Ligand Conformation Dictates Membrane and Endosomal Trafficking of Arginine‐Glycine‐Aspartate (RGD)‐Functionalized Mesoporous Silica Nanoparticles

Abstract

Recent breakthrough research on mesoporous silica nanoparticle (MSN) materials has illustrated their significant potential in biological applications due to their excellent drug delivery and endocytotic behavior. We set out to determine if MSN, covalently functionalized with conformation specific bioactive molecules (either linear or cyclic RGD ligands), behave towards mammalian cells in a similar manner as the free ligands. We discovered that RGD immobilized on the MSN surface did not influence the integrity of the porous matrix and improved the endocytosis efficiency of the MSN materials. Through competition experiments with free RGD ligands, we also discovered a conformation specific receptor-integrin association. The interaction between RGD immobilized on the MSN surface and integrins plays an important role in endosome trafficking, specifically dictating the kinetics of endosomal escape. Thus, covalent functionalization of biomolecules on MSN assists in the design of a system for controlling the interface with cancer cells.

Lactosaminated mesoporous silica nanoparticles for asialoglycoprotein receptor targeted anticancer drug delivery

“…More importantly, the external surface of MSNs can be modified with tumor-recognition molecules to increase the active targetability through the receptor-mediated endocytosis. Several well-known targeting molecules, such as folate [21], mannose [22], hyaluronic acid [23], arginine-glycineaspartate (RGD) [24], and lactobionic acid [25] have been conjugated to MSNs successfully, resulting in significantly enhanced antitumor efficiency.…”

Novel tumor-targeting, self-assembling peptide nanofiber as a carrier for effective curcumin delivery

“…20,21 It has been widely used for tumor diagnosis and targeting therapy. Liposomes, 22 micelles, 23 dendrimers 24 and silica nanoparticles 25 have been conjugated with RGD to introduce tumor-targeting activity. RGD has also been used in positron emission tomography, 26 single photon emission computed tomography, 27 magnetic resonance imaging, 28 and optical 29 imaging for diagnosis of cancer.…”

Targeted and stimuli–responsive mesoporous silica nanoparticles for drug delivery and theranostic use

“…Both tumor cells and angiogenic endothelial cells exhibit the overexpression of endothelial αvβ3 integrins that are the targets of RGD peptides (Hu et al, ). Various studies have reported the conjugation of MPSNPs with a variety of linear and cyclic RGD peptides having free primary amine group of lysine amino acid or free thiol groups of cysteine amino acid (Fang, Slowing, Wu, Lin, & Trewyn, ). A study reported the covalent conjugation of MPSNPs with a cyclic RGDFK and a linear peptide having a sequence of seven continuous lysine residues (K 7 RGD).…”

“…A study reported the covalent conjugation of MPSNPs with a cyclic RGDFK and a linear peptide having a sequence of seven continuous lysine residues (K 7 RGD). The developed system was used for the assessment of the RGD conformation in an uptake by mammalian cells (Fang et al, 2012). In comparison with MPSNPs without functionalization, the cyclic RGD uptake by HeLa cells was 3.6 times higher, while its internalization was approximately two times higher into MCF-7 cells, and conversely, the linear K 7 RGD uptake by HeLa cells was approximately three times higher, while its internalization was 1.1 times higher into MCF-7 cells.…”