title: RGD peptide-modified multifunctional dendrimer platform for drug encapsulation and targeted inhibition of cancer cells.
abstract: Development of multifunctional nanoscale drug-delivery systems for targeted cancer therapy still remains a great challenge. Here, we report the synthesis of cyclic arginine-glycine-aspartic acid (RGD) peptide-conjugated generation 5 (G5) poly(amidoamine) dendrimers for anticancer drug encapsulation and targeted therapy of cancer cells overexpressing αvβ3 integrins. In this study, amine-terminated G5 dendrimers were used as a platform to be sequentially modified with fluorescein isothiocyanate (FI) via a thiourea linkage and RGD peptide via a polyethylene glycol (PEG) spacer, followed by acetylation of the remaining dendrimer terminal amines. The developed multifunctional dendrimer platform (G5.NHAc-FI-PEG-RGD) was then used to encapsulate an anticancer drug doxorubicin (DOX). We show that approximately six DOX molecules are able to be encapsulated within each dendrimer platform. The formed complexes are water-soluble, stable, and able to release DOX in a sustained manner. One- and two-dimensional NMR techniques were applied to investigate the interaction between dendrimers and DOX, and the impact of the environmental pH on the release rate of DOX from the dendrimer/DOX complexes was also explored. Furthermore, cell biological studies demonstrate that the encapsulation of DOX within the G5.NHAc-FI-PEG-RGD dendrimers does not compromise the anticancer activity of DOX and that the therapeutic efficacy of the dendrimer/DOX complexes is solely related to the encapsulated DOX drug. Importantly, thanks to the role played by RGD-mediated targeting, the developed dendrimer/drug complexes are able to specifically target αvβ3 integrin-overexpressing cancer cells and display specific therapeutic efficacy to the target cells. The developed RGD peptide-targeted multifunctional dendrimers may thus be used as a versatile platform for targeted therapy of different types of αvβ3 integrin-overexpressing cancer cells.
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
authors.forename: Xuedan
authors.initials: X
authors.lastname: He
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Alves
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
authors.forename: Nilsa
authors.initials: N
authors.lastname: Oliveira
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal.
authors.forename: João
authors.initials: J
authors.lastname: Rodrigues
authors.affiliation: State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, People's Republic of China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Colloid and Environmental Chemistry, Faculty of Science, University of Debrecen, H4032 Egyetem t.1, Debrecen, Hungary. Electronic address: ibanyai@delfin.klte.hu.
authors.forename: István
authors.initials: I
authors.lastname: Bányai
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal. Electronic address: lenat@uma.pt.
authors.forename: Helena
authors.initials: H
authors.lastname: Tomás
authors.affiliation: CQM-Centro de Química da Madeira, Universidade da Madeira, Campus da Penteada, 9000-390 Funchal, Portugal; State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, People's Republic of China. Electronic address: xshi@dhu.edu.cn.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Shi
mesh_terms: D000107:Acetylation; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004339:Drug Compounding; D065546:Drug Liberation; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D015870:Gene Expression; D006801:Humans; D006863:Hydrogen-Ion Concentration; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry*; D011073:Polyamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013194:Staining and Labeling; D013890:Thiourea / Q000737:chemistry
chemical_list: D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; D004337:Drug Carriers; D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C531249:Poly(amidoamine); D011073:Polyamines; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; D013890:Thiourea; D016650:Fluorescein-5-isothiocyanate
keywords: Dendrimers; Doxorubicin; Host–guest interaction; RGD peptide; Targeted cancer therapy.