Poly(2-alkylacrylic acid) polymers deliver molecules to the cytosol by pH-sensitive disruption of endosomal vesicles.
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.
Jones
Rachel A
RA
Department of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia.
Cheung
Charles Y
CY
Black
Fiona E
FE
Zia
Jasmine K
JK
Stayton
Patrick S
PS
Hoffman
Allan S
AS
Wilson
Mark R
MR
D001681:Biological Assay; D001693:Biological Transport, Active; D002401:Cathepsin B / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D005452:Fluoresceins / Q000378:metabolism; D017930:Genes, Reporter; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D010627:Phenethylamines / Q000378:metabolism*; D010796:Phthalic Anhydrides / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D011109:Polymethacrylic Acids / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D005452:Fluoresceins; D010627:Phenethylamines; D010796:Phthalic Anhydrides; D011108:Polymers; D011109:Polymethacrylic Acids; C030613:polymethacrylic acid; C045870:polyterephthalic acid anhydride; C050457:3-((2-phenylethyl)amino)alanine; D002401:Cathepsin B; C007740:fluorexon