Targeted Nanoencapsulation of Tunicamycin Reduces Toxicity While Improving its Therapeutic Effectiveness in Pancreatic Cancer Cells

TL;DR

A new nanoencapsulated form of Tunicamycin reduces toxicity and improves its effectiveness in treating pancreatic cancer by targeting key cancer pathways.

Contribution

A pH/Hypoxia-responsive iRGD-tagged nano-encapsulated Tunicamycin was developed to enhance therapeutic efficacy and reduce toxicity in pancreatic cancer.

Findings

The nanoencapsulated Tunicamycin inhibits PDAC cell growth via apoptosis and reduces drug resistance.

It significantly prolongs survival in a KPC-xenograft mouse model and reduces tumor growth.

Tunicamycin targets K-Ras G12D-dependent pathways and CCN1 to promote anticancer effects.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the leading sources of cancer mortality worldwide. An initial response to chemotherapy, such as Gemcitabine (GEM) alone or in combination with other chemotherapies, is often followed by emergent resistance, underscoring the urgent need for targeted therapies. PDAC cells are highly addicted to oncogenic K-RAS mutations for their growth, progression, immunosuppression, and drug resistance, but mutant K-RAS in PDAC is still challenging to target. A glycosylation inhibitor, Tunicamycin (TM), is a potent killer of PDAC cells. However, the free TM is very toxic in clinical settings. We developed a pH/Hypoxia-responsive iRGD-tagged biodegradable nano-encapsulated TM (
NP
TM) that overcomes the limitations of free TM and shows promising results inhibiting PDAC cell growth via apoptosis. The
NP
TM has shown significant promise, reducing cellular heterogeneity, drug resistance, in vitro desmoplasia, and subcutaneous tumor growth and markedly prolonging the survival in a KPC-xenograft mouse model. The studies suggest that TM targets K-Ras
G12D
-dependent multiple signaling pathways such as eIF4E, STAT3, and STAT5 activities and CCN1 to promote its anticancer efficacy. Together, these studies reveal the potential of simultaneously targeting a K-Ras
G12D
-dependent signal and CCN1 with first-line chemotherapy and provide a rationale for future clinical testing of
NP
TM for PDAC therapy.