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 17β-Estradiol (E2) 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 E2 appendage influences the cell internalization, intracellular trafficking, and antitumor efficacy of the supramolecularly complexed
drug. We observed that the combination of DOX with E2-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@E2-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 E2-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@E2-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.