Abstract:
Drug delivery systems involving polymer therapeutics enhance drug potency by improved
solubility and specificity and may assist in circumventing chemoresistance in pancreatic cancer (PC).
We compared the effectiveness of the naturally occurring drug, betulinic acid (BA), alone and in a
polymer conjugate construct of polyethylene glycol (PEG), (PEG–BA), on PC cells (MIA PaCa-2), a
normal cell line (Vero) and on peripheral blood mononuclear cells (PBMCs). PEG–BA, was tested
for its effect on cell death, immunomodulation and chemoresistance-linked signalling pathways.
The conjugate was significantly more toxic to PC cells (p < 0.001, IC50 of 1.35 0.11 M) compared
to BA (IC50 of 12.70 0.34 M), with a selectivity index (SI) of 7.28 compared to 1.4 in Vero cells.
Cytotoxicity was confirmed by increased apoptotic cell death. PEG–BA inhibited the production of
IL-6 by 4–5.5 fold compared to BA-treated cells. Furthermore, PEG–BA treatment of MIA PaCa-2 cells
resulted in the dysregulation of crucial chemoresistance genes such as WNT3A, TXNRD1, SLC2A1
and GATA3. The dysregulation of chemoresistance-associated genes and the inhibition of cytokines
such as IL-6 by the model polymer construct, PEG–BA, holds promise for further exploration in
PC treatment.
Description:
SUPPLEMAENTARY MATERIAL : Figure S1: Line graph showing the effect of BA and PEG–BA IL-6; Figure S2: Effect of BA and PEG–BA on IL-17A, IFN- , TNF- , IL-10, IL-6, IL-4 and IL-2; Figure S3: The 96-plate layout of the human signal transduction RT2 profiler PCR array panel with the position of the genes; Table S1: Full names of dysregulated genes.
