Aging is an irreversible physiological process, with the occurrence of aging, the function of the body continues to decline, a variety of age-related diseases, such as type II diabetes, cancer, cardiovascular disease, the incidence of significantly increased, to the whole society brings a huge burden.
As an important means to delay senescence, the removal of senescent cells has been the focus of research in recent years.
Previous studies have also found that a variety of effective anti-aging drugs can kill senescent cells.
Due to the reuse strategy of some drugs, anti-aging treatments are often associated with systemic toxicity, adverse side effects, and off-target effects.
How to accurately eliminate senescent cells has become an urgent problem to be solved.
Recently, The team of Professor Vassilis G. Gorgoulis from the National Kapodistrian University of Athens published a paper entitled “Generation of a selective senolytic platform using a” in the journal Nature Aging micelle-encapsulated Sudan Black B conjugated analog “.
The study constructed a novel drug delivery platform that encapsulates the GL392 compound (a dasatinib-carrying compound) in micellar nanocarriers (called mGL392) to selectively eliminate senescent cells in vitro and in vivo by targeting the release of an aging scavger, achieving precise anti-aging efficacy.
It is worth pointing out that the platform can minimize the systemic toxicity of drugs without affecting the clearance of senescent cells.
Given that the accumulation of lipofuscin is a common manifestation of senescent cells, the researchers targeted it as a target for selective elimination of senescent cells.
An innovative platform designed as a nanocarrier for the precise elimination of senescent cells.
The platform consists of three main components: (1) LBD scaffold (identification and anchoring of lipofuscin); (2) linker; (3) aging clearance part.
Specifically, the researchers chose GL9 as the most potent LBD because it has previously shown to have high affinity and selectivity for lipofuscin.
As a proof of concept, dasatinib, a mature anti-aging drug undergoing clinical trials, selected to provide the anti-aging component, and the resulting compound called GL392.
Once GL392 is anchored to lipofuscin, the cell esterase can target the bond, ultimately releasing the active dasatinib.
For better performance, the researchers encapsulated it in micelles to synthesize micellar preparations (hereinafter referred to as mGL392).
The researchers then tested it in both types of cells and found that mGL392, either alone or in combination with quercetin, significantly reduced the viability of senescent cells.
Most importantly, mGL392 did not affect the viability of non-senescent proliferating cells, an off-target effect that is very common when used with dasatinib alone or in combination with quercetin.
In addition, visualization of senescent and apoptotic cells using immunofluorescence and assessment of apoptosis/necrosis by flow cytometry demonstrated that mGL392 treatment (alone or in combination with quercetin) achieved selective elimination of senescent cells.
Similarly, compared with mGL392, the same concentration of free dasatinib severely impaired cell proliferation, and the elimination of senescent cells was less effective.
Next, the researchers tested mGL392’s anti-aging abilities in an in vitro 3D organoid culture generated from healthy lung specimens.
It found that mGL392 successfully delivered in a 3D environment and significantly reduced senescent cells without affecting proliferating/non-senescent cells.
These data demonstrate the selective and highly effective anti-aging properties of mGL392 in both 2D and 3D environments.
Finally, the researchers tested the anti-aging effects of mGL392 in vivo using a senescent mouse model of melanoma treated with Piperocillin (a CDK4/6 inhibitor).
The results showed that mGL392 administration significantly eliminated senescent cells and associated with increased apoptosis.
Given that mGL392 does not inhibit proliferating B16 melanoma cells, nor does it inhibit tumors in the absence of senescence, and that a significant reduction in tumor size observed in mice treated with piperoxili and mGL392 together, the observed anti-tumor effects of mGL392 can attributed to selective senescent cell clearance.
The research developed a delivery platform to selectively eliminate senescent cells in vitro and in vivo through targeted release of aging scavengers, achieving precise anti-aging efficacy.
It is worth pointing out that the platform can minimize the systemic toxicity of drugs without affecting the clearance of senescent cells.
Reference: https://www.nature.com/articles/s43587-024-00747-4
