Synthesis and biological evaluation of novel doxorubicin-containing ASGP-R-targeted drug-conjugates

Ivanenkov, Yan A.; Majouga, Alexander G.; Petrov, Rostislav A.; Petrov, Stanislav A.; Ковалев, С. В.; Maklakova, Svetlana Yu.; Yamansarov, Emil Yu.; Saltykova, Irina V.; Deyneka, Ekaterina V.; Filkov, Gleb I.; Kotelianski, Victor; Zatsepin, Timofei S.; Белоглазкина, Е. К.

doi:10.1016/j.bmcl.2017.12.004

Cited by 13 publications

(9 citation statements)

References 38 publications

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“…We recently obtained and studied covalent drug delivery systems based on paclitaxel (PTX) and doxorubicin. , The developed conjugates showed a high potential against HCC due to excellent ASGPR binding affinity and cytotoxicity against HepG2 cells, retained a mechanism of action against cancerous cells similar to the unmodified drugs, and exhibited good accumulation in HCC cells. The next-generation taxane agent DTX has a higher level of cytotoxic activity against HCC cells.…”

Section: Introductionmentioning

confidence: 99%

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

et al. 2020

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In this work, we have developed covalent and low molecular weight docetaxel delivery systems based on conjugation with N-acetyl-d-galactosamine and studied their properties related to hepatocellular carcinoma cells. The resulting glycoconjugates have an excellent affinity to the asialoglycoprotein receptor (ASGPR) in the nanomolar range of concentrations and a high cytotoxicity level comparable to docetaxel. Likewise, we observed the 21–75-fold increase in water solubility in comparison with parent docetaxel and prodrug lability to intracellular conditions with half-life values from 25.5 to 42 h. We also found that the trivalent conjugate possessed selective toxicity against hepatoma cells vs control cell lines (20–35 times). The absence of such selectivity in the case of monovalent conjugates indicates the effect of ligand valency. Specific ASGPR-mediated cellular uptake of conjugates was proved in vitro using fluorescent-labeled analogues. In addition, we showed an enhanced generation of reactive oxygen species in the HepG2 cells, which could be inhibited by the natural ligand of ASGPR. Overall, the obtained results highlight the potential of ASGPR-directed cytostatic taxane drugs for selective therapy of hepatocellular carcinoma.

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Section: Introductionmentioning

confidence: 99%

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

et al. 2020

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“…Liver fibrosis is caused by chronic hepatocyte damage, generally followed by chronic inflammation, and tissue regeneration, characterized by excessive scar tissue formation [34,[40][41][42]. In each phase of the disease, different cell-types play a key role and different types of drugs therefore need to be delivered to either hepatocytes, Kupffer cells or hepatic stellate cells and carriers to all of these cell types are available [22,39] Galactose or the galactose-containing disaccharide lactose bind to the asialoglycoprotein receptor (ASGP-R) on hepatocytes [43] and coupling of these sugar moieties to several constructs led to selective uptake of these compounds in hepatocytes [44][45][46] or hepatocellular carcinoma [47]. In the past decades, this strategy has been applied for the delivery of many hepatoprotective drugs to these cells, and the benefits of selective delivery of anti-viral drugs using such carriers has been presented in recent publications.…”

Section: Drug Targeting Approaches In Fibrotic Liversmentioning

confidence: 99%

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

Salvati

Poelstra

2022

Pharmaceutics

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Drug targeting and nanomedicine are different strategies for improving the delivery of drugs to their target. Several antibodies, immuno-drug conjugates and nanomedicines are already approved and used in clinics, demonstrating the potential of such approaches, including the recent examples of the DNA- and RNA-based vaccines against COVID-19 infections. Nevertheless, targeting remains a major challenge in drug delivery and different aspects of how these objects are processed at organism and cell level still remain unclear, hampering the further development of efficient targeted drugs. In this review, we compare properties and advantages of smaller targeted drug constructs on the one hand, and larger nanomedicines carrying higher drug payload on the other hand. With examples from ongoing research in our Department and experiences from drug delivery to liver fibrosis, we illustrate opportunities in drug targeting and nanomedicine and current challenges that the field needs to address in order to further improve their success.

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“…Transporters on the sinusoidal site of hepatocytes, such as several types of organic anion transporters (OATs), organic cation transporters (OCTs), and the Na-Taurocholate Co-Transporting Polypeptide (NTCP), transport a wide variety of drugs from the blood into the hepatocyte through recognition of their physico-chemical properties, such as charge and lipophilicity, with often a broad overlap in substrate specificity (reviewed elsewhere [9,10]. Next to these receptors, uptake of plasma glycoproteins by hepatocytes can occur via several lectin receptors such as the asialoglycoprotein receptor (ASGP-R) [11], and in particular, the ASGP-receptor that binds galactose residues has been applied in many studies to deliver proteins or other drug carriers to hepatocytes [11] by decorating core molecules with galactose or lactose moieties. However, even without drug targeting strategies, most drugs are taken up by the liver and uptake of these drugs mostly reflects uptake by hepatocytes.…”

Section: Uptake Of Drugs and Nanomedicines In The Livermentioning

confidence: 99%

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

Poelstra

2020

Curr. Tissue Microenviron. Rep.

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Purpose of Review Treatment of liver fibrosis benefits from hepatic stellate cell (HSC)-specific delivery. Since the description of first carrier to HSC, many developments have taken place in this area. The purpose is to give an overview of the different carriers and homing moieties that are available for HSC targeting and illustrate the opportunities and hurdles they provide. Recent Findings There is a growing number of homing devices to deliver drugs to HSC, and options to deliver siRNA to HSC have emerged. Other developments include controlling corona formation, development of linker technology, and design of theranostic approaches. We are on the eve of reaching the clinic with innovative HSC-specific compounds. Summary An overview of different core molecules is presented together with an overview of targeting strategies toward different receptors on HSC, providing a versatile toolbox. Many therapeutics, ranging from small chemical entities and proteins to RNAor DNA-modulating substances, have already been incorporated in these constructs in the recent years.

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Synthesis and biological evaluation of novel doxorubicin-containing ASGP-R-targeted drug-conjugates

Cited by 13 publications

References 38 publications

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

New Small-Molecule Glycoconjugates of Docetaxel and GalNAc for Targeted Delivery to Hepatocellular Carcinoma

Drug Targeting and Nanomedicine: Lessons Learned from Liver Targeting and Opportunities for Drug Innovation

Innovative Nanotechnological Formulations to Reach the Hepatic Stellate Cell

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