Shell-Free Copper Indium Sulfide Quantum Dots Induce Toxicity in Vitro and in Vivo

Abstract

Semiconductor quantum dots (QDs) are attractive fluorescent contrast agents for in vivo imaging due to their superior photophysical properties, but traditional QDs comprise toxic materials such as cadmium or lead. Copper indium sulfide (CuInS2, CIS) QDs have been posited as a nontoxic and potentially clinically translatable alternative; however, previous in vivo studies utilized particles with a passivating zinc sulfide (ZnS) shell, limiting direct evidence of the biocompatibility of the underlying CIS. For the first time, we assess the biodistribution and toxicity of unshelled CIS and partially zinc-alloyed CISZ QDs in a murine model. We show that bare CIS QDs breakdown quickly, inducing significant toxicity as seen in organ weight, blood chemistry, and histology. CISZ demonstrates significant, but lower, toxicity compared to bare CIS, while our measurements of core/shell CIS/ZnS are consistent with literature reports of general biocompatibility. In vitro cytotoxicity is dose-dependent on the amount of metal released due to particle degradation, linking degradation to toxicity. These results challenge the assumption that removing heavy metals necessarily reduces toxicity: indeed, we find comparable in vitro cytotoxicity between CIS and CdSe QDs, while CIS caused severe toxicity in vivo compared to CdSe. In addition to highlighting the complexity of nanotoxicity and the differences between the in vitro and in vivo outcomes, these unexpected results serve as a reminder of the importance of assessing the biocompatibility of core QDs absent the protective ZnS shell when making specific claims of compositional biocompatibility.

NIR-quantum dots in biomedical imaging and their future

“…Recently, Kays and co-workers studied the influence of ZnS shelling (d = 4.5-10 nm, l em = 682 nm) and Zn doping of CuInS 2 QDs (d = 3.5 nm, l em = 822 nm) on their toxicity. The synthesis followed a hot-injection method, by adding the sulfur precursor hexamethyldisilathiane into a solution of Cu(II) and In(III) salts with TOP and ODE as solvents (Kays et al, 2020). Shelling the bare CuInS 2 cores with ZnS reduced the wavelength of the emission maxima from 822 to 681 nm, whereas the diameter increased from 3.5 to 4.5 nm.…”

Indium Chalcogenide Nanomaterials in the Forefront of Recent Technological Advancements

“…Although CuInS 2 is a reputably known non-toxic material displaying attractive properties which are already exploited intensively in biomedical-based applications, there are however recent reports which have shown compelling experimental evidence contradicting this non-toxic behavior. A recent research study has observed the instability of zinc sulfide (ZnS) shell-free CuInS 2 quantum dots relative to the shelled counterparts in the in vitro studies [31], degradation was demonstrated by rapid dissolution in simulated biological fluid (SBF) and artificial lysosomal fluid (ALS) through absorption spectroscopy measurements shown in Figure 5. Furthermore, it was demonstrated that shell-free CuInS 2 induces severe toxicity in the in vivo studies compared to the infamous, toxic cadmium selenide.…”

Phytotoxic effects of CdTe quantum dots on root meristems of Allium cepa L.

“…Unfortunately, an inherent drawback of all the above Cd-free QDs is the large spectral width of the PL band, 100 -200 nm, which does not allow as fine color tunability as in the case of Cd-based QDs. Moreover, recent studies show toxicity also of QDs consisting of rather non-toxic elements (Kays et al 2020). Therefore, intense research of II-VI QDs with advanced optical properties continues (Yeshchenko et al 2020), currently focused mostly on developing various functionalization of the NC surface and reducing toxicity (Borovaya et al 2016;Filali et al 2019;Garmanchuk et al 2019;Lima et al 2019).…”