期刊
MOLECULAR PHARMACEUTICS
卷 10, 期 9, 页码 3404-3416出版社
AMER CHEMICAL SOC
DOI: 10.1021/mp4002409
关键词
cancer; intranuclear drug delivery; estrogen; carbon nanotubes; antitumor efficacy
资金
- Indian Council of Medical Research (ICMR), Government of India (GOI), New Delhi [35/28/2010/-BMS]
- Department of Science and Technology (DST), GOI, New Delhi
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.
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