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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Efficient liver-specific (hepatocyte) targeting (this is organ-specific delivery that relies on the bystander effect to increase the probability of efficacy) was demonstrated clinically using HPMA copolymer-doxorubicin conjugates containing additionally galactosamine to target the asialoglycoprotein receptor of hepatocytes and hepatoma [132]. Patient SPECT gamma camera imaging indicated that this conjugate achieved liver targeting of 15–20% dose after 24 h. The majority of radioactivity was associated with normal liver (16.9%, 24 h) with lower accumulation in hepatic tumor (3.2% dose). This is not surprising, as hepatoma cells tend to lose the asialoglycoprotein receptor as the disease progresses. Nevertheless the doxorubicin concentration in hepatoma was estimated to be 12–50-fold higher than could be achieved by administration of free doxorubicin. Specific physiological transport mechanisms may also aid translocation into the tumor by endothelial cell transcytosis (Fig. 13.4c). It has been suggested [211] that the albumin-paclitaxel nanoparticle Abraxane elicits improved tumor targeting due to interaction with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) which promotes gp60 and caveolae-mediated endothelial transcytosis. Preliminary evidence that SPARC expression in head and neck cancer patients correlates with response to therapy supports this theory [270].
Bioceramics for Development of Bioartificial Liver
Published in Severian Dumitriu, Valentin Popa, Polymeric Biomaterials, 2020
Tomokazu Matsuura, Mamoru Aizawa
In the development of BAL, scaffolds for cells are needed. The scaffolds play a role of a matrix for which hepatocytes attached to proliferate. Generally, such scaffolds are prepared from polymer materials. For example, Funatsu and Nakazawa [10] have used polyurethane foam in their BAL development. Akaike et al. [11] have used the polymer with side chain of galactose, PVLA (poly[N-p-vinylbenzyl-4-O-β-d-galactopyranosyl-d gluconamine]). The PVLA can specifically recognize hepatocytes through asialoglycoprotein receptor (ASGPR). In addition to those described earlier, the BAL system developed in the United States, “HeaptAssist,” was used as hollow fibers for dialysis of a renal disease as a matrix for cells [12]. Recently, we have reported that novel bioceramics with biocompatibility can be applied as the carrier of the BAL [13]. The bioceramics will be described in the next section.
Cell Physiology
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
The glycan structure on a glycoprotein affects its half-life in blood circulation and its immunogenicity. For IgG molecules, N-glycosylation in the Fc region affects their biological activities. The presence of glycans on interferon produced in mammalian cells prolongs its clearance from blood, as compared to its non-glycosylated counterpart produced in E. coli. Higher sialic acid content on erythropoietin (EPO) increases its circulation half-life. Under-sialylated glycoproteins are cleared by liver uptake via the hepatic asialoglycoprotein binding protein faster. It has been postulated that glycosylated recombinant proteins are better retained by the extracellular matrix, thus giving them a longer bioavailability in vivo than their unglycosylated variants.
Construction of polysaccharide scaffold-based perfusion bioreactor supporting liver cell aggregates for drug screening
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Lei Cao, Huicun Zhao, Mengyuan Qian, Chuxiao Shao, Yan Zhang, Jun Yang
Hepatocytes are anchorage-dependent cells and are highly sensitive to the ECM milieu for the maintenance of their viability and differentiated functions [24, 25]. The scaffold is considered the core component of the perfusion hepatocyte bioreactor serving as a cell carrier to provide a suitable extracellular microenvironment in vitro [26–28]. Diversified synthetic and natural polymers, such as poly(ε-caprolactone) and silk proteins, have been applied to fabricate a 3 D structure to reproduce the physical and chemical proprieties of the native ECM that represents the physiological, native cellular environment [29, 30]. Among them, alginate has been widely used in the construction of scaffolds as its properties of good biocompatibility and rapid ionic gelation [31–33], but the lack of hepatocyte-specific adhesion sites limits its application in hepatocyte culture. Pectin is an edible and water-soluble polysaccharide, which consists primarily of D-galacturonic acid (GalA) that can specifically bind to the asialoglycoprotein receptor (Asgpr) located on the surfaces of hepatocytes [34]. Similar to alginate, pectin can form a hydrogel in the presence of divalent cations (such as Ca2+) yet the stability is unsatisfactory [35, 36]. It was reported that mixing pectin with alginate was able to improve the viscoelasticity and structure stability of pectin-based scaffold [37]. We speculate that combining these two natural polysaccharides to form a specific scaffold may overcome the drawbacks and would be beneficial to hepatocyte survival and functional expression.
The roadmap towards cure of chronic hepatitis B virus infection
Published in Journal of the Royal Society of New Zealand, 2022
Because siRNAs and ASOs will be digested if administered orally, they must be delivered parenterally with the associated risk of off-target toxicities. The earliest attempts to develop a liver-targeting delivery system were through liver-tropic cholesterol-conjugated siRNAs (ARC-520/521) or siRNAs packaged within lipid nanoparticles (ARB-1467/1740; ALN-HBV). Both delivery systems required intravenous administration which was associated with frequent and severe infusion reactions necessitating complex premedication protocols. In addition, the frequency of IV dosing needed to be at least weekly to avoid virologic rebound between doses. These unwanted off-target effects were reduced by conjugating the siRNA with N-acetylgalactosamine (GalNAc), thereby enhancing hepatocyte uptake via Asialoglycoprotein Receptor (ASGPR). These newer liver-targeting formulations can be administered subcutaneously without premedication. Patient tolerability is improved by less side effects and longer dosing intervals (at least monthly or less frequently).
Microplastics and human health: Integrating pharmacokinetics
Published in Critical Reviews in Environmental Science and Technology, 2023
Microplastics may also be eliminated, to a lesser extent, by other cells. Hepatocytes and liver endothelial cells play a small role in particle clearance and capture smaller particle sizes (e.g. limited by 200 nm fenestrations in endothelial cells) (Ogawara et al., 1999). PS (50 nm) was internalized by hepatocytes, and then excreted in the bile, by recognition of adsorbed apolipoprotein-E from the blood by the asialoglycoprotein receptor (demonstrated by pharmacological modulation) after intravenous perfusion of rat livers (Furumoto et al., 2001). Particles could be found intracellularly in hepatocytes after 1 h, being then released in the biliary canaliculus released from or bypassing lysosomes, with 4% being excreted as intact particles in the bile after 24 h (Ogawara et al., 1999). While excretion in the bile seems quicker for smaller particle diameters, possibly limited by the diameters of biliary canaliculi (1–2 µm), bile ductules (20 µm), and lobular ducts (20–100 µm), it can be bypassed by direct secretion into the bile of larger particles (1–3 µm) from the blood through paracellular exchange in the bile duct epithelium (Jani et al., 1996). This could explain why particles were found in the gallbladder of fish embryos exposed to 5 µm polystyrene (Zhang et al., 2021), in addition to interspecific differences and immature development. The bile is released into the small intestine, contributing to the presence of microplastics in the digestive system, which are then eliminated in the feces or reabsorbed (enterohepatic circulation). Thus, elimination through the bile could also contribute to reports of microplastics in human feces (Schwabl et al., 2019; Zhang et al., 2021).