Related Experiment Video
Updated: Oct 21, 2025
Author Spotlight: Validating Cancer Therapy Responses with Desmoplastic Spheroid Models
Published on: September 27, 2024
Penetration Cascade of Size Switchable Nanosystem in Desmoplastic Stroma for Improved Pancreatic Cancer Therapy
Xiaozheng Zhao1,2, Xiao Yang1, Xudong Wang1
1CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, P. R. China.
Abstract:
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.
Insights
This study introduces a novel nanosystem for pancreatic cancer therapy. It combines drugs to overcome the dense tumor stroma, enhancing chemotherapy effectiveness.
Area of Science:
- Oncology
- Nanotechnology
- Biomedical Engineering
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) that impedes therapeutic agent delivery, leading to poor chemotherapy response.
- Transforming growth factor-β1 (TGF-β1) signaling is critical in forming the desmoplastic stroma in PDAC, presenting a therapeutic target.
Purpose of the Study:
- To develop a size-switchable nanosystem for combined delivery of vactosertib (VAC), a TGF-β1 inhibitor, and paclitaxel (TAX) to overcome ECM barriers in PDAC.
- To enhance drug penetration and improve the efficacy of chemotherapy in pancreatic cancer models.
Main Methods:
- Development of a liposome-encapsulated PEG-PLGA nanosphere system for sequential drug release.
- Surface modification of liposomes with APTEDB peptide for tumor-associated fibronectin targeting.
- Evaluation of the nanosystem's ability to inhibit ECM, release drugs, and shrink tumor xenografts in vivo.
Main Results:
- The developed nanosystem effectively targets PDAC stroma and switches size, releasing both TAX and VAC.
- VAC inhibition of ECM hyperplasia facilitated better TAX penetration.
- The nanosystem demonstrated superior efficacy in shrinking pancreatic tumor xenografts compared to free drug combinations.
Conclusions:
- The size-switchable nanosystem facilitates sequential drug delivery and enhanced drug penetration for improved chemotherapy in desmoplastic tumors.
- This approach offers a simplified administration and a promising cascade strategy for treating challenging cancers like PDAC.
