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Targeted Delivery of a Ligand−Drug Conjugate via Formyl Peptide Receptor 1 through Cholesterol-Dependent Endocytosis
Junlin Wang; Meiwan Chen; Shaoping Li; Richard D. Ye
2019-06
Source PublicationMOLECULAR PHARMACEUTICS
ISSN1543-8384
Volume16Issue:6Pages:2636-2647
Abstract

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-ε-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.

Keywordg Protein-coupled Receptors Ph-sensitive Peptides Conjugates Formyl Peptides Receptor Internalization Targeted Drug Delivery
DOI10.1021/acs.molpharmaceut.9b00188
Indexed BySCI
Language英语
WOS Research AreaResearch & Experimental Medicine ; Pharmacology & Pharmacy
WOS SubjectMedicine, Research & Experimental ; Pharmacology & Pharmacy
WOS IDWOS:000470332100035
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Cited Times [WOS]:1   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
AffiliationInstitute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau,Macau Special Administrative Region 999078, China
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Junlin Wang,Meiwan Chen,Shaoping Li,et al. Targeted Delivery of a Ligand−Drug Conjugate via Formyl Peptide Receptor 1 through Cholesterol-Dependent Endocytosis[J]. MOLECULAR PHARMACEUTICS,2019,16(6):2636-2647.
APA Junlin Wang,Meiwan Chen,Shaoping Li,&Richard D. Ye.(2019).Targeted Delivery of a Ligand−Drug Conjugate via Formyl Peptide Receptor 1 through Cholesterol-Dependent Endocytosis.MOLECULAR PHARMACEUTICS,16(6),2636-2647.
MLA Junlin Wang,et al."Targeted Delivery of a Ligand−Drug Conjugate via Formyl Peptide Receptor 1 through Cholesterol-Dependent Endocytosis".MOLECULAR PHARMACEUTICS 16.6(2019):2636-2647.
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