Intravenously delivered graphene nanosheets and multiwalled carbon nanotubes induce site-specific Th2 inflammatory responses via the IL-33/ST2 axis

Abstract

Abstract:Carbon-based nanomaterials (CBN), such as graphene nanosheets (GNS) and multiwalled carbon nanotubes (MWCNT), have been proposed for potential nanomedicine applications such as biomedical devices and carriers for drug delivery. However, our current understanding regarding the systemic toxicity of these CBN through intravenous (iv) injection is limited. In this study, we compare the immune response resulting from GNS and MWCNT exposure. We hypothesize that iv administration of GNS and MWCNT would result in divergent systemic inflammatory responses due to physicochemical differences between these two CBN. In the lungs of C57BL/6 mice, GNS actuate a Th2 immune response 1 day following iv administration, which consists of neutrophilic influx and a significant increase in interleukin (IL)-5, IL-13, IL-33, and its soluble receptor (sST2) in the bronchoalveolar lavage fluid. MWCNT elicited a significant increase in the messenger ribonucleic acid expression of cytokines in the spleen including IL-4 and IL-33, which are associated with an increase in splenic cell differentiation (CD)4 + and CD8 + T-cells in C57BL/6 mice following iv injection. The observed Th2 responses in both the lung and spleen are absent in ST2 -/-mice administrated GNS or MWCNT, suggesting a critical role for IL-33. In conclusion, the use of GNS or MWCNT as nanocarriers for drug delivery may result in Th2 immune responses that are mediated through the IL-33/ST2 axis and therefore may promote adverse allergic reactions.

A work group report on ultrafine particles (American Academy of Allergy, Asthma & Immunology): Why ambient ultrafine and engineered nanoparticles should receive special attention for possible adverse health outcomes in human subjects

“…119 A recent study concluded that intravenously administered CNT and graphene nanosheets induce T helper 2-immune responses via the IL-33/ST2 axis, since responses were partially attenuated in ST2-deficient mice. 120 In the case of NP, immune effects are influenced by particle size and shape. Intratracheal administration of agglomerated CNT results in granuloma formation 121 , whereas dispersed CNT (e.g., coated by surfactant) results in more diffuse fibrosis.…”

Vascular Tissue Contractility Changes Following Late Gestational Exposure to Multi-Walled Carbon Nanotubes or their Dispersing Vehicle in Sprague Dawley Rats

“…The zeta potential of the particles in (S)-MWCNTs suspension was −57.3 mV with a mean hydrodynamic size of 915 nm. MWCNTs suspended in the DPPC, serum albumin and sterile phosphate buffered saline medium [(D)-MWCNTs] was characterized previously by Wang et al [29] with a zeta potential of −20.8 mV with a mean hydrodynamic size of 793 nm.…”

“…A MWCNT suspension of 150 μg/ml was made with DPPC/RSA and the mixture was cup-horn sonicated using a Misonix ultrasonic liquid processor -1510R-MTH (Branson Ultrasonics Corp. Danbury, CT, USA) at 65% amplitude for 2 minutes. This intravenous suspension will be referred to as “(D)-MWCNTs” and was previously described by Wang et al [29]. …”

Vascular distribution of nanomaterials

“…This type of contact also leads to systemic exposure to and organ accumulation of the injected material via vascular distribution. It was also noted that the tissues mount a tissue specific “nanoparticle-induced inflammatory response” in reaction to this direct interaction and deposition 38 ; this response is more detrimental with materials of a higher aspect ratio 38 . Evaluation of alveolar regions of the lung after pulmonary exposures document MWCNT deposition and penetrations 39 ; it is reasonable to suspect that the endothelial vascular lining would suffer the same fate after intravenous exposure, ENM deposition, and speculated penetration.…”