Targeted Therapeutics Delivery by Exploiting Biophysical Properties of Senescent Cells

Abstract

Cellular senescence refers to a state of irreversible arrest of cell proliferation in response to various forms of cellular stress. It is known that the accumulation of senescent cells is a hallmark of aging, and mounting evidence has shown that the chronic accumulation of senescent cells is a significant contributor to various deleterious age-related pathologies. To limit the detrimental impacts of cellular senescence, there has been growing interest in targeted delivery of therapeutics to senescent cells to treat age-related pathologies and promote healthy aging. Two popular strategies include the elimination of senescent cells using senolytic drugs, and rejuvenation of senescent cells. To that end, it is integral that the delivery of senolytics, senomorphics or rejuvenating biomolecules to senescent cells are highly selective to enhance delivery efficacy and safety. However, there is little understanding of how senescence-associated biophysical changes such as cellular size and stiffness can be exploited for targeted therapeutics delivery. In this review, the biomolecular and biophysical markers of senescence along with senescence models and emerging therapeutics are first described. This review then focuses on how biophysical properties can be exploited for targeted therapeutics delivery, using approaches like nanoparticles, electroporation, sonoporation, photoporation and high aspect-ratio nanostructures to senescent cells.

Multimodal multiphoton and vibrational microscopy reveals early therapy-induced senescence in human tumors: a non-invasive tool to prevent the risk of cancer relapse

“…Such TIS hallmarks, revealed at an unprecedented early stage via non-invasive multimodal NLO microscopy, feature high statistically significance. These results are in agreement with senescence markers previously reported via standard invasive and/or destructive techniques 3 , not suited for any direct usage on unperturbed cells in translational research.…”

Noninvasive morpho-molecular imaging reveals early therapy-induced senescence in human cancer cells

“…Overall, our findings demonstrate notable lipid accumulation in TIS human cancer cells with a quantitative measure through noninvasive NLO SRS imaging. These results align with highlights of the up-regulation of lipid processing and metabolism in TIS cells via standard and invasive techniques, such as colorimetric assays (e.g., Oil Red O), which rely on label-related signals, and Western blot gene expression analysis, which implies sample destruction ( 47 ). Flor et al .…”

“…Overall, our findings demonstrate notable lipid accumulation in TIS human cancer cells with a quantitative measure through noninvasive NLO SRS imaging. These results align with highlights of the up-regulation of lipid processing and metabolism in TIS cells via standard and invasive techniques, such as colorimetric assays (e.g., Oil Red O), which rely on label-related signals, and Western blot gene expression analysis, which implies sample destruction (47). Flor et al (10) proved via a combination of validated assays that proteins and pathways involved in lipid biosynthesis, binding, import, and storage are prominent in human TIS cancer cells treated with etoposide, doxorubicin, and camptothecin chemotherapeutic agents, leading to an overall accumulation of lipids.…”

Mechano-responsive hydrogel for direct stem cell manufacturing to therapy

“…Interestingly, evidence is emerging that the immune response to dead MSCs contributes to therapeutic efficacy [ [19] , [20] , [21] , [22] ]. Unfortunately, with conventional systemic injection of cells, it is not possible to control and optimize for the best ratio of live to dead MSCs which is key to exploiting the immune system for tissue regeneration [ 23 ]. Out of existing manufacturing methods, only the 3D biomaterial system can improve MSC delivery [ 18 ].…”