The combined use of targeting capacity and the ultrasound sensitizing effect, make FA-PEG-GNP promising candidates for the site-specific cancer treatment.
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.
The colloidal stability, in vitro
toxicity, cell association, and
in vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly(ethylene
glycol)-lipids (mPEG-lipids) with different chemical features were
comparatively investigated. Structural differences of the mPEG-lipids
used in the study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol),
and cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 and 5 kDa mPEG114); and (c) mPEG shape (linear and branched
PEG). In vitro results demonstrated that branched (mPEG114)2-DSPE confers the highest stealth properties to liposomes
(∼31-fold lower cell association than naked liposomes) with
respect to all PEGylating agents tested. However, the pharmacokinetic
studies showed that the use of cholesterol as anchoring group yields
PEGylated liposomes with longer permeance in the circulation and higher
systemic bioavailability among the tested formulations. Liposomes
decorated with mPEG114-Chol had 3.2- and ∼2.1-fold
higher area under curve (AUC) than naked liposomes and branched (mPEG114)2-DSPE-coated liposomes, respectively, which
reflects the high stability of this coating agent. By comparing the
PEGylating agents with same size, namely, linear 5 kDa PEG derivatives,
linear mPEG114-DSPE yielded coated liposomes with the best
in vitro stealth performance. Nevertheless, the in vivo AUC of liposomes
decorated with linear mPEG114-DSPE was lower than that
obtained with liposomes decorated with linear mPEG114-Chol.
Computational molecular dynamics modeling provided additional insights
that complement the experimental results.
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