pH-Reversible Cationic RNase A Conjugates for Enhanced
Cellular Delivery and Tumor Cell Killing
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Abstract
Intracellularly-acting
therapeutic proteins are considered promising
alternatives for the treatment of various diseases. Major limitations
of their application are low efficiency of intracellular delivery
and possible reduction of protein activity during derivatization.
Herein, we report pH-sensitive covalent modification of proteins with
a histidine-rich cationic oligomer (689) for efficient intracellular
transduction and traceless release of functional proteins. Enhanced
Green fluorescent protein (EGFP), as model for the visualization of
protein transduction, and RNase A, as therapeutic protein with antitumoral
effect, were modified with the pH-sensitive bifunctional AzMMMan linker
and varying amounts of cationic oligomer. The modification degree
showed impact on the internalization and cellular distribution of
EGFP as well as the biological effect of RNase A conjugates, which
mediated considerable toxicity against cancer cells at optimal ratio.
The presented conjugates demonstrate their qualification to achieve
efficient intracellular delivery and controlled release without protein
inactivation and potential prospective applications in protein-based
therapies