Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles

Abstract

The permeability barrier posed by cell membranes represents a challenge for the delivery of hydrophilic molecules into cells. We previously proposed that poly(2-alkylacrylic acid)s are endocytosed by cells into acidified vesicles and are there triggered by low pH to disrupt membranes and release the contents of endosomes/lysosomes to the cytosol. If this hypothesis is correct, these polymers could be valuable in drug-delivery applications. The present paper reports functional comparisons of a family of three poly(2-alkylacrylic acid)s. Poly(2-propylacrylic acid) (PPAA), poly(2-ethylacrylic acid) (PEAA) and poly(2-methylacrylic acid) (PMAA) were compared in red-blood-cell haemolysis assays and in a lipoplex (liposome-DNA complex) assay. We also directly examined the ability of these polymers to disrupt endosomes and lysosomes in cultured human cells. Our results show that: (i) unlike membrane-disruptive peptides, the endosomal-disruptive ability of poly(2-alkylacrylic acid)s cannot necessarily be predicted from their haemolytic activity at low pH, (ii) PPAA (but not PEAA or PMAA) potently facilitates gene transfection by cationic lipoplexes and (iii) endocytosed poly(2-alkylacrylic acid)s are triggered by luminal acidification to selectively disrupt endosomes (not lysosomes) and release their contents to the cytosol. These results will facilitate the rational design of future endosomal-disrupting polymers for drug delivery.

Doxorubicin Loaded pH-sensitive Micelle: Antitumoral Efficacy against Ovarian A2780/DOXR Tumor

“…3(c), a hemolysis test evaluated red blood cells (RBC) membrane disruption by polyHis-b-PEG and PLLA-b-PEG at different pHs. This assay describes the membrane disruption property of polyHis indirectly, using the RBC membrane as an endosomal membrane model (38). The hemolytic activity of polyHis-b-PEG was low at pH 7.4, near that of the control sample.…”

Recent advances of chitosan nanoparticles as drug carriers

“…At a pH lower than 6.0, its high membrane fragmentation ability was shown to cause rupture of endosomal membrane and release vesicular materials into cytochylema. 38 Therefore, Kiang et al 39 added PPAA to chitosan-DNA complex to improve gene transfection efficiency. The results showed that adding PPAA to chitosan-DNA complexes enhanced gene expression in both HEK293 and HeLa cells compared with chitosan nanoparticles alone.…”

Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

“…Cationic and anionic polymers with pH-sensitive activity, including derivatives of poly (acrylic acid) (Jones et al 2003;Kusonwiriyawong et al 2003;Kyriakides et al 2002), methacrylic acid copolymers (Yessine et al 2003), imidazole-containing polymers (Seo and Kim 2010) and pseudo-peptidic polymers (Chen et al 2008(Chen et al , 2009, have also been developed 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 to promote endosomal release. Cationic polymers have been described to enhance membrane lysis at low pH via electrostatic interactions between protonated amines and the negatively charged membranes (Yessine et al 2003).…”