Exploring the Potential of Mitochondria-Targeted Drug Delivery for Enhanced Breast Cancer Therapy

Abstract

Breast cancer stands as the utmost prevalent malignancy in women, impacting the epithelial tissue of the breast and often displaying resistance to effective treatment due to its diverse molecular and histological features. Current treatment modalities may exhibit decreasing efficacy over time and can lead to disease progression. The mitochondria, a crucial organelle responsible for cellular metabolism and energy supply, stand highly sensitive to both heat and reactive oxygen species, presenting an assuring target for photodynamic and photothermal therapies (PTTs) in cancer cure. The employment of nanodrug carriers for combination deliveries holds promise in addressing challenges related to drug degradation and off-target toxicity. By circumventing the reticuloendothelial system, nanocarriers bolster the drug's bioavailability at the intended site and ensure controlled codelivery of multiple drugs, thereby maintaining the normal pharmacokinetic features and the regular pharmacodynamic characteristics of different therapeutic mechanisms. The precision and efficacy of this innovative technology have revolutionized drug delivery, substantially enhancing treatment effectiveness. In the pursuit of targeting mitochondrial modifications in cancer cells, various combination therapies such as photodynamic therapy (PDT), PTT, and chemodynamic therapy (CDT) have been explored. These therapies have improved the efficiency of mitochondria-targeted cancer treatment due to their advantageous properties of minimal toxicity, noninvasiveness, reduced drug resistance, and a safer profile. Our review article provides an exhaustive overview of alterations in the mitochondrial environment in BC, their impact on BC development, potential mitochondrial targets for BC treatment, nanotherapeutic approaches for targeting mitochondria, and the limitations of these approaches.

Keywords: breast cancer; immunological properties; mitochondria; nanotechnology.

Figure 1

Mitochondrial alterations in cancer cells. The Warburg effect, which causes increased lactate generation in cancer cells even in the presence of oxygen, is a hallmark of mitochondrial failure. Aside from this, a number of additional changes are noticeable. These include disturbances to the TCA cycle and ETC dynamics. Furthermore, the activation of genes such as NF-κB, NRF2, AP1, and P53, as well as the overexpression of GTPases such as Mfn1/2 and dynamin-related protein 1, contribute to mitochondrial dysfunction. These collective modifications eventually lead to increased reactive oxygen species (ROS) generation, highlighting the complex connection between mitochondrial abnormalities and cancer growth. Furthermore, cancer cell mitochondria show enhanced permeability and morphological changes such as enlargement and fragmentation. Lipophilic cations, liposomes, micelles, and dendrimers discussