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A Facile and Efficient Approach for the Production of Reversible Disulfide Cross-linked Micelles
Published on: December 23, 2016
Generation of a selective senolytic platform using a micelle-encapsulated Sudan Black B conjugated analog
Sophia Magkouta1,2,3, Dimitris Veroutis1,3, Angelos Papaspyropoulos1
1Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Abstract:
The emerging field of senolytics is centered on eliminating senescent cells to block their contribution to the progression of age-related diseases, including cancer, and to facilitate healthy aging. Enhancing the selectivity of senolytic treatments toward senescent cells stands to reduce the adverse effects associated with existing senolytic interventions. Taking advantage of lipofuscin accumulation in senescent cells, we describe here the development of a highly efficient senolytic platform consisting of a lipofuscin-binding domain scaffold, which can be conjugated with a senolytic drug via an ester bond. As a proof of concept, we present the generation of GL392, a senolytic compound that carries a dasatinib senolytic moiety. Encapsulation of the GL392 compound in a micelle nanocarrier (termed mGL392) allows for both in vitro and in vivo (in mice) selective elimination of senescent cells via targeted release of the senolytic agent with minimal systemic toxicity. Our findings suggest that this platform could be used to enhance targeting of senotherapeutics toward senescent cells.
Insights
Scientists developed a senolytic platform targeting senescent cells using lipofuscin accumulation. This novel approach enhances senolytic drug delivery, reducing side effects and promoting healthy aging.
Area of Science:
- Biomedical Engineering
- Gerontology
- Pharmacology
Background:
- Senolytics aim to eliminate senescent cells to combat age-related diseases and promote healthy aging.
- Current senolytic interventions face challenges with selectivity, leading to adverse effects.
- Senescent cells accumulate lipofuscin, a characteristic that can be exploited for targeted drug delivery.
Purpose of the Study:
- To develop a highly efficient and selective senolytic platform.
- To create a drug delivery system that targets senescent cells based on lipofuscin accumulation.
- To validate the platform's efficacy and safety in vitro and in vivo.
Main Methods:
- Development of a senolytic platform using a lipofuscin-binding domain scaffold conjugated with a senolytic drug (dasatinib moiety).
- Generation of a senolytic compound (GL392) and its encapsulation in a micelle nanocarrier (mGL392).
- In vitro and in vivo (mice) evaluation of mGL392 for selective senescent cell elimination and toxicity assessment.
Main Results:
- Successful development of the GL392 compound and mGL392 nanocarrier.
- Demonstrated selective elimination of senescent cells in vitro and in vivo.
- mGL392 showed minimal systemic toxicity, indicating targeted drug release.
Conclusions:
- The developed senolytic platform effectively targets and eliminates senescent cells.
- This platform offers a promising strategy to enhance the selectivity of senotherapeutics.
- The approach holds potential for improving treatments for age-related diseases and facilitating healthy aging.
