Designing Superoxide-Generating Quantum Dots for Selective Light-Activated Nanotherapy

Abstract

The rapid emergence of superbugs, or multi-drug resistant (MDR) organisms, has prompted a search for novel antibiotics, beyond traditional small-molecule therapies. Nanotherapeutics are being investigated as alternatives, and recently superoxide-generating quantum dots (QDs) have been shown as important candidates for selective light-activated therapy, while also potentiating existing antibiotics against MDR superbugs. Their therapeutic action is selective, can be tailored by simply changing their quantum-confined conduction-valence band (CB-VB) positions and alignment with different redox half-reactions—and hence their ability to generate specific radical species in biological media. Here, we show the design of superoxide-generating QDs using optimal QD material and size well-matched to superoxide redox potential, charged ligands to modulate their uptake in cells and selective redox interventions, and core/shell structures to improve their stability for therapeutic action. We show that cadmium telluride (CdTe) QDs with conduction band (CB) position at −0.5 V with respect to Normal Hydrogen Electron (NHE) and visible 2.4 eV bandgap generate a large flux of selective superoxide radicals, thereby demonstrating the effective light-activated therapy. Although the positively charged QDs demonstrate large cellular uptake, they bind indiscriminately to cell surfaces and cause non-selective cell death, while negatively charged and zwitterionic QD ligands reduce the uptake and allow selective therapeutic action via interaction with redox species. The stability of designed QDs in biologically-relevant media increases with the formation of core-shell QD structures, but an appropriate design of core-shell structures is needed to minimize any reduction in charge injection efficiency to adsorbed oxygen molecules (to form superoxide) and maintain similar quantitative generation of tailored redox species, as measured using electron paramagnetic resonance (EPR) spectroscopy and electrochemical impedance spectroscopy (EIS). Using these findings, we demonstrate the rational design of QDs as selective therapeutic to kill more than 99% of a priority class I pathogen, thus providing an effective therapy against MDR superbugs.

Near‐Infrared‐Light‐Triggered Antimicrobial Indium Phosphide Quantum Dots

“…This allows QDs to act synergistically with existing antibiotics, or even potentiate failed antibiotics, making them effective again . Such dual use as an effective antimicrobial and antibiotic potentiator opens new avenues for addressing the imminent problem of rapidly developing MDR superbugs …”

“…Previous studies have used QDs in combination with visible light to eliminate bacteria, including 45 MDR strains, many of which are resistant to almost all known and last‐resort antibiotics . Upon illumination, absorbed light triggers the photo‐electrochemical reduction of oxygen to generate therapeutic superoxide intracellularly . The bottom‐up design of QD nanotherapeutics involves optimizing several aspects: material selection, reduction and oxidation potentials, biocompatibility, and surface chemistry.…”

“…The bottom‐up design of QD nanotherapeutics involves optimizing several aspects: material selection, reduction and oxidation potentials, biocompatibility, and surface chemistry. These variables tightly control the desired phototherapeutic effect, eliminate undesired material toxicity, can modulate the innate host immune response, and ensure efficient QD transport . While cadmium telluride (CdTe) QDs demonstrate selective bacterial killing (even of MDR superbugs), its green‐light absorbing band gap and cadmium content present some concerns.…”

Quantum dot therapeutics: a new class of radical therapies

“…1) [24, 25], where these redox species would be toxic even for host mammalian cells [26–28]. However, superoxide was found to be a potent bactericidal at low nanomolar doses—killing a range of multidrug-resistant (MDR) pathogens without affecting the viability or growth of host mammalian cells in in vitro measurements [19, 20, 24, 29]. This difference in nanotherapeutic toxicity between host and the targeted pathogen is important for designing the safest possible treatment.…”

Gold nanoclusters cause selective light-driven biochemical catalysis in living nano-biohybrid organisms

“…[19][20][21][22] We focused on Au NCs capped with the zwitterionic ligand, glutathione (GSH), due to their demonstrated low hydrodynamic radius for cellular uptake. [23][24][25] These atomically-precise Au NCs can be synthesized using simple wet-chemistry, with tunable optoelectronic properties ( Fig. 1a), hydrodynamic size ( Fig.…”