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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

Authors

C. Brazzale

Francesca Mastrotto francesca.mastrotto@nottingham.ac.uk

P. Moody

P.D. Watson

A. Balasso

A. Malfanti

Giuseppe Mantovani giuseppe.mantovani@nottingham.ac.uk

Paolo Caliceti

Cameron Alexander

A.T. Jones

Stefano Salmaso



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.

Journal Article Type Article
Journal Nanoscale
Print ISSN 2040-3364
Electronic ISSN 2040-3372
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 9
Issue 31
APA6 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), doi:10.1039/C7NR02595E
DOI https://doi.org/10.1039/C7NR02595E
Publisher URL http://pubs.rsc.org/en/Content/ArticleLanding/2017/NR/C7NR02595E#!divAbstract
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Nanoscale-1 accepted July 2017.pdf (963 Kb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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