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

被引:25
|
作者
Brazzale, C. [1 ]
Mastrotto, F. [1 ,2 ]
Moody, P. [3 ]
Watson, P. D. [4 ]
Balasso, A. [1 ]
Malfanti, A. [1 ]
Mantovani, G. [2 ]
Caliceti, P. [1 ]
Alexander, C. [2 ]
Jones, A. T. [3 ]
Salmaso, S. [1 ]
机构
[1] Univ Padua, Dept Pharmaceut & Pharmacol Sci, Via F Marzolo 5, I-35131 Padua, Italy
[2] Univ Nottingham, Sch Pharm, Univ Pk, Nottingham NG7 2RD, England
[3] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales
[4] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales
基金
英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
DRUG-DELIVERY SYSTEMS; CELLULAR UPTAKE; IN-VIVO; FOLATE; DESIGN; FUNCTIONALIZATION; NANOCARRIERS; STRATEGIES; MICELLES; THERAPY;
D O I
10.1039/c7nr02595e
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 pK(a) 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 were 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.
引用
收藏
页码:11137 / 11147
页数:11
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