Cyclopamine treatment disrupts extracellular matrix and alleviates solid stress to improve nanomedicine delivery for pancreatic cancer

Abstract

As one of the most intractable tumours, pancreatic ductal adenocarcinoma (PDA) has a dense extracellular matrix (ECM) which could increase solid stress within tumours to compress tumour vessels, reduce tumour perfusion and compromise nanomedicine delivery for PDA. Thus, alleviating solid stress represents a potential therapeutic target for PDA treatment. In this study, cyclopamine, a special inhibitor of the hedgehog signalling pathway which contributes a lot to ECM formation of PDA, was exploited to alleviate solid stress and improve nanomedicine delivery to PDA. Results demonstrated that cyclopamine successfully disrupted ECM and lowered solid stress within PDA, which increased functional tumour vessels and resulted in enhanced tumour perfusion as well as improved tumour nanomedicine delivery in PDA-bearing animal models. Therefore, solid stress within PDA represents a new therapeutic target for PDA treatment.

Keywords:

• cyclopamine
• solid stress
• pancreatic ductal adenocarcinoma
• nanomedicine
• fibronectins

Disclosure statement

The authors disclose no potential conflicts of interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China [81472757, 81361140344, 31620103909 and 81600175], Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST, Clinical Research Physician Program of Tongji Medical College, HUST and Fundamental Research Funds For the Central Universities.