Engineering Buffering and Hydrolytic or Photolabile
Charge Shifting in a Polycarboxybetaine Ester Gene Delivery Platform
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Abstract
Polycarboxybetaine
esters (PCB-esters) can condense plasmid DNA
into nanosized polyplexes for highly effective gene delivery with
low toxicity. The design and characterization of tertiary CB-ester
monomers and PCB-ester polymers are presented here to study the effects
of molecular variation on functions important to nonviral gene transfer.
Both buffering capacity and charge-shifting behavior can be tuned
by modifying the distance between the charged groups and the ester
size or type. A carbon spacer length (CSL) of one was found to bring
the p<i>K</i><sub>a</sub> of the tertiary amine into the
optimal range for proton buffering. Ester hydrolytic degradation switches
this polymer from cationic (DNA binding) to zwitterionic (DNA releasing)
form while conferring nontoxicity. To allow rapid and externally controlled
degradation, the effect of this charge-switching behavior on DNA release
from polyplexes was directly studied with a novel photolabile PCB-nitrobenzyl
ester (PCB-NBE). Photoinitiated ester degradation precipitated the
rapid release of 72 ± 5% of complexed DNA from PCB-NBE polyplexes.
These insights reveal the key parameters important for the PCB-ester
platform and the significance of charge switching to an effective
and nontoxic nonviral gene delivery platform