A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism

Rapid
proliferation of cancer cells assisted by endothelial cell-mediated
angiogenesis and acquired inflammation at the tumor microenvironment
(TME) lowers the success rate of chemotherapeutic regimens. Therefore,
targeting these processes using localized delivery of a minimally
toxic drug combination may be a promising strategy. Here, we present
engineering of a biocompatible self-assembled lithocholic acid-dipeptide
derived hydrogel (TRI-Gel) that can maintain sustained delivery of
antiproliferating doxorubicin, antiangiogenic combretastatin-A4 and
anti-inflammatory dexamethasone. Application of TRI-Gel therapy to
a murine tumor model promotes enhanced apoptosis with a concurrent
reduction in angiogenesis and inflammation, leading to effective abrogation
of tumor proliferation and increased median survival with reduced
drug resistance. In-depth RNA-sequencing analysis showed that TRI-Gel
therapy induced transcriptome-wide alternative splicing of many genes
responsible for oncogenic transformation including sphingolipid genes.
We demonstrate that TRI-Gel therapy targets the reversal of a unique
intron retention event in β-glucocerebrosidase 1 (Gba1), thereby increasing the availability of functional Gba1 protein.
An enhanced Gba1 activity elevates ceramide levels responsible for
apoptosis and decreases glucosylceramides to overcome drug resistance.
Therefore, TRI-Gel therapy provides a unique system that affects the
TME via post-transcriptional modulations of sphingolipid metabolic
genes, thereby opening a new and rational approach to cancer therapy.