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Nanomedicine(s) under the Microscope *
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].
Antigenic Mimicry in Neisseria Species
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Peter C. Giardina, Michael A. Apicella, Brad Gibson, Andrew Preston
Previous evidence has suggested that the tight inter-cellular adhesions between the outer membrane of gonococci displaying the opacity colony phenotype occurred because Opa proteins expressed on one gonococcus adhered to the LOS of the opposing bacterium. Blade and coworkers, employing a noncompetitive inhibition assay previously used to determine the carbo hydrate structures recognized by the major hepatic asialoglycoprotein receptor, demonstrated that gonococcal LOS structures bind Opa proteins (67). The LOS carbohydrate used in these assays were LOS structures purified from pyocin-resistant LOS mutants of N. gonorrhoeae strain 1291 (21). These data suggest that the gonococcal Opa proteins had the highest affinity for the Gal β(1→4)GlcNAc residue present on the gonococcal lactoneoseries LOS. This affinity was comparable to that reported for the binding of the major hepatic asialoglycoprotein receptor to glycoconjugates containing terminal galactose and TV-acetylgalactosamine. After sialylation of the lactoneoseries LOS, presumably on the terminal galactose residue, the interaction with the Opa proteins was ablated.
Hepatic Regulation of Fibrinolysis in Normal and Disease States
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
The second major function of the liver with regard to PA/PAI regulation is related to clearance mechanisms for t-PA, UK, and PA-PAI complexes. Cells in the liver express the well-characterized asialoglycoprotein receptor, which mediates removal of glycoproteins with altered carbohydrate moieties from the plasma. In addition, these cells express receptors for α2-macroglobulin-proteinase complexes.11 Based on results indicating that clearance of radiolabeled t-PA, UK, or PA-PAI complexes rapidly end up in the liver (Table 2),12,13 a number of investigators have attempted to identify and characterize receptors for these components in liver, hepatocytes, and hepatoma cells from a variety of species. Some of the evidence for these receptors is summarized in Table 2.
All-trans retinoic acid in anticancer therapy: how nanotechnology can enhance its efficacy and resolve its drawbacks
Published in Expert Opinion on Drug Delivery, 2021
Gabriel Silva Marques Borges, Flávia Alves Lima, Guilherme Carneiro, Gisele Assis Castro Goulart, Lucas Antônio Miranda Ferreira
Shimizu et al. (2003) and Takahashi et al. (2003) developed ATRA-loaded liposomes modified with stearylglucoside for active targeting to the liver. Sterylglucoside binds to the asialoglycoprotein receptor present only on the hepatocytes. The researchers found an increase in survival rate of M5076 (sarcoma)-bearing mice, probably due to the diminishing of hepatic metastasis foci caused by the tumor [122,123]. ATRA was also loaded in PLGA polymeric nanoparticles coated with anti-PD-L1 (programmed death-ligand 1) antibody. PD-L1 receptors are highly expressed in some cancer cells and are linked to evasion of the immune system. After intravenous administration in CH3 (sarcoma)-bearing mice, these nanoparticles had higher accumulation in the tumor compared with nanoparticles without anti-PD-L1 antibodies. Moreover, these polymeric nanoparticles protected the animals from liver and kidney injuries caused by free ATRA administration [124]. Li et al. (2018) produced albumin nanoparticles loading ATRA with hyaluronic acid (HA) as active targeting. HA is a ligand for CD44 receptors. CD44 is a cell surface adhesion receptor, being highly expressed in many types of cancer. The HA coating increased the tumor tissue accumulation of the nanoparticles in B16F10 tumor-bearing mice, generating a much higher antitumor activity and reducing lung metastasis foci in the mice. Moreover, the nanoparticles did not evoke any significant toxicity to the animals [125].
Hepatic targeting of glycyrrhetinic acid via nanomicelles based on stearic acid-modified fenugreek gum
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Minghui Zhou, Shuang Li, Sheng Shi, Shaolong He, Yanni Ma, Wenping Wang
Asialoglycoprotein receptor (ASGP-R), a specific receptor of galactose ligands that is highly expressed on the surfaces of hepatocytes, was a promising target for improving targeting efficiency by clathrin-enabled receptor-mediated endocytosis [8]. Thus, a nanocarrier with galactose residues is critical for targeted drug delivery into the liver. Fenugreek gum (FG) is a natural polysaccharide with non-toxic, biocompatible and biodegradable properties. FG was extracted from the seeds of fenugreek (Trigonella foenum-graecum L.) and consists of a backbone of 1→4 linked β-D mannose units with (1→6) D-galactose units as side chains at a molar ratio of 1:1 [9]. FG has been widely applied in the food field [10], but few reports of FG as a nanocarrier have been made because its high swelling and hydrophilic characteristics resulted in low encapsulation efficiency for poorly water-soluble drugs [11]. In our previous study, FG was successfully modified with the hydrophobic chain of stearic acid (C18) [12]. The obtained amphiphilic derivative showed a favourable self-assembly ability in water and good biocompatibility. The FG-C18 NMs were expected to possess a certain degree of liver-targeting ability for drug delivery.
Multifunctional nanoplatform based on star-shaped copolymer for liver cancer targeting therapy
Published in Drug Delivery, 2019
Xianling Gong, Yi Zheng, Guangzhi He, Kebing Chen, Xiaowei Zeng, Zhihong Chen
The asialoglycoprotein receptor (ASGPR), a liver-associated surface receptor, is abundantly and specifically present on hepatocytes (Stockert et al., 1974; Ashwell & Harford, 1982; Fiete et al., 1991; Rensen et al., 2001; D'Souza & Devarajan, 2015). The receptor specifically recognizes the end group coupling galactose residues or lactose moieties and combines with it. After the complex is formed, the complex ligand-ASGPR receptor can be quickly internalized. When the complex approaches the lysosomal compartment, the ligand is released. Next, the ligand is degraded in the lysosome and the drug is released. The receptor will be re-oriented toward the plasma membrane (Ashwell & Harford, 1982). So, by special recognition of ASGPR receptor and binding to galactose residues or lactose moieties of NPs, the NPs can exert liver-targeting effect. Previous studies have shown NPs conjugating galactose residues or lactose moieties can effectively and specifically target the sites of hepatoma tumor through the ASGP receptor-mediated recognition (Liang et al., 2006; Craparo et al., 2014; Iacobazzi et al., 2017; Tsend-Ayush et al., 2017).