Cytotoxicity of Poly(Alkyl Cyanoacrylate) Nanoparticles

Abstract

Although nanotoxicology has become a large research field, assessment of cytotoxicity is often reduced to analysis of one cell line only. Cytotoxicity of nanoparticles is complex and should, preferentially, be evaluated in several cell lines with different methods and on multiple nanoparticle batches. Here we report the toxicity of poly(alkyl cyanoacrylate) nanoparticles in 12 different cell lines after synthesizing and analyzing 19 different nanoparticle batches and report that large variations were obtained when using different cell lines or various toxicity assays. Surprisingly, we found that nanoparticles with intermediate degradation rates were less toxic than particles that were degraded faster or more slowly in a cell-free system. The toxicity did not vary significantly with either the three different combinations of polyethylene glycol surfactants or with particle size (range 100–200 nm). No acute pro- or anti-inflammatory activity on cells in whole blood was observed.

The alkyl side chain of PACA nanoparticles dictates the impact on cellular stress responses and the mode of particle-induced cell death

“…When particle cytotoxicity was compared across a panel of cancer cell lines (MDA-MB-231, SW480, Huh7, HCT116, MCF7, and HeLa) the POCA particles consistently exerted the highest cytotoxicity, whereas PEBCA particles were the least toxic ( Figure 1C). This is in agreement with our previous screening study with a set of 12 other cancer cell lines [11]. Importantly, we have found that this pattern of cytotoxicity is not caused by gross differences in cellular uptake of the particles [11,18].…”

“…Here, we have taken advantage of this to study whether minor alterations in NP composition can affect the type or magnitude of cellular stress responses, and whether this may also affect particle cytotoxicity or even the mode of cell death. We have previously shown that particles synthesized from the monomers butyl-, ethylbutyl-, or octyl cyanoacrylate, termed PBCA, PEBCA, and POCA, respectively, exhibit similar physicochemical characteristics, such as size, polydispersity, and surface charge [11,12]. Intriguingly, we here find that the subtle differences of the alkyl side chains of cyanoacrylate dictate both the type and extent of particle-induced stress responses, and determine the mode of cell death induced by the PACA particles.…”

“…The PACA particles exert differential cytotoxicity and induction of heat shock proteins PACA particles with only minor differences in their cyanoacrylate side chains ( Figure 1B) were produced by in situ polymerization of the alkylcyanoacrylate monomers butyl-(PBCA), ethylbutyl-(PEBCA), or octyl-cyanoacrylate (POCA) as previously described [11,12]. The resulting particles exhibited similar mean sizes, in the range of 133-153 nm, with a relatively narrow size distribution.…”

“…PACA NPs were prepared using the mini-emulsion polymerization method as previously described [11]. Briefly, PBCA, PEBCA, or POCA NPs were made by mixing the oil phase, consisting of the monomers butyl-, ethylbutyl-, or octyl cyanoacrylate, a neutral oil, and the fluorescent dye pentamer hydrogen thiophene acetic acid methyl ester (pHTAM), with the aqueous phase consisting of hydrochloric acid and the PEG-surfactants Kolliphor ® HS15 and Pluronic ® F68.…”

“…PACA NPs have the ability to cross the blood-brain barrier [10], and are currently in Phase III clinical trials for treatment of advanced hepatocellular carcinoma (ClinicalTrials.gov NCT01655693). Particles are prepared by in situ polymerization of alkylcyanoacrylate monomers, and NPs with slightly different chemical compositions can be obtained by using monomers differing only in their alkyl side chains [11,12]. Here, we have taken advantage of this to study whether minor alterations in NP composition can affect the type or magnitude of cellular stress responses, and whether this may also affect particle cytotoxicity or even the mode of cell death.…”