Control of targeting ligand display by pH-responsive polymers on gold nanoparticles mediates selective entry into cancer cells

Brazzale, C.; Mastrotto, Francesca; Moody, P.; Watson, P.D.; Balasso, A.; Malfanti, A.; Mantovani, Giuseppe; Caliceti, Paolo; Alexander, Cameron; Jones, A.T.; Salmaso, Stefano

Abstract

Selective targeting of cells for intracellular delivery of therapeutics represents a major challenge for pharmaceutical intervention in disease. Here we show pH triggered receptor-mediated endocytosis of nanoparticles via surface ligand exposure. Gold nanoparticles were decorated with two polymers: a 2 kDa PEG with a terminal folate targeting ligand, and a di-block copolymer including a pH-responsive and a hydrophilic block. At the normal serum pH of 7.4, the pH-responsive block (apparent pKa of 7.1) displayed a hydrophilic extended conformation, shielding the PEG-folate ligands, which inhibited cellular uptake of the nanoparticles. Under pH conditions resembling those of the extracellular matrix around solid tumours (pH 6.5), protonation of the pH-responsive polymer triggered a coil-to-globule polymer chain contraction, exposing folate residues on the PEG chains. In line with this, endocytosis of folate-decorated polymer-coated gold nanoparticles in cancer cells overexpressing folate receptor was significantly increased at pH 6.5, compared with pH 7.4. Thus, the tumour acidic environment and high folate receptor expression was effectively exploited to activate cell binding and endocytosis of these nanoparticles. These data provide proof-of-concept for strategies enabling extracellular pH stimuli to selectively enhance cellular uptake of drug delivery vectors and their associated therapeutic cargo.

Citation

Brazzale, C., Mastrotto, F., Moody, P., Watson, P., Balasso, A., Malfanti, A., …Salmaso, S. (in press). Control of targeting ligand display by pH-responsive polymers on gold nanoparticles mediates selective entry into cancer cells. Nanoscale, 9(31), https://doi.org/10.1039/C7NR02595E

• Journal Article Type: Article
• Acceptance Date: Jul 13, 2017
• Online Publication Date: Jul 14, 2017
• Deposit Date: Jul 18, 2017
• Publicly Available Date: Jul 18, 2017
• Journal: Nanoscale
• Print ISSN: 2040-3364
• Electronic ISSN: 2040-3372
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 9
• Issue: 31
• DOI: https://doi.org/10.1039/C7NR02595E
• Public URL: https://nottingham-repository.worktribe.com/output/872656
• Publisher URL: http://pubs.rsc.org/en/Content/ArticleLanding/2017/NR/C7NR02595E#!divAbstract
• Contract Date: Jul 18, 2017