Mitochondria-targeted cancer therapy based on functional peptides

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Abstract

Mitochondria are critical for tumor growth and metastasis. A number of traditional antitumor drugs have poor water solubility and must penetrate multiple cellular barriers to reach the mitochondria. Because mitochondria have a unique transmembrane potential and an inner membrane with a low permeability, it is difficult for most drugs to enter mitochondria. In recent years, mitochondria-targeted delivery systems that use functional peptides to modify drugs have received increasing attention. Introducing functional peptides can change the original physicochemical properties of drugs and actively target mitochondria. Functional peptide-drug conjugates (PDCs, peptide-drug conjugates) can decompose and release drugs over time or due to certain stimuli in tumors. This preserves the biological activity of the drug while increasing intratumor uptake through the enhanced permeability and retention effect (EPR, the enhanced permeability and retention effect). In this review, we focus on the direction of cancer therapy and review the application of different functional peptides in the mitochondria-targeted tumor treatments reported in recent years.

Graphical abstract

This review focuses on the direction of cancer therapy and mainly summarizes the application of different functional peptides in the mitochondria-targeted tumor treatments reported in recent years.

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Introduction

Mitochondria are subcellular organelles in mammalian cells. They are the energy pumps for cellular adenosine triphosphate (ATP, adenosine triphosphate) production, the main sites for regulating cellular reactive oxygen species (ROS, reactive oxygen species) and redox homeostasis, as well as the centers of intrinsic apoptosis control [1,2]. The abnormalities and dysfunctions of mitochondria lead to a variety of health-threatening diseases, ranging from neurodegenerative diseases [3,4] and cardiovascular diseases [5] to cancers [6]. Most notably, increasing evidence has revealed the profound impacts of mitochondria used for energy production and the biosynthesis of metabolic substrates on cancer growth, proliferation, metastasis, or recurrence [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. To meet the higher metabolic demand due to rapidly proliferating tumor cells, dysregulated and healthy mitochondria typically exhibit several different structures and functions, such as membrane potential, energy production pathway, respiratory rate, and gene mutation [17]. These differences between cancerous and normal mitochondria offer possibilities to achieve effective cancer treatments by selectively killing tumor cells [18]. Therefore, intensive research efforts have been devoted to developing cancer therapies that target mitochondria [6,19,20].

Since the mitochondrial inner membrane is approximately −180 mV, which indicates a high transmembrane potential [21], the use of lipophilic or cationic molecules as mitochondrial targeting agents is widespread. Common molecules are lipophilic cationic triphenylphosphine (TPP, triphenylphosphine) [22], rhodamine 123 [23], and peptides, such as mitochondrial penetrating peptide (MPP, mitochondrial penetrating peptide) [24] and SS (Szeto-Schiller) peptide [25,26]. TPP can reduce the activation energy passing through the biological phospholipid bilayer, thus TPP has the ability to pass through the mitochondrial membrane and aggregate in the mitochondrial matrix [27,28]. Another way to target mitochondria is to use nanoparticles, such as dequalinium micelles (DQAsomes) [29], [30], [31], [32], [33], liposomes [34], [35], [36], inorganic nanoparticles [37], [38], [39], DNA nanostructures [40,41], and polymeric nanomicelles [42], [43], [44], [45], [46]. The most significant difference between DQAsomes and other nanoparticles is that they can actively target mitochondria without other targeting groups. DQAsomes, liposome-like vesicles containing dequalinium chloride, can accumulate in mitochondria, destroy mitochondrial membrane potential, and induce apoptosis or necrosis [47]. However, DQAsomes are rarely used in targeted mitochondrial antitumor therapy due to their low ability for endosomal escape and transfection efficiency [48].

