Surface charge-mediated rapid hepatobiliary excretion of mesoporous silica nanoparticles

Abstract

Nanoparticle-assisted drug delivery has been emerging as an active research area in recent years. The in vivo biodistribution of nanoparticle and its following mechanisms of biodegradation and/or excretion determine the feasibility and applicability of such a nano-delivery platform in the practical clinical translation. In this work we report the synthesis of the highly positive charge, near-infrared fluorescent mesoporous silica nanoparticles (MSNs) that demonstrate rapid hepatobiliary excretion, for use as traceable drug delivery platforms of high capacity. MSNs were incorporated with near-infrared fluorescent dye indocyanine green (ICG) via covalent or ionic bonding, to derive comparable constructs of significantly different net surface charge. In vivo fluorescence imaging and subsequent inductively coupled plasma-mass spectroscopy of harvested tissues, urine, and feces revealed markedly different uptake and elimination behaviors between the two conjugations; with more highly charged moieties (+34.4 mV at pH 7.4) being quickly excreted from the liver into the gastrointestinal tract, while less charged moieties (-17.6 mV at pH 7.4) remained sequestered within the liver. Taken together, these findings suggest that charge-dependent adsorption of serum proteins greatly facilitates the hepatobiliary excretion of silica nanoparticles, and that nanoparticle residence time in vivo can be regulated by manipulation of surface charge.

Perturbation of physiological systems by nanoparticles

“…Under such an acidic microenvironment, some metallic nanoparticles, such as silver, 30 quantum dots, 31,32 and iron oxide nanoparticles, 33,34 may undergo dissolution and release metallic ions. Non-metallic nanoparticles, like mesoporous SiO 2 nanoparticles 35 may be also partially dissolved in cells or in vivo by this way. Based on this understanding, manipulation of suitable coatings can prolong the nanoparticles' lifespan and reduce their toxicity.…”

“…For example, two months View Article Online after intravenous injection, SWCNTs were partially cleared in feces; 39 surface charge on the particles accelerated their secretion rate. 35 Eleven days after exposure, approximately 5% of total hydroxylated SWCNTs administered intraperitoneally were excreted in feces. 247 Although the liver possesses a self-protecting capability due to its antioxidant system and its various metabolizing enzymes, the long-term retention of nanoparticles increases the risk of hepatotoxicity 188,307 (Fig.…”

Biokinetics of zinc oxide nanoparticles: toxicokinetics, biological fates, and protein interaction

“…High retention of ZnO nanoparticles in lungs for the first hour can be explained by the fact that particles of 30-80 nm tend to be generally sequestered in lung tissue. 31 The same target organs for ZnO nanoparticles were determined by applying optical imaging of Cy5.5-conjugation and positron emission tomography imaging of fluorinated particles. 32,33 ZnO nanoparticles of 40 nm distributed to the liver and kidneys following repeated oral administration to rats for 13 weeks; however, lung distribution was not included in this study.…”

Cisplatin-loaded core cross-linked micelles: comparative pharmacokinetics, antitumor activity, and toxicity in mice

“…Biliary clearance was indeed shown to be the dominant route for elimination of silica nanoparticles of similar size and negative ζ-potential. 28,29 It is quite likely that cisplatin/cl-micelles carrying macrophages will undergo several rounds of apoptotic cell and recapture of apoptotic bodies by surrounding macrophages before any significant elimination takes place. Therefore, clearance is expected to be slow and is consistent with our data indicating a significantly reduced PEG staining in liver and spleen tissue sections from day 28 toxicity analysis relative to respective day 13 tissue sections ( Figure 9).…”