Cationic amphiphilic drugs (CADs) can be repurposed as anti-cancer drugs via induction of lysosomal
cell death (LCD), but combination treatment and improved tumor targeting are key to boost antitumor
effects. Recent research has identified CADs as cellular delivery enhancers of RNA drugs via
non-lethal lysosomal membrane permeabilization (LMP), thus enabling cancer combination therapy.
To allow co-encapsulation and concurrent tumor targeted delivery of CADs and RNAs, this project
will apply poly(2-alkyl-2-oxazoline)s (PAOx) as a biocompatible carrier for pH-reversible CAD
conjugation. The resulting cationic polymer will be used for polyplex formation with siRNA and
mRNA. Upon IV administration, these polyplexes will extravasate through the leaky tumor
vasculature to allow endocytosis by tumor-associated target cells. Acidic release of the conjugated
CADs in the endolysosomes will enable LCD and/or non-lethal LMP, allowing the cytosolic release of
anti-tumor RNAs. First, the anti-tumoral effect and RNA delivery potential of specific CADs, including
the antihistaminic ebastine, will be compared to their polymeric counterpart. Next, the cationic
PAOx-CAD conjugate will be tested for the complexation and delivery of both siRNA, targeting the
tumor immunosuppressive regulator STAT3 and mRNA, encoding the anti-tumoral IL-12. Finally, the
therapeutic effect of unconjugated CADs, PAOx-CAD conjugates and PAOx-CAD-RNA complexes will
be critically compared in a melanoma model.