The influence of aromatic side-chains on the aqueous properties of pH-sensitive poly(L-lysine iso-phthalamide) derivatives.
The endosomal membrane has proven to be a challenging barrier for the delivery of therapeutic biomacromolecules, including DNA, siRNA and proteins, which are taken up by endosomes but cannot freely diffuse across lipid bilayers. Anionic polymers that undergo conformational changes and become membrane disruptive in low-pH environments have the potential to assist in the delivery of these biomacromolecules across the endosomal membrane to the cytosol. Such endosomolytic polymers have been synthesized through the grafting of hydrophobic side-chains to a poly(L-lysine iso-phthalamide) backbone. The phenylalanine grafted form of poly(L-lysine iso-phthalamide) has a pH-sensitive membrane disruptive profile corresponding to the pH range of maturing endosomes and, thus, has a favourable endosomolytic profile. In order to understand the influence of hydrophobicity versus pi-pi interactions mediated by aromatic rings, a tyrosine grafted form of poly(L-lysine iso-phthalamide) was synthesized and its aqueous pH-sensitive properties, cytotoxicity and endosomal disruptive capacity were compared to phenylalanine-grafted poly(L-lysine iso-phthalamide). The similarity between these two polymers' properties, despite the large difference in hydrophobicity between their side-chains, supports the conclusion that the aromatic character of sidechains in poly(L-lysine iso-phthalamide) is an important property, as opposed to hydrophobicity alone, in determining the effectiveness of acidic pH triggered endosomolysis.
Khormaee
Sariah
S
Department of Chemical Engineering and Biotechnology, University of Cambridge, Pembroke Street, Cambridge CB23RA, UK.
Chen
Rongjun
R
Park
John K
JK
Slater
Nigel K H
NK
D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D011232:Chemical Precipitation; D011992:Endosomes / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D044367:Phase Transition; D010795:Phthalic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011107:Polylysine / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D012996:Solutions; D014867:Water / Q000737:chemistry*
D010795:Phthalic Acids; D011108:Polymers; D012996:Solutions; C507264:poly(L-lysine iso-phthalamide); D014867:Water; D011107:Polylysine