantyl group, where β-CD served as an end-capper to keep the loaded drug within HMSNs. β-CD-LA on HMSNs could also act as a targeting agent towards tumor cells (i.e., HepG2 cells), since the lactose group in β-CD-LA is a specific ligand binding with the asialoglycoprotein receptor (ASGP-R) on HepG2 cells. In vitro studies demonstrated that DOX-loaded nanoreservoirs could be selectively endocytosed by HepG2 cells, releasing therapeutic DOX into cytoplasm and efficiently inducing the apoptosis and cell death. In vivo investigations further confirmed that DOX-loaded nanoreservoirs could permeate into the tumor sites and actively interact with tumor cells, which inhibited the tumor growth with the minimized side effect. On the whole, this drug delivery system exhibits a great potential as an efficient carrier for targeted tumor therapy in vitro and in vivo.
在这项研究中，开发了一种具有肿瘤特异性的细胞内氧化还原触发的中空介孔硅纳米储库（HMSNs），以便将抗癌药物（即阿霉素（DOX））高效递送至靶肿瘤细胞，同时降低副作用。首先，通过使用氧化还原可裂解的二硫键作为中间连接体，将金刚烷胺接枝到 HMSNs 的孔口上。随后，通过与金刚烷基团的特异性络合，将合成的功能分子，即乳糖酸接枝-β-环糊精（β-CD-LA）固定在 HMSNs 的表面上，其中β-CD 作为端封剂将负载的药物保持在 HMSNs 内。HMSNs 上的β-CD-LA 也可以作为针对肿瘤细胞（即 HepG2 细胞）的靶向剂，因为β-CD-LA 中的乳糖基团是与 HepG2 细胞上的去唾液酸糖蛋白受体（ASGP-R）特异性结合的配体。体外研究表明，负载 DOX 的纳米储库可以被 HepG2 细胞选择性内吞，将治疗性 DOX 释放到细胞质中，并有效地诱导细胞凋亡和死亡。体内研究进一步证实，负载 DOX 的纳米储库可以渗透到肿瘤部位，并与肿瘤细胞积极相互作用，从而抑制肿瘤生长，同时最小化副作用。总的来说，这种药物递送系统作为体外和体内靶向肿瘤治疗的有效载体具有很大的潜力。
