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

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 pK 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.

Application of Oil-in-Water Nanoemulsion Carrying Size-Defined Gold Nanoparticles Synthesized by Non-thermal Plasma for the Human Breast Cancer Cell Lines Migration and Apoptosis

“…To enhance the efficiency of the AuNPs in the cancer treatment and detection, several ligands, including lycopene [44], folate-decorated polymers [45], prostate-specific membrane antigen (PSMA-1) [46], as well as 4,6-diamino-2-mercaptopyrimidine (DAMP) and glutathione (GSH) [47], have successfully been attached to the surface of these nanostructures. However, Curcuma longa (turmeric or "Indian saffron"), a popular herbal raw material [48], is particularly interesting for that purpose.…”

A light-induced nitric oxide controllable release nano-platform based on diketopyrrolopyrrole derivatives for pH-responsive photodynamic/photothermal synergistic cancer therapy

“… 5 – 13 PDT and PTT depend on photon energy absorbed by photosensitizers to generate reactive oxygen species (ROS) or heat, causing damage or death of blood vessels and tumor cells. 14 – 18 Owing to the difference of pH value between the tumor microenvironment (pH 4.5–5.0) and normal tissues (pH 7.4), 19 – 22 smart pH-activated photosensitizers are extremely desirable. Lysosomes with weak acidity in tumour cells can act as a pH-activated reactor, 23 – 25 which provides the most effective approach for imaging and therapy in vitro and in vivo .…”

Triggerable Multivalent Glyconanoparticles for Probing Carbohydrate–Carbohydrate Interactions

“… 28 Mastrotto et al have used the reversible collapse of poly( N -isopropylacrylamide) to present folate on particle surfaces for cellular delivery using thermal 29 and pH stimuli. 30 Sequential revealing of ligands on liposomes has enabled improved delivery of liposome formulations. 31 Spain and Alexander have used DNA strand displacement for oligonucleotide-specific ligand expression.…”