Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate

Abstract

We have devised a nanocarrier using “tocopheryl polyethylene glycol succinate (TPGS) conjugated to triphenylphosphonium cation” (TPP-TPGS) for improving the efficacy of doxorubicin hydrochloride (DOX). Triphenylphosphonium cation (TPP) has affinity for an elevated transmembrane potential gradient (mitochondrial), which is usually high in cancer cells. Consequently, when tested in molecular docking and cytotoxicity assays, TPP-TPGS, owing to its structural similarity to mitochondrially directed anticancer compounds of the “tocopheryl succinate” family, interferes specifically in mitochondrial CII enzyme activity, increases intracellular oxidative stress, and induces apoptosis in breast cancer cells. DOX loaded nanocarrier (DTPP-TPGS) constructed using TPP-TPGS was positively charged, spherical in shape, sized below 100 nm, and had its drug content distributed evenly. DTPP-TPGS offers greater intracellular drug delivery due to its rapid endocytosis and subsequent endosomal escape. DTPP-TPGS also efficiently inhibits efflux transporter P glycoprotein (PgP), which, along with greater cell uptake and inherent cytotoxic activity of the construction material (TPP-TPGS), cumulatively results in 3-fold increment in anticancer activity of DOX in resistant breast cancer cells as well as greater induction of necroapoptosis and arrest in all phases of the cell cycle. DTPP-TPGS after intravenous administration in Balb/C mice with breast cancer accumulates preferentially in tumor tissue, which produces significantly greater antitumor activity when compared to DOX solution. Toxicity evaluation was also performed to confirm the safety of this formulation. Overall TPP-TPGS is a promising candidate for delivery of DOX.

Development, Optimization and Evaluation of 2-Methoxy-Estradiol Loaded Nanocarrier for Prostate Cancer

“…Significant (p < 0.05) increase in apoptosis in the blank micelles treatment group might be explained by the apoptotic potential of TPGS. According to the literature, this TPGS in the blank micelles possesses the potential to increase ROS load within the cancer cells, facilitating apoptosis of the cancer cells (Singh et al, 2019). Incubation of prostate cancer cells with all tested samples for a period of 24 h showed a significant increase (p < 0.05) in apoptotic potential when compared to the control cells (2.8 ± 0.2%).…”

“…Thus, the increased ROS within the cancer cells might have increased the oxidative stress of the cells, leading to increased loss of mitochondrial membrane potential. Similarly, TPGS had also been reported to generate ROS within the treated cells (Singh et al, 2019), which ultimately induce apoptosis of the cells. Our results on the significant increase in mitochondrial membrane potential by the treatment of blank micelles might be because of increasing ROS by the action of TPGS in the formulation.…”

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents

“…The surface of nanovehicles has been decorated with TPP (e.g. [55][56][57]; the synthesis of TPP-lipid conjugates has been described by [58]) and peptides (e.g. [59,60]).…”

Development of multifunctional celastrol nanoparticles to enhance antitumor effects by interfering with the function of mitochondria in breast cancer

“…Cela could act on mitochondrial respiratory chain (MRC) complex I and induce cell apoptosis via ROSdependent mitochondrial pathways [9][10][11]. Mitochondria also have signi cant roles in regulating apoptosis, calcium handling, and phospholipid synthesis [12].…”