Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy

Xiaozheng Zhao, Xiao Yang, Xudong Wang, Xiao Zhao, Yinlong Zhang, Shaoli Liu, Gregory J. Anderson, Seong Jin Kim, Yiye Li, Guangjun Nie

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


Pancreatic ductal adenocarcinoma (PDAC) cells are surrounded by a dense extracellular matrix (ECM), which greatly restricts the access of therapeutic agents, resulting in poor clinical response to chemotherapy. Transforming growth factor-β1 (TGF-β1) signaling plays a crucial role in construction of the desmoplastic stroma and provides potential targets for PDAC therapy. To surmount the pathological obstacle, we developed a size switchable nanosystem based on PEG-PLGA nanospheres encapsulated within liposomes for the combined delivery of vactosertib (VAC), a TGF-β1 receptor kinase inhibitor, and the cytotoxic drug paclitaxel (TAX). By surface modification of the liposomes with a peptide, APTEDB, the nanosystem can be anchored to abundant tumor-associated fibronectin in PDAC stroma and decreases its size by releasing encapsulated TAX-loaded nanospheres, as well as VAC after collapse of the liposomes. The inhibition of ECM hyperplasia by VAC allows TAX more ready access to the cancer cells in addition to its small size, thereby shrinking pancreatic tumor xenografts more effectively than a combination of the free drugs. This size switchable nanosystem enables sequential delivery of drugs at a fixed dose combination with simplified administration and provides an encouraging cascade approach of drug penetration for enhanced chemotherapy in cancers with a dense desmoplastic stroma.

Original languageEnglish (US)
Pages (from-to)14149-14161
Number of pages13
JournalACS Nano
Issue number9
StatePublished - Sep 28 2021


  • TGF-β1 inhibitor
  • combination therapy
  • drug penetration
  • pancreatic cancer
  • size switchable nanosystem

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)


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