Abstract
Many nanoparticles are designed for use as potential nanomedicines for parenteral administration. However, emerging evidence suggests that hemocompatibility is important, but is highly particle- and test-bed dependent. Thus, knowledge of bulk material properties does not predict the hemocompatibility of uncharacterized nanoparticles, including silk nanoparticles. This study compares the hemocompatibility of silk versus silica nanoparticles, using whole human blood under quasi-static and flow conditions. Substantial hemocompatibility differences are noted for some nanoparticles in quasi-static versus dynamic studies; i.e., the inflammatory response to silk nanoparticles is significantly lower under flow versus quasi-static conditions. Silk nanoparticles also have very low coagulant properties - an observation that scales from the macro- to the nano-level. These nanoparticle hemocompatibility studies are complemented by preliminary live cell measurements to evaluate the endocytosis and trafficking of nanoparticles in human blood cells. Overall, this study demonstrates that nanoparticle hemocompatibility is affected by several factors, including the test bed design.
Highlights
Nanoparticles for drug delivery were introduced in the 1970s; Abraxane® was the firstin-class drug delivery nanoparticle to entered routine clinical use in 2005.1 This success has renewed interest in nanoparticles as drug delivery agents, and numerous nanoparticles are currently in clinical trials for a broad range of indications, including cancer.[2]
Scanning electron microscopy confirmed that all nanoparticles were spherical and had the expected sizes and surface charge: native silk nanoparticles (106.1 nm ± 0.8, zeta potential −53 mV ± 1.7), PEGylated silk nanoparticles (116.1 nm ± 0.2, zeta potential −43.6 mV ± 2.8), native silica nanoparticles (101.7 nm ± 9.0, zeta potential −31.8 mV ± 0.3), and amine functionalized silica nanoparticles (101.5 nm ± 7.4, zeta potential −16.1 mV ± 0.6)
Exposure of silk nanoparticles to 100 mM phosphate buffered saline (PBS) substantially increased the native silk nanoparticle size over time, whereas no changes were observed for PEGylated silk nanoparticles (Supplementary Figure 1)
Summary
Nanoparticles for drug delivery were introduced in the 1970s; Abraxane® (albumin-paclitaxel nanoparticle) was the firstin-class drug delivery nanoparticle to entered routine clinical use in 2005.1 This success has renewed interest in (protein) nanoparticles as drug delivery agents, and numerous nanoparticles are currently in clinical trials for a broad range of indications, including cancer.[2]. Maitz et al / Nanomedicine: Nanotechnology, Biology, and Medicine 13 (2017) 2633–2642 nanoparticles – for example, with hydrophilic poly(ethylene glycol) (PEG) chains – to yield “stealth” nanoparticles, (reviewed in[7,8]) This ‘PEGylation’ renders nanoparticles more hydrophilic, provides steric hindrance, suppresses protein adsorption from the plasma (for example, the FXIIa-Kallikrein-FXI activation complex) and aggregation by hydrophobic interactions, thereby increasing the nanoparticle circulation time 40- to 90-fold, improving blood compatibility and inhibiting accumulation by the reticuloendothelial system.[6,9] assessment of “blood performance” is a critical aspect when designing nanoparticles for solid tumor targeting. A number of studies have examined the hemocompatibility of Bombyx mori silk using macroscale planar silk surfaces.[29,30,31,32] These studies have indicated minimal coagulant but substantial complement activation.[31,32] a direct transfer of the results obtained from macroscopic surfaces to nanoparticles is not appropriate because of the previously mentioned specific and non-typical interactions of nanoparticles with blood.[33,34] hemocompatibility requirements for nanoparticles in the blood circulation appear even more stringent than those for solid surfaces because any incompatibility reaction of systemically administered nanoparticles would affect multiple organs
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