Pal, Sanjay and Medatwal, Nihal and Kumar, Sandeep and Kar, Animesh and Komalla, Varsha and Yavvari, Prabhu Srinivas and Mishra, Deepakkumar and Rizvi, Zaigham Abbas and Nandan, Shiv and Malakar, Dipankar and Pillai, Manoj and Awasthi, Amit and Das, Prasenjit and Sharma, Ravi Datta and Srivastava, Aasheesh and Sengupta, Sagar and Dasgupta, Ujjaini and Bajaj, Avinash (2019) A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism. ACS Central Science, 5 (10). pp. 1648-1662. ISSN 2374-7943

Preview

Text A Localized Chimeric Hydrogel Therapy Combats Tumor Progression through Alteration of Sphingolipid Metabolism.pdf Download (7Mb) | Preview

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 βglucocerebrosidase 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.

Item Type:	Article
Subjects:	Biomedical Science Bioengineering & Devices
Depositing User:	RCB Library
Date Deposited:	14 Mar 2023 10:09
Last Modified:	14 Mar 2023 10:09
URI:	http://rcb.sciencecentral.in/id/eprint/264

Actions (login required)

View Item