Improving the In Vivo Therapeutic Index of siRNA Polymer
Conjugates through Increasing pH Responsiveness
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Abstract
Polymer
based carriers that aid in endosomal escape have proven
to be efficacious siRNA delivery agents in vitro and in vivo; however,
most suffer from cytotoxicity due in part to a lack of selectivity
for endosomal versus cell membrane lysis. For polymer based carriers
to move beyond the laboratory and into the clinic, it is critical
to find carriers that are not only efficacious, but also have margins
that are clinically relevant. In this paper we report three distinct
categories of polymer conjugates that improve the selectivity of endosomal
membrane lysis by relying on the change in pH associated with endosomal
trafficking, including incorporation of low p<i>K</i><sub>a</sub> heterocycles, acid cleavable amino side chains, or carboxylic
acid pH sensitive charge switches. Additionally, we determine the
therapeutic index of our polymer conjugates in vivo and demonstrate
that the incorporation of pH responsive elements dramatically expands
the therapeutic index to 10โ15, beyond that of the therapeutic
index (less than 3), for polymer conjugates previously reported