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Updated: Jun 30, 2026
Contrast Ultrasound Targeted Treatment of Gliomas in Mice via Drug-Bearing Nanoparticle Delivery and Microvascular Ablation
Published on: December 15, 2010
Microthrombi targeted nano-micelle synchronizing endothelial gap opening and matrix decompression for augmenting drug
Mengnan Yang1, Yuqing Tong1, Shaoping Yin2
1Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211198, China.
Abstract:
Local inhibition of the "patching" function of tumor-associated platelets against neutrophil infiltration-caused vascular breaches has been used as an "enhanced permeability and retention (EPR) amplification" strategy. Nevertheless, the vascular leakage-resulted elevation of interstitial fluid pressure (IFP) could impact tumoral perfusion and convection of nanodrugs. Especially for hypoperfused and desmoplastic pancreatic ductal adenocarcinoma (PDAC), solely relying on vascular destruction would predictably diminish tumoral drug perfusion. According to multi-thrombosis formation in PDAC, a microthrombi and matrix co-targeted dasatinib (DAS) nano-micelle (CPHD/DAS) synchronizing endothelial gap opening and matrix decompression was constructed for sustained augmentation of drug perfusion within PDAC. CPHD/DAS was composed of CREKA peptide-modified hyaluronic acid-deoxycholate conjugates co-assembled with DAS. In vitro and in vivo results demonstrated CPHD/DAS not only retarded tumor-associated platelet activation to enhance vascular permeability and expose subvascular matrix, but also inhibited pancreatic stellate cell activation to alleviate stroma barrier. Thus, the matrix decompression resisted IFP elevation caused by endothelial gap opening, facilitating sustained up-regulation of functional vessels. Based on superior tumor accumulation and penetration, CPHD/DAS exhibited favorable potency in Panc02 tumor model. This study provides a paradigm to improve the efficiency and application scope of "EPR amplification" strategy in antitumor therapy.
Insights
This study developed a novel nanomedicine (CPHD/DAS) to enhance drug delivery in pancreatic cancer by opening tumor blood vessels and reducing matrix pressure. This approach improves drug perfusion and antitumor efficacy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Enhanced permeability and retention (EPR) strategy amplifies drug delivery but elevated interstitial fluid pressure (IFP) hinders nanodrug perfusion, especially in pancreatic ductal adenocarcinoma (PDAC).
- PDAC's hypoperfusion and desmoplasia limit drug delivery, necessitating strategies beyond simple vascular destruction.
Purpose of the Study:
- To develop a dual-targeting nanomedicine (CPHD/DAS) for pancreatic ductal adenocarcinoma (PDAC) that synchronizes endothelial gap opening and matrix decompression.
- To overcome the limitations of the EPR amplification strategy by addressing interstitial fluid pressure (IFP) elevation and improving nanodrug perfusion in PDAC.
Main Methods:
- Constructed CPHD/DAS using CREKA peptide-modified hyaluronic acid-deoxycholate conjugates co-assembled with dasatinib (DAS).
- Evaluated CPHD/DAS in vitro and in vivo for its effects on tumor-associated platelet activation, vascular permeability, matrix, and pancreatic stellate cell activation.
- Assessed tumor accumulation, penetration, and antitumor potency in a Panc02 PDAC model.
Main Results:
- CPHD/DAS retarded tumor-associated platelet activation, enhancing vascular permeability and exposing the subvascular matrix.
- CPHD/DAS inhibited pancreatic stellate cell activation, alleviating the stromal barrier and resisting IFP elevation.
- The nanomedicine facilitated sustained up-regulation of functional vessels, leading to superior tumor accumulation, penetration, and antitumor potency in the Panc02 model.
Conclusions:
- CPHD/DAS provides a paradigm for improving the EPR amplification strategy in antitumor therapy by simultaneously addressing vascular and matrix barriers.
- This approach enhances nanodrug perfusion and efficacy in challenging tumor microenvironments like PDAC.
- The study demonstrates a promising strategy to overcome limitations in nanomedicine delivery for cancer treatment.
