“…2 B could be attributed to the acetal group, and the disappeared peaks at δ = 5.5–6.5 ppm indicated the successful conjugation of the targeted PAP with an explicit chemical structure. The PTX content in the PAP prodrug was calculated to be 48.1%, which is higher than those of most reported PTX prodrugs [ 31 , 32 ]. Fig.…”
“…2 B could be attributed to the acetal group, and the disappeared peaks at δ = 5.5–6.5 ppm indicated the successful conjugation of the targeted PAP with an explicit chemical structure. The PTX content in the PAP prodrug was calculated to be 48.1%, which is higher than those of most reported PTX prodrugs [ 31 , 32 ]. Fig.…”
“…[94][95][96][97] In a recent study, Zhu's group developed a novel theranostic prodrug 3 by linking paclitaxel with a fluorescence reporter, 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol, through a disulfide linker (Figure 5). 98 Upon activation by GSH in weakly acidic media, theranostic prodrug 3 undergoes dissociation to yield free paclitaxel and a visible fluorescence reporter, enabling visual monitoring of drug release. Cytotoxicity research showed that the prodrug exhibited stronger anticancer activity against Hep G2, MCF-7, and HeLa cells, while showing reduced toxicity to normal cells (293T) compared to the parent drug.…”
Section: Gsh-triggered Prodrugs Based On Cleavage Of Disulfide Linkagesmentioning
The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH‐triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer‐based and organic–inorganic nanomaterial constructs. Although the GSH‐triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple‐targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH‐triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH‐triggered prodrugs in the future. By assessing the pros and cons of current GSH‐triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH‐triggered prodrugs.
“…Innovatively, Kim’s team devised a multifunctional probe, which reacted with the relatively high content of free thiols in cancer cells, resulting in the cleavage of disulfide bond and the release of anticancer drug CPT in 2012 . Subsequently, based on the same theory, many other outstanding works have also been developed for the treatment of tumors. − Thus, the release of drugs through overexpression of GSH in tumor cells provides a very excellent approach for the treatment of cancer. To further improve the therapeutic effect, some subcellular organelles are wonderful treated targets, − since they have a high relationship with a variety of cellular activities and act an extremely major part in manipulating cellular status. − Obviously, the development of molecules that target organelles and control the release of drugs by overexpressing GSH in tumor cells is of great significance for cancer treatment.…”
Cancer is a serious threat to human health, and there is an urgent need to develop new treatment methods to overcome it. Organelle targeting therapy, as a highly effective and less toxic side effect treatment strategy, has great research significance and development prospects. Being an essential organelle, the Golgi apparatus plays a particularly major role in the growth of cancer cells. Acting as an indispensable and highly expressed antioxidant in cancer cells, glutathione (GSH) also contributes greatly during the Golgi oxidative stress. Therefore, it counts for much to track the changes of GSH concentration in Golgi for monitoring the occurrence and development of tumor cells, and exploring Golgi-targeted therapy is also extremely important for effective treatment of cancer. In this work, we designed and synthesized a simple Golgi-targeting fluorescent probe GT-GSH for accurately detecting GSH. The probe GT-GSH reacting with GSH decomposes toxic substances to Golgi, thereby killing cancer cells. At the same time, the ratiometric fluorescent probe can detect the concentration changes of GSH in Golgi stress with high sensitivity and selectivity in living cells. Therefore, such a GSH-responsive fluorescent probe with a Golgi-targeted therapy effect gives a new method for accurate treatment of cancer.
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