Nanoparticles Consisting of Tocopheryl Succinate Are a Novel Drug-Delivery System with Multifaceted Antitumor Activity

Abstract

Tumor heterogeneity hampers the clinical efficacy of cancer chemotherapy. Therefore, it is necessary to develop a multifaceted, rational treatment strategy with the potential to modulate overall tumor heterogeneity. Since combination therapy using several drugs has been shown to have enhanced therapeutic effects compared with monotherapy, combining agents with different antitumor effects would be a multifaceted form of therapy to overcome tumor heterogeneity. Therefore, the development of effective drug-delivery system (DDS) carriers for combination therapy is required. The ideal DDS carrier for combination therapy should itself have antitumor activity in addition to the ability to deliver drugs to tumors. α-Tocopheryl succinate (TS), a succinic acid ester of α-tocopherol, has attracted attention as a unique antitumor agent, and TS itself can form nanoparticles. In this review, we introduce nanoparticles consisting of TS as a novel DDS carrier with multifaceted antitumor effects for combination therapy.

Oxidative stress and the unfulfilled promises of antioxidant agents

“…Together with these plant derivatives, a variety of different antioxidants are available for clinical purposes. These include endogenous molecules, such as α-tocopherol, β-carotene, glutathione, ascorbic acid, adenosine, lipoic acid, coenzyme Q, lactoferrin, as well as synthetic antioxidants, such as thiols, ebselen (selenium-based peroxide scavenger) [ 5 ], idebenone (coenzyme Q-analogue) and the more recently developed mitoQ (mitochondrial-targeted ubiquinone) [ 6 ], or α-tocopheryl-succinate nanoparticles [ 7 ]. Notably, several cardioprotective drugs, such as probucol and carvediol, or neuroprotective drugs, such as edaravone, are potent and effective antioxidant against the overload of ROS upon ischemia/reperfusion [ 8 ].…”

Intraperitoneal administration of nanoparticles containing tocopheryl succinate prevents peritoneal dissemination

“…α‐Tocopheryl succinate (TS), a succinic acid ester of α‐tocopherol (α‐T), is a redox‐silent analog of α‐T 30 . Although physiological actions of α‐tocopherol and its analogs are based on their antioxidative effects, 30 TS exerts multifaceted anticancer effects such as the induction of cancer cell‐specific apoptosis and inhibition of tumor angiogenesis and multidrug‐resistant protein 30 .…”

“… 30 Because esterase activity of healthy cells is higher than that of cancer cells, TS is easily hydrolyzed to α‐T, a silent agent with anticancer effects, leading to mitigation of undesirable side effects. 30 Alternatively, TS with both hydrophilic and hydrophobic moieties is easily vesiculated, while nanoparticles consisting only of TS undergo structural changes and disassemble in the presence of divalent cations and serum in vivo . 31 We have previously developed nanoparticles (TS‐NP) containing TS and egg phosphatidylcholine (EPC) to improve particle stability in vivo .…”

“…α-Tocopheryl succinate (TS), a succinic acid ester of α-tocopherol (α-T), is a redox-silent analog of α-T. 30 Although physiological actions of α-tocopherol and its analogs are based on their antioxidative effects, 30 TS exerts multifaceted anticancer effects such as the induction of cancer cell-specific apoptosis and inhibition of tumor angiogenesis and multidrug-resistant protein. 30 Because esterase activity of healthy cells is higher than that of cancer cells, TS is easily hydrolyzed to α-T, a silent agent with anticancer effects, leading to mitigation of undesirable side effects. 30 Alternatively, TS with both hydrophilic and hydrophobic moieties is easily vesiculated, while nanoparticles consisting only of TS undergo structural changes and disassemble in the presence of divalent cations and serum in vivo.…”