Inherently targeted estradiol-derived carbon dots for selective killing of ER (+) breast cancer cells via oridonin-triggered p53 pathway activation†

Abstract

One of the most prevalent cancers globally is breast cancer and approximately two thirds of the breast cancers are hormone receptor positive with estrogen receptors (ER) being a prominent target. Notably, p53 that controls several cellular functions and prevents tumor formation, gets suppressed in breast cancers. Reactivation of p53 can lead to cell cycle arrest as well as apoptosis. Therefore, targeting the estrogen receptor for selective delivery of anticancer drugs that can reactivate p53 in ER (+) breast cancers can be a crucial method in breast cancer therapy. Herein, we have designed and developed estradiol-derived inherently targeted specific carbon dots (E₂-CA-CD) from 17β-estradiol and citric acid following a solvothermal method. The synthesized carbon dots were characterized using spectroscopic and microscopic techniques. The water soluble, intrinsically fluorescent E₂-CA-CD showed excellent biocompatibility in MCF-7, MDA-MB-231 as well as NIH3T3 cells and demonstrated target specific bioimaging in ER (+) MCF-7 cells due to the overexpressed ER receptors. Furthermore, oridonin, a well-known hydrophobic anticancer drug capable of upregulating the p53 pathway, was loaded on the carbon dots to increase its bioavailability. E₂-CA-CD-Ori caused ∼2.2 times higher killing in ER (+) MCF-7 cells compared to ER (−) MDA-MB-231 cells and normal cells NIH3T3. Also, E₂-CA-CD-Ori showed ∼3 fold better killing in MCF-7 cells compared to native oridonin. E₂-CA-CD-Ori-induced killing of MCF-7 cells took place through the early to late apoptotic pathway along with the elevation of the intracellular ROS level. Importantly, E₂-CA-CD-Ori triggered the activation of the p53 pathway in MCF-7 cells, which in turn induced apoptosis involving the upregulation of Bax and downregulation of Bcl-2 leading to the selective and efficient killing of ER (+) MCF-7 cells.