Triphenylphosphine-Based Mitochondrial Targeting Nanocarriers: Advancing Cancer Therapy

Abstract

Numerous chemotherapeutic drugs are commercially available for cancer treatment; however, their efficacy is often compromised by diminishing therapeutic effectiveness and unpredictable adverse effects. The lack of specific targeting limits their optimal therapeutic potential. Mitochondria are the primary sites of cellular energy production and play a critical role in cell survival and death. Furthermore, numerous studies have found an apparent association between mitochondrial metabolism and carcinogenesis and progression. Therefore, significant attention has been directed toward nanocarriers specifically designed for mitochondrial delivery, aiming to enhance the precision of chemotherapeutic agent transport to these critical organelles. Among these, triphenylphosphonium has emerged as a prominent mitochondrial targeting agent due to its superior targeting capabilities. This approach not only reduces the required drug dosage but also minimizes adverse effects on healthy tissues. This review provides a concise analysis of nanotechnology's contributions to cancer therapy, emphasizing its potential for targeting at both cellular and sub-cellular levels. Additionally, it delves into mitochondrial targeting, with a particular focus on nanocarriers engineered for efficient mitochondrial drug delivery. Moreover, it focuses on strategies employed by researchers to introduce TPP in nanocarrier systems for mitochondrial delivery and concludes by addressing challenges associated with TPP including hemolytic activity and how researchers mitigate this issue.

Keywords: cancer; mitochondrial targeting; nanomedicine; nanoparticles; triphenylphosphine.

Graphical abstract

Figure 1

Mitochondria-targeted cancer therapies enabled by nanoplatforms including chemotherapy, photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), sonodynamic therapy (SDT), radiodynamic therapy (RDT), and combined immunotherapy, reproduced from Gao Y, Tong H, Li J, et al. Mitochondria-targeted nanomedicine for enhanced efficacy of cancer therapy. Front Bioeng Biotechnol. 2021;9:720508. Copyright © 2021 Gao, Tong, Li, Li, Huang, Shi and Xia., licensed under CC BY 4.0.

Figure 2

Schematic illustrating mitochondria as a primary driver and therapeutic target of cancer. The figure depicts the chaotic development of cell death events. The respiratory activities of complexes I, III, and IV cause proton translocation across the inner mitochondrial membrane, resulting in the production of ATP from ADP and Pi. Quinone oxidoreductase reduces coenzyme quinone (Q) after oxidizing the mitochondrial electron transport chain. Reduced Q produces cytochrome C (by complex III), which catalyzes the reduction of molecular oxygen to water (via complex IV). The formation of reactive oxygen species (ROS) by complex I, together with the accumulation of calcium ions, increases the opening of the mitochondrial permeability transition pore (MPTP), leading to programmed cell death, reproduced from Tabish TA, Hamblin MR. Mitochondria-targeted nanoparticles (mitoNANO): an emerging therapeutic shortcut for cancer. Biomater Biosyst. 2021;3:100023. copyright 2021, Elsevier.

Figure 3

Important distinguishing features of mitochondria of cancer cells from mitochondria of normal cells, reproduced from Mani S, Swargiary G, Tyagi S, et al. Nanotherapeutic approaches to target mitochondria in cancer. Life Sci. 2021;281:119773., copyright 2021, Elsevier.

Figure 4

TPP conjugated substances are uptaken by cells via plasma and mitochondria membrane potentials. Created in BioRender. Gowda b.h., J. (2025) https://BioRender.com/ qxll1ii.

Figure 5

PDs-TPP (PTX) synthesis, the mechanism of selective PTX release, and mitochondrial targeting in cancer cells are shown schematically. Image reproduced from Kim SG, Robby AI, Lee BC, Lee G, Park SY. Mitochondria-targeted ROS- and GSH-responsive diselenide-crosslinked polymer dots for programmable paclitaxel release. J Ind Eng Chem. 2021;99:98–106. Copyright (2021), with permission from Elsevier.

Figure 6

TPP-conjugated-ZnCuO NPs (ZNP) and IR780-loaded polymer-lipid hybrid NPs (TPP-Z-I-PNPs), which target mitochondria, are shown schematically. Image reproduced from Ruttala HB, Ramasamy T, Ruttala RRT, et al. Mitochondria-targeting multi-metallic ZnCuO nanoparticles and IR780 for efficient photodynamic and photothermal cancer treatments. J Mater Sci Technol. 2021;86:139–150, Copyright (2021), with permission from Elsevier.

Figure 7

(A) TPP-Che6 synthetic scheme. (B) Schematic representation of combination chemo-sonodynamic therapy (chemo-SDT) employing biocompatible extracellular vesicles (EVs) containing pro-oxidant piperlongumine (PL) and mitochondria-targeting TPP-Che6. The release of TPP-Che6 and PL from the EVs was activated by ultrasonic (US) irradiation after EV (TPP-Che6/PL) was internalized into breast cancer cells by endocytosis. Under US irradiation, the released TPP-Che6 effectively builds up in the mitochondria and produces reactive oxygen species (ROS). The ROS causes mitochondrial damage, which leads to apoptosis. Through the excessive production of intracellular ROS caused by the released PL, mitochondria-targeted sonodynamic cancer therapy in conjunction with chemotherapy is made possible. Image reproduced from Nguyen Cao TG, Truong Hoang Q, Hong EJ, et al. Mitochondria-targeting sonosensitizer-loaded extracellular vesicles for chemo-sonodynamic therapy. J Control Release. 2023;354:651–663, Copyright (2023), with permission from Elsevier.