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Medication: Nanoparticles for Imaging and Drug Delivery
Published in Harry F. Tibbals, Medical Nanotechnology and Nanomedicine, 2017
A number of potential candidates of this type have been investigated, using saccharides, antibodies, proteins, and peptides as targeting ligands, but so far none have proven effective without toxicity or other obstacles. For example, hepatocytes, the functional cells of the liver, display a unique asialoglycoprotein receptor (ASGPR), which could possibly be used to target liver cancer. A conjugate using N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer in an HPMA-doxorubicin-galactosamine particle formulation (PK2, FCE28069) was investigated for effectiveness against hepato-cellular carcinoma, but was discontinued after preliminary trials [157-159]. The galactose ligand was used to target the ASGPR that is expressed on hepatocytes, but it did not provide enough differentiation between tumor cells and healthy hepatocytes.
Pharmaceutical Applications of Carrageenan
Published in Amit Kumar Nayak, Md Saquib Hasnain, Dilipkumar Pal, Natural Polymers for Pharmaceutical Applications, 2019
A. Papagiannopoulos, S. Pispas
Curcumin-loaded nanoparticles have been produced based on Gantrez polymer in order to exploit the therapeutic properties of curcumin against hepatic diseases (D’Souza et al., 2013). κ-Carrageenan was one of the three polysaccharides introduced to create a series of different nanocarriers. Asialoglycoprotein receptor is overexpressed in hepatic disease and has a strong affinity for galactose-based carbohydrates. The size of the particles was in the order of 500 nm, and the ligand binding was proved by changes in their surface charge. Hepatic accumulation of carrageenan nanoparticles was intermediate in comparison to the other two polysaccharides as shown by in vivo biodistribution in rats and radiolabeled complexes (D’Souza et al., 2013).
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).