National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China.
International Nanobody Research Center of Guangxi, Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China.
Int J Nanomedicine. 2020 Oct 29;15:8383-8400. doi: 10.2147/IJN.S272495. eCollection 2020.
Cancer tissue-specific and nuclei-targeted drug delivery is ideal for the delivery of chemotherapy. However, it has only been achieved in in vitro studies mainly due to low efficiency in vivo. In this study, we aimed to establish an efficient dual-targeted system that targets liver cancer tissue as well as the nuclei of cancer cells in vivo.
We first synthesized TAT peptide (TATp)-mesoporous silica nanoparticle (MSN) complex (TATp-MSN) and generated liposomes that carried liver cancer-specific aptamer TLS11a (TLS11a-LB). We then generated the drug TLS11a-LB@TATp-MSN/doxorubicin (DOX) by mixing TLS11a-LB and DOX-loaded TATp-MSN. After physical and chemical characterization of the nanoparticles, DOX release from these formulations was evaluated at pH 5.0 and 7.4. Furthermore, we also evaluated nuclear localization and cytotoxicity of the drug in H22 cells in vitro and investigated the liver cancer targeting and antitumor activities of the nano-drug in vivo using a H22 tumor-bearing mice model.
TLS11a-LB@TATp-MSN/DOX and its controls were confirmed as nano-drugs (<100 nm) using transmission electron microscopy (TEM). The DOX release rate of TLS11a-LB@TATp-MSN/DOX was significantly faster at pH 5.0 than at pH 7.4. TLS11a-LB@TATp-MSN/DOX effectively targeted the nuclei of H22 cells and released DOX with a higher efficiency than that of the control groups. In addition, TLS11a-LB@TATp-MSN/DOX exhibited slight cytotoxicity, but not significantly more than controls. In vivo studies showed that TLS11a-LB@TATp-MSN accumulated in subcutaneous H22 tumors in the right axilla of BALB/c mice, reaching peak levels at 48 h after intravenous injection, respectively, and demonstrated that TLS11a-LB@TATp-MSN/DOX group enhanced tumor treatment efficacy while reducing systemic side effects.
TLS11a-LB@TATp-MSN/DOX can efficiently deliver DOX to the nuclei of liver cancer cells by dual targeting liver cancer tissue and the nuclei of the cancer cells in mice. Thus, it is a promising nano-drug for the treatment of liver cancer.
癌症组织特异性和核靶向药物递药系统是化疗药物递药的理想选择。然而，由于体内效率低，这种方法仅在体外研究中得到实现。本研究旨在建立一种有效的双重靶向系统，该系统能够在体内靶向肝癌组织和癌细胞的核。
我们首先合成了 TAT 肽（TATp）-介孔硅纳米颗粒（MSN）复合物（TATp-MSN），并制备了携带肝癌特异性适体 TLS11a 的脂质体（TLS11a-LB）。然后，我们将 TLS11a-LB 和载有阿霉素（DOX）的 TATp-MSN 混合，生成了药物 TLS11a-LB@TATp-MSN/DOX。对纳米粒子进行物理化学特性表征后，在 pH 值为 5.0 和 7.4 条件下评价了 DOX 的释放情况。此外，我们还在体外研究了药物在 H22 细胞中的核定位和细胞毒性，并在 H22 荷瘤小鼠模型中研究了纳米药物的肝癌靶向和抗肿瘤活性。
透射电子显微镜（TEM）证实，TLS11a-LB@TATp-MSN/DOX 及其对照物为纳米药物（<100nm）。TLS11a-LB@TATp-MSN/DOX 在 pH 值为 5.0 时的 DOX 释放速率明显快于 pH 值为 7.4 时。TLS11a-LB@TATp-MSN/DOX 能够有效地靶向 H22 细胞的核，并以比对照组更高的效率释放 DOX。此外，TLS11a-LB@TATp-MSN/DOX 表现出轻微的细胞毒性，但并不比对照组更明显。体内研究表明，TLS11a-LB@TATp-MSN 在 BALB/c 小鼠右腋窝皮下 H22 肿瘤中蓄积，分别在静脉注射后 48 小时达到峰值，并且表明 TLS11a-LB@TATp-MSN/DOX 组增强了肿瘤治疗效果，同时减少了全身副作用。
TLS11a-LB@TATp-MSN/DOX 可通过双重靶向肝癌组织和癌细胞的核，在小鼠体内有效地将 DOX 递送至肝癌细胞的核内。因此，它是一种有前途的肝癌治疗纳米药物。
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