Boosting Oxidative Stress with Hydroxyethyl Starch Smart Nanomedicines to Eliminate Cancer Stem Cells

Abstract

The significance of cancer stem cells (CSCs), a rare population of cells in tumor tissues, in biology and the treatment of solid malignancies has been widely appreciated for more than two decades. Due to a peculiar self-renewal capability, even one single cancer stem cell can grow into a bulk tumor mass. For this reason, CSCs have long been blamed as the major culprit of tumor initiation, tumor progression, treatment resistance, metastasis, and recurrence. Therefore, it has been postulated that targeting CSCs could provide tremendous clinical benefits for patients with solid tumors. Accumulating studies corroborated that CSCs maintained a tight regulation of redox homeostasis and that the fate of CSCs was extremely sensitive to elevated oxidative stress. Accordingly, a plethora of therapeutic drugs that can generate reactive oxygen species (ROS) have been leveraged to target CSCs. Nonetheless, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs thus far.

Hydroxyethyl starch (HES) has been widely utilized as a plasma volume expander in clinical settings for more than 50 years. Owing to its merits of excellent biocompatibility and biodegradability, good water solubility and manufacture practice, and abundant hydroxy groups for easy chemical modifications, HES has attracted great attention for tumor-targeted drug delivery. Specifically, HES has been leveraged as a nanoparticle stabilizer, as a nanocarrier to conjugate with chemotherapeutic drugs by stimuli-responsive linkers, and as a hydrophilic polymer to link with hydrophobic polymers to form self-assembled nanoparticles. In this Account, we summarize HES smart nanomedicines, developed in our group during the past five years, that could boost oxidative stress for CSC elimination. According to their effects on redox homeostasis, we categorize these nanomedicines into three classes. The first ones are nanomedicines that could generate excessive ROS, by means of mitochondria-targeted photodynamic therapy (Mito-PDT), cuproptosis, and ferroptosis. The second groups of nanomedicines own the capability to counteract endogenous reducing substances via inhibiting glutaminolysis and depleting glutathione (GSH). The third types of nanomedicines simultaneously amplify ROS generation and suppress antioxidant agents through combination strategies of Mito-PDT plus glutaminolysis inhibition, chemical dynamic therapy (CDT) plus GSH depletion, and CDT plus GSH depletion as well as inhibition. These rationally designed nanomedicines not only suppress CSCs in vitro but also eliminate CSCs in numerous tumor-bearing mice models in vivo, giving novel insights into anti-CSC therapy. As HES is widely used in the clinic, these HES smart nanomedicines hold significant potential for clinical translation.