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Sequential Rocket-Mode Bioactivating Ticagrelor Prodrug Nanoplatform Combining Light-Switchable Diphtherin Transgene
Jiafeng Zou1,2,3, Rui Sun1, Muye He1
1Shanghai Frontier Science Research Base of Optogenetic Techniques for Cell Metabolism, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
Abstract:
The increased risk of breast cancer metastasis is closely linked to the effects of platelets. Our previously light-switchable diphtheria toxin A fragment (DTA) gene system, known as the LightOn system, has demonstrated significant therapeutic potential; it lacks antimetastatic capabilities. In this study, we devised an innovative system by combining cell membrane fusion liposomes (CML) loaded with the light-switchable transgene DTA (pDTA) and a ticagrelor (Tig) prodrug. This innovative system, named the sequential rocket-mode bioactivating drug delivery system (pDTA-Tig@CML), aims to achieve targeted pDTA delivery while concurrently inhibiting platelet activity through the sequential release of Tig triggered by reactive oxygen species with the tumor microenvironment. In vitro investigations have indicated that pDTA-Tig@CML, with its ability to sequentially release Tig and pDTA, effectively suppresses platelet activity, resulting in improved therapeutic outcomes and the mitigation of platelet driven metastasis in breast cancer. Furthermore, pDTA-Tig@CML exhibits enhanced tumor aggregation and successfully restrains tumor growth and metastasis. It also reduces the levels of ADP, ATP, TGF-β, and P-selectin both in vitro and in vivo, underscoring the advantages of combining the bioactivating Tig prodrug nanoplatform with the LightOn system. Consequently, pDTA-Tig@CML emerges as a promising light-switchable DTA transgene system, offering a novel bioactivating prodrug platform for breast cancer treatment.
Insights
This study introduces a new drug delivery system combining a light-switchable toxin gene with a platelet-inhibiting drug to combat breast cancer metastasis. The system effectively reduces tumor growth and spread by targeting cancer cells and inhibiting platelet activity.
Area of Science:
- Biomedical Engineering
- Oncology
- Nanotechnology
Background:
- Platelets significantly increase breast cancer metastasis risk.
- Existing light-switchable diphtheria toxin A fragment (DTA) gene systems (LightOn) show therapeutic promise but lack antimetastatic effects.
Purpose of the Study:
- To develop an innovative drug delivery system combining a light-switchable DTA transgene with a ticagrelor (Tig) prodrug for enhanced breast cancer treatment.
- To create a system that targets DTA delivery and inhibits platelet activity via sequential Tig release triggered by tumor microenvironment factors.
Main Methods:
- Development of a sequential rocket-mode bioactivating drug delivery system (pDTA-Tig@CML) using cell membrane fusion liposomes (CML).
- Loading CML with light-switchable DTA (pDTA) and a ticagrelor (Tig) prodrug.
- Investigating the system's efficacy in vitro and in vivo for targeted drug delivery, platelet inhibition, and anti-metastatic effects.
Main Results:
- pDTA-Tig@CML sequentially releases Tig and pDTA, effectively suppressing platelet activity and mitigating platelet-driven breast cancer metastasis.
- The system demonstrated enhanced tumor aggregation, restrained tumor growth and metastasis, and reduced levels of ADP, ATP, TGF-β, and P-selectin in vitro and in vivo.
- Successful combination of the bioactivating Tig prodrug nanoplatform with the LightOn system.
Conclusions:
- pDTA-Tig@CML is a promising light-switchable DTA transgene system for breast cancer treatment.
- The developed system offers a novel bioactivating prodrug platform with significant antimetastatic capabilities.
- This approach highlights the synergistic benefits of combining targeted gene therapy with platelet inhibition for improved cancer outcomes.
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