Unfortunately, after insoluble drugs are modified, the drug solubility does not change significantly, and it is difficult for TPP to perform modifications directly. Usually, a backbone group needs to be added for the modification. In addition, TPP is cytotoxic at concentrations higher than 10 µmol/L [48]. Some lipophilic cations have poor water solubility and phototoxicity, which in turn lead to poor circulation in the body [49]. In contrast, peptides with biocompatibility and design variations are more advantageous. These peptides have low immunogenicity and can also mediate precise self-assembly. Functional peptides usually have shorter peptide chains [50], which can be modified on small molecule drugs to form peptide-drug conjugates (PDCs). In addition, peptide-based drug delivery systems have the following advantages: a simple preparation process, good targeting, in vivo degradability, and high absorption in vivo [49]. The systems can change the drug's original physicochemical properties and enhance their biological functions; for example, the time spent in blood circulation can be increased and their therapeutic effects can be enhanced. Some PDCs can also self-assemble to form nanoparticles, fibers, or gels under changes in temperature, pH, or noncovalent interactions. In addition to enhancing tumor tissue penetration and targeting mitochondria in tumor cells [50], these functional PDCs have also been shown to inhibit tumor proliferation and metastasis. The advantages of functional peptides have led researchers to design and synthesize various functional peptides for increasing applications in cancer therapy [51]. The purpose of this review was to examine the application of peptides with different functions in targeting tumor mitochondria for therapeutic purposes.

Section snippets

Mechanism of mitochondrial targeting

Targeting the mitochondria of tumor cells has been found to be a very promising method of inhibiting tumor proliferation and metastasis [52,53]. At present, some anticancer drugs, such as lonidamine, doxorubicin (DOX), and cisplatin, have the potential ability to act on the mitochondria of tumor cells.

The main targets of tumor cell mitochondria include mitochondrial DNA (mtDNA, mitochondrial DNA), voltage-dependent anion channel (VDAC, voltage-dependent anion channel), Bcl-2 anti-apoptotic

Peptides for mitochondrial targeting

Mitochondrial-targeting sequences (MTSs) are usually endogenous peptide sequences consisting of 15–55 amino acids. MTSs vary in size and sequence, but they share the following common feature: the amphiphilic α-helical structure that interacts with negatively charged mitochondrial surfaces and is subsequently internalized by mitochondrial membrane transporters [79]. Using MTSs, proteins synthesized by mitochondrial ribosomes can be delivered to mitochondria. However, MTSs have a poor ability to

Peptides for mitochondrial penetration

MPPs are specific targeting carriers of small molecules localized to the mitochondrial matrix and exhibit improved cellular uptake and mitochondrial membrane penetration. The structure and function of mitochondria in tumor cells are different from those in healthy cells. The mitochondrial membrane potential of tumor cells was higher than that of normal cells [83]. In addition, mitochondria are stimulated by a series of apoptotic signals (e.g., Bax and Bak) in tumor cells, leading to increased

Peptides for mitochondrial destruction

Mitochondrial destroying peptides are a kind of peptide that utilize self-assembly characteristics and combine with nanotargeted ligands to achieve in vivo morphological transformation and ultimately induce cell dysfunction. Mitochondrial destroying peptides can accelerate the formation of nanofibers under special conditions (such as enzymes and photothermal agents) [92], [93], [94], [95], [96]. Due to the increased mitochondrial membrane permeability and potential of tumor cells, the targeted

Peptides for mitochondrial responsiveness

The addition of a tumor-targeting fraction and antifouling segment to drug carriers is an effective strategy to form nanoplatforms for cancer therapy, which can both prolong blood circulation time and enhance the level of drug delivery within tumor cells [105,106]. Since the important characteristics of the tumor microenvironment include the significantly low pH, low oxygen content, high pressure, and dysregulated enzymatic activity, it can deactivate the performance of antifouling segments and

Conclusion and outlook

In this review, we described mitochondria-targeted cancer therapy strategies based on functional peptides and some promising examples of the rational design of drugs or nanoparticles modified by functional peptides in targeting mitochondria for cancer therapy. Currently, the applications of these functional peptide-based targeted mitochondrial drugs for cancer therapy mainly include the delivery of anticancer drugs or nanoparticles to mitochondria, destruction of mitochondria by

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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