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.

Enzyme-responsive doxorubicin release from dendrimer nanoparticles for anticancer drug delivery

“…24 These authors confirmed that this RGD peptide-conjugated dendrimer targeted cancer cells through specific interaction with α v β3 integrin.…”

“…This characteristic enables dendrimers to conjugate with various molecules, such as anticancer drugs and poly(ethylene glycol) (PEG), and a targeting moiety and peptide can be simultaneously conjugated to the dendrimer. 20,23,24 In a report by He et al an RGD peptide for targeting cancer cells, PEG for avoidance of the reticuloendothelial system, and an anticancer drug were simultaneously introduced to a poly(amidoamine) (PAMAM) dendrimer. 24 These authors showed that a multifunctional dendrimer efficiently targeted U87MG cells via a receptor-mediated pathway and could inhibit cell viability.…”

“…20,23,24 In a report by He et al an RGD peptide for targeting cancer cells, PEG for avoidance of the reticuloendothelial system, and an anticancer drug were simultaneously introduced to a poly(amidoamine) (PAMAM) dendrimer. 24 These authors showed that a multifunctional dendrimer efficiently targeted U87MG cells via a receptor-mediated pathway and could inhibit cell viability. Further, Kaminskas et al reported that PEGylated dendrimer-methotrexate conjugates having matrix metalloproteinase-2/9 cleavable peptide are efficiently targeted to tumor cells, suppressed growth of cancer cells, and circulated in the blood stream for a longer period.…”

Dendrimers for theranostic applications

“…Stable encapsulation was observed between the interior hydrophobic spaces of the dendrimers and DOX. The complex exhibited sustained release and specific internalization into cells via a receptor-mediated endocytosis pathway (33).…”

Dendrimer-entrapped gold nanoparticles modified with RGD peptide and alpha-tocopheryl succinate enable targeted theranostics of cancer cells

“…Our previous work has shown that dendrimers conjugated with RGD peptide are able to target ␣ v ␤ 3 integrinoverexpressing cancer cells [49,50]. The targeted cellular uptake of the Au-TOS-RGD DENPs was examined using U87MG cells by flow cytometric analysis (Fig.…”