Evaluation of toxicological and teratogenic effects of carbosilane glucose glycodendrimers in zebrafish embryos and model rodent cell lines

Abstract

Glycodendrimers (Glyco-DDMs) represent a rapidly growing class of nanoparticles with promising properties for biomedical applications but concerns regarding the impact on human health and environment are still justified. Here we report, for the first time, the comparative study of in vivo developmental toxicity of carbosilane Glyco-DDMs and their cytotoxicity in vitro. Carbosilane Glyco-DDMs (generation 1-3) containing 4, 8, and 16 β-d-glucopyranosyl units at the periphery (DDMGlu, DDMGlu, and DDMGlu) were synthesized and characterized by H,C and Si NMR, mass spectrometry, dynamic light scattering, atomic force microscopy (AFM), and computer modeling. In vitro cytotoxicity assay (MTT) of DDMGlu was performed on three different rodent cell lines (Cricetulus griseus) - B14 (ATCC, CCL-14.1), BRL 3A (ATCC, CRL-1442), and NRK 52E (ATCC, CRL-1571). Overall, very low cytotoxicity was observed with calculated IC in mM range with slight difference between each cell line and DDM generation investigated. Modified fish embryo test (FET) was further used for DDMGlu developmental toxicity testing on zebrafish (Danio rerio) embryos. While seemingly harmless to intact embryos, adverse effects of DDMs on the embryonic development become evident after chorion removal (LD=2.78 µM at 96 hpe). We summarized that the modified FET test showed a two to three orders of magnitude difference between the in vitro cytotoxicity and in vivo developmental toxicity of DDMGlu. While, in general, the Glyco-DDMs show great promises as efficient vectors in targeted drug delivery or as therapeutic molecules itself, we suggest that their developmental toxicity should be thoroughly investigated to exclude safety risks associated with their potential biomedical use.

Controlled Anchoring of (Phenylureido)sulfonamide-Based Receptor Moieties: An Impact of Binding Site Multiplication on Complexation Properties

“…The carriers for attachment of the receptor moieties were based on carbosilane molecules differing in the number of azido groups within the structure ( Scheme 2 ). The respective starting azides were prepared according to published procedures [ 27 , 28 , 29 ], except 7 and 9a . The synthesis of compound 7 started with reaction of butyllithium with chloro(3-chloropropyl)dimethylsilane, giving 5 in 91% yield.…”

Safety Challenges and Application Strategies for the Use of Dendrimers in Medicine

“…In contrast, neither neutral nor anionic PAMAM dendrimers (G2-OH, G7-OH, G1.5-COOH, and G7.5-COOH) showed significant toxicity at concentrations of 1 to 100 µg/mL [75]. The calculated IC 50 of the carbosilane glucose glycodendrimers in three different grey hamster cell lines, B14, BRL 3A, and NRK 52E, was in the mM range, while the IC 50 /EC 50 of glycodendrimers G3 in embryos was greater than 100 µM, indicating that the carbosilane glucose glycodendrimers have a very low cytotoxicity and toxicity in vivo [77].…”

Adaptive Synthesis of Functional Amphiphilic Dendrons as a Novel Approach to Artificial Supramolecular Objects

“…As the size of nanoparticles and their surface charge were previously identified as important factors influencing both the cellular uptake [58] and cytotoxicity effects [29,31,[59][60][61][62][63][64], the behavior of prepared amphiphilic dendrons in water was investigated in terms of hydrodynamic size and Zeta potential. These parameters are crucial in the case of nanoparticles intended for biomedical applications.…”

“…Our long-term interest has been focused on CS dendrimers with a well-defined structure that express multivalent presentation of functional moieties at their periphery [27][28][29][30][31] and, due to the incompatibility of their hydrophobic interior with polar periphery, can be considered as unimolecular micelles [32]. Here we turn our attention to a development of new versatile synthetic protocols for amphiphilic building blocks capable of self-assembly to regular micelles and other supramolecular objects.…”