Dietary Antioxidant-Constructed Nanodrugs Can High-Efficiently Kill Cancer Cells while Protecting Noncancer Cells

Abstract

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (R)-(+)-lipoic acid (LA), we herein develop a nanodrug VC@cLAV featuring the above function. After entering cells, cLAV dissociates into LA and DHLA (dihydrolipoic acid, reduced form of LA) and releases VC and DHA (dehydroascorbate, oxidized form of VC). In cancer cells, the two redox pairs recycle each other and dramatically promote the intracellular reactive oxygen species production to kill cancer cells at low doses comparable to cytotoxic drugs. Oppositely in noncancer cells, the LA/DHLA and VC/DHA pairs exert anti-oxidant action to actively protect the organism by preventing the normal cells from oxidative stress and repairing cells suffering from oxidative stress. When compared with the first-line cytotoxic drug, VC@cLAV displayed superior therapeutic outcomes yet without side effects in diverse tumor models including patient-derived xenograft (PDX). This drug with efficient cancer cell killing and noncancer cell protection represents a new cancer therapy.

Nanodrug constructed using dietary antioxidants for immunotherapy of metastatic tumors

“…13 As we reported earlier, the VC@cLAV was obtained by physically entrapping VC in cLAV driven by the VC concentration gradient between the solution outside and the aqueous core in cLAV, and the loading content was 62.5% (see Methods for details). 44 The mechanism of VC@cLAV in high cytotoxicity involves the amplification of oxidative stress caused by recycling between the redox couples of LA/DHLA and VC/DHA in cancer cells. 44 We thus first verified whether it could also amplify the oxidative stress in 4T1 cells.…”

“…Afterward, the solution was extracted with CH 2 Cl 2 (3 Â 10 mL), neutralized with 1.0 M HCl solution, and dialyzed against deionized water for 48 h (Spectra/Pore, MWCO 2000) to obtain cLAV as the pale solution. 44,45…”

“…After 12 h incubation under constant mild agitation in the sink at 4 1C, the solutions were neutralized by 1.0 M HCl solution and dialyzed against deionized water for 48 h (Spectra/Pore, MWCO 2000) to obtain the VC@cLAV as a pale solution. 44 In vitro cytotoxicity assay-MTT…”

“…44 The mechanism of VC@cLAV in high cytotoxicity involves the amplification of oxidative stress caused by recycling between the redox couples of LA/DHLA and VC/DHA in cancer cells. 44 We thus first verified whether it could also amplify the oxidative stress in 4T1 cells. Briefly, 4T1 cells were incubated with VC, cLAV, or VC@cLAV for 6 h, and then the intracellular ROS was evaluated using confocal laser scanning microscopy (CLSM) with DCFH-DA as a probe, which could be converted into highly fluorescent 2 0 ,7 0 -dichlorofluorescein (DCF) under intracellular oxidative stress.…”

“…[37][38][39][40] Recently, we developed a dietary antioxidant-only constructed nano-drug-crosslinked (R)-(+)-lipoic acid vesicles loaded with vitamin C (VC@cLAV). 44 In tumor cells, the nano-drug would dissociate into LA in the presence of glutathione (GSH) and/or thioredoxin reductase (TrxR) and dihydrolipoic acid (DHLA, a reduced form of LA) and release VC and dehydroascorbate (DHA, oxidized form of VC). In cancer cells, the two redox pairs would recycle each other and dramatically promote intracellular ROS production to induce apoptosis of tumor cells at low doses comparable to those of cytotoxic drugs.…”