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

Abstract

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.

Alternative splicing of ceramide synthase 2 alters levels of specific ceramides and modulates cancer cell proliferation and migration in Luminal B breast cancer subtype

“…Any traces of genomic DNA were removed by DNase (Invitrogen, Am2238) treatment for 30 min at 37 °C followed by heat inactivation using 50 mM EDTA (Sigma, E5134). cDNA synthesis and real-time PCR were done as described previously 27 . Relative quantitation of gene expression was done using β -actin as the endogenous reference gene for normalization.…”

“…Recently, our group has shown that a combination chemotherapy induces the AS in glucocerebrosidase β ( Gba1 ), and increases Gba1 expression in murine tumor tissues. This enhanced Gba1 expression catalyzes the degradation of glucosylceramides to ceramides responsible for tumor regression, and lowers the glucosylceramide levels critical for drug resistance 27 .…”

Advances and trends of hydrogel therapy platform in localized tumor treatment: A review

“…For lung cancer treatment, CA4 could also cooperate with other elements. Sanjay Pal et al 133 synthesized a self‐assembled lithocholic acid‐dipeptide hydrogel (TRI‐Gel) for co‐delivery of DOX, CA4, and dexamethasone (DEX). Beyond the anticancer effect of DOX and the antiangiogenesis of CA4, the anti‐inflammatory function of DEX contributed to the abrogation of carcinoma tissue.…”

Potential Applications of Advanced Nano/Hydrogels in Biomedicine: Static, Dynamic, Multi‐Stage, and Bioinspired

“…Sustained release of these drugs resulted in increased apoptosis, reduced inflammation and inhibition of angiogenesis, all of which led to increased survival rate in a murine tumor model, indicating the synergistic effect of multiple drugs. [104] Off-target delivery of drugs results in undesirable toxicity to healthy cells. Appropriate carriers are able to overcome such challenges.…”