Intranuclear Drug Delivery and Effective in Vivo Cancer Therapy via Estradiol-PEG-Appended Multiwalled Carbon Nanotubes
Intranuclear Drug Delivery and Effective in Vivo Cancer Therapy via Estradiol-PEG-Appended Multiwalled Carbon Nanotubes
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DOI：
10.1021/mp4002409
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发表时间：
2013-09-01
影响因子：
4.9
通讯作者：
Jain, Sanyog
中科院分区：
文献类型：
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作者：
Das, Manasmita;Singh, Raman Preet;Jain, Sanyog
癌细胞选择性的、核靶向有望增强无数抗癌药物的治疗功效，特别是那些药效学作用部位是核的药物。在这项研究中，基于PEG连接的17 β-雌二醇（E-2）的类固醇-大分子生物缀合物被附加到固有的细胞可穿透的多壁碳纳米管（MWCNT）上，用于核内药物递送和有效的乳腺癌治疗，无论是在体外还是在体内。本文以阿霉素（DOX）为模型药物，探讨了E-2附件对超分子复合药物的细胞内化、胞内转运及抗肿瘤作用的影响。我们观察到DOX与E-2-PEG-MWCNTs的组合不仅通过雌激素受体（ER）介导的途径促进核靶向，而且还在体内破译协同抗癌反应。DOX@E-2-PEG-MWCNT在化学诱导的乳腺癌雌性大鼠中的抗肿瘤功效分别比暴露于盐水、药物剥夺的E-2-PEG-MWCNT、游离DOX和DOX@m-PEG-MWCNT的组高约18、17、5和2倍。虽然游离DOX处理在动物中诱导严重的心脏毒性，但是用DOX@m-PEG-MWCNT和DOX@E-2-PEG-MWCNT处理的动物没有任何可感知的心脏毒性、肝毒性和肾毒性。据我们所知，这是第一次癌细胞。选择性的核内药物递送，以及随后的有效的体内乳腺癌治疗已经使用附加雌激素的MWCNT作为分子转运蛋白实现。
Cancer cell-selective, nuclear, targeting is expected to enhance the therapeutic efficacy of a myriad of antineoplastic drugs, particularly those whose pharmacodynamic site of action is the nucleus. In this study, a steroid-macromolecular bioconjugate based on PEG linked 17 beta-Estradiol, (E-2) was appended to intrinsically cell penetrable multiwalled carbon nanotubes (MWCNTs) for intranuclear drug delivery and effective breast cancer treatment, both in vitro and in vivo. Taking Doxorubicin (DOX) as a model, anticancer agent, we 'tried to elucidate how E-2 appendage influences the cell internalization, intracellular trafficking, and antitumor efficacy of the supramolecularly complexed drug. We observed that the combination of DOX with E-2-PEG-MWCNTs not only facilitated nuclear targeting through an estrogen receptor (ER)-mediated pathway but also deciphered to a synergistic anticancer response in vivo. The antitumor efficacy of DOX@E-2-PEG-MWCNTs in chemically breast cancer induced female rats was approximately 18, 17, 5, and 2 times higher compared to the groups exposed to saline, drug deprived E-2-PEG-MWCNTs, free DOX, and DOX@m-PEG-MWCNTs, respectively. While free DOX treatment induced severe cardiotoxicity in animals, animals treated with DOX@m-PEG-MWCNTs and DOX@E-2-PEG-MWCNTs were devoid of any perceivable cardiotoxicity, hepatotoxicity, and nephrotoxicity. To the best of our knowledge, this is the first instance in which cancer cell. selective, intranuclear drug delivery, and, subsequently, effective in vivo breast cancer therapy has been achieved using estrogen appended MWCNTs as the molecular transporter.