Huzhou Key Laboratory of Medical and Environmental Applications Technologies, School of Life Sciences, Huzhou University, Huzhou, 313000, People's Republic of China.
Jiangxi Provincial Key Laboratory of System Biomedicine, Jiujiang University, Jiujiang, 332000, People's Republic of China.
Int J Nanomedicine. 2023 Feb 10;18:663-677. doi: 10.2147/IJN.S398802. eCollection 2023.
Metastasis is a major challenge in breast cancer therapy. The successful chemotherapy of breast cancer largely depends on the ability to block the metastatic process. Herein, we designed a dual-targeting and stimuli-responsive drug delivery system for targeted drug delivery against breast cancer metastasis.
AS1411 aptamer-modified chondroitin sulfate A-ss-deoxycholic acid (ACSSD) was synthesized, and the unmodified CSSD was used as the control. Chemotherapeutic drug doxorubicin (DOX)-containing ACSSD (D-ACSSD) micelles were prepared by a dialysis method. The ACSSD conjugate was confirmed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), dynamic light scattering (DLS), and transmission electron microscopy (TEM). In vitro cellular uptake and cytotoxicity of D-ACSSD micelles were studied by confocal laser scanning microscopy (CLSM) and MTT assay in breast tumor cells. The inhibition capability of D-ACSSD micelles in cell migration and invasion was carried out in 4T1 cells. In vivo antitumor activity of DOX-containing micelles was investigated in metastatic 4T1-bearing Balb/c mice.
D-ACSSD and DOX-loaded CSSD (D-CSSD) micelles exhibited high drug encapsulation content and reduction-responsive characteristics. D-ACSSD micelles were spherical in shape. Compared with D-CSSD, D-ACSSD showed higher cellular uptake and more potent killing activity in 4T1 and MDA-MB-231 cells. Additionally, D-ACSSD exhibited stronger inhibitory effects on the invasion and migration of highly metastatic 4T1 cells than unmodified D-CSSD. Among the DOX-containing formulations, D-ACSSD micelles presented the most effective inhibition of tumor growth and lung metastasis in orthotopic 4T1-bearing mice in vivo. It also revealed that ACSSD micelles did not exhibit obvious systemic toxicity.
The smart D-ACSSD micelles could be a promising delivery system for the therapy of metastatic breast cancer.
转移是乳腺癌治疗的主要挑战。乳腺癌的成功化疗在很大程度上取决于阻断转移过程的能力。在此，我们设计了一种双靶向和刺激响应型药物传递系统，用于针对乳腺癌转移的靶向药物传递。
合成了 AS1411 适体修饰的硫酸软骨素 A-ss-去氧胆酸（ACSSD），并将未修饰的 CSSD 用作对照。通过透析法制备载有化疗药物阿霉素（DOX）的 ACSD（D-ACSSD）胶束。通过傅里叶变换红外光谱（FTIR）、核磁共振（NMR）、动态光散射（DLS）和透射电子显微镜（TEM）确认了 ACSD 缀合物。通过共聚焦激光扫描显微镜（CLSM）和 MTT 测定法研究了 D-ACSSD 胶束在乳腺癌细胞中的摄取和细胞毒性。在 4T1 细胞中进行了 D-ACSSD 胶束对细胞迁移和侵袭的抑制能力研究。在转移性 4T1 荷瘤 Balb/c 小鼠中研究了载 DOX 胶束的体内抗肿瘤活性。
D-ACSSD 和载 DOX 的 CSSD（D-CSSD）胶束表现出高药物包封含量和还原响应特性。D-ACSSD 胶束呈球形。与 D-CSSD 相比，D-ACSSD 在 4T1 和 MDA-MB-231 细胞中表现出更高的细胞摄取和更强的杀伤活性。此外，D-ACSSD 对高度转移性 4T1 细胞的侵袭和迁移表现出更强的抑制作用，优于未修饰的 D-CSSD。在载 DOX 的制剂中，D-ACSSD 胶束在体内荷瘤 4T1 小鼠中对肿瘤生长和肺转移的抑制作用最为明显。还表明 ACSD 胶束没有明显的全身毒性。
智能 D-ACSSD 胶束可能是治疗转移性乳腺癌的有前途的药物传递系统。
