- Targeted Delivery of a Ligand-Drug Conjugate via Formyl Peptide Receptor 1 through Cholesterol-Dependent Endocytosis
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G protein-coupled receptors (GPCRs) undergo ligand-induced internalization that carries the cognate ligands into intracellular compartments. The present study explores this property for the use of formyl peptide receptor 1 (FPR1), a class A GPCR that binds formylated peptides, as a potential target for drug delivery. A pH-sensitive peptide-drug conjugate consisting of doxorubicin (DOX), N-?-maleimidocaproic acid hydrazide (EMCH), and the formyl peptide fMet-Leu-Phe-Cys (abbreviated as DEF) was prepared. DEF retained pharmacological activities of formyl peptides in binding to FPR1 and mobilization of Ca2+ from intracellular stores. However, the conjugated DOX was no longer cell membrane-permeable and relied on FPR1 for cellular entry. DOX was released from DEF into acidic compartments labeled with fluorescent trackers for endosomes. Treatment of cells with pharmacological inhibitors that block clathrin- or caveolae-mediated endocytosis did not abrogate FPR1-dependent DEF internalization, nor did inhibition of macropinocytosis and phagocytosis. In contrast, cholesterol depletion abrogated DEF internalization through FPR1, suggesting characteristics of cholesterol-dependent uptake mediated by a cell surface receptor. These results demonstrate the possibility of using FPR1 for targeted drug delivery.
- Wang, Junlin,Chen, Meiwan,Li, Shaoping,Ye, Richard D.
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- A nanocarrier based on a genetically engineered protein cage to deliver doxorubicin to human hepatocellular carcinoma cells
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Herein, we report the preparation of genetically engineered protein cages (HspG41C-SP94), taken up selectively by human hepatocellular carcinoma (HCC) cells. An engineered protein cage-doxorubicin (DOX) conjugate was as cytotoxic as free DOX against HCC cells but much less cytotoxic against normal hepatocytes.
- Toita, Riki,Murata, Masaharu,Abe, Kana,Narahara, Sayoko,Piao, Jing Shu,Kang, Jeong-Hun,Hashizume, Makoto
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- Anti-tumor peptide-adriamycin derivative and preparation method thereof as well as anti-tumor drug
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The invention relates to the technical field of biomedicines and in particular relates to an anti-tumor peptide-adriamycin derivative and a preparation method thereof as well as an anti-tumor drug. According to the anti-tumor peptide-adriamycin derivative provided by the invention, adriamycin and anti-tumor KLAK peptide are bonded through a hydrazone bond with an acid response property; under a weak acidity environment (with the pH (Potential of Hydrogen) of 5.5 to 6.5) in tumor cells, two anti-cancer drugs (including the adriamycin and the anti-tumor KLAK peptide) are responsively released, the toxic and side effect on normal tissues is reduced and the killing capability to the tumor cells is enhanced, so that the two released anti-cancer drugs exert a cooperative anti-tumor effect through respective action mechanisms and an ideal treatment effect is finally realized.
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Paragraph 0038; 0048; 0049; 0051; 0052; 0054; 0055
(2019/05/08)
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- ANTICANCER PRODRUG THERAPIES
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The invention provides prodrug compounds with superior efficacy and reduced incidence of nonspecific adverse effects when used for the treatment of cancers expressing carboxylesterase 2. Also provided are pharmaceutical compositions containing these prodrug compounds of the invention, together with at least one pharmaceutically acceptable carrier. Also provided are methods of treating or preventing cancers comprising administering to a mammal in need thereof, therapeutically effective amounts of at least one of the prodrug compounds of the invention.
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Page/Page column 32
(2013/02/28)
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- ALBUMIN BINDING MOLECULES AND USES THEREOF
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The invention relates to portable albumin binders, which are useful for improving the pharmacokinetic properties of diagnostic or therapeutic agents, in particular increasing the blood circulation time and/or the tissue penetration capacity of such agents. Molecules of the invention include compounds represented by Formula (1).
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Page/Page column 46
(2008/12/05)
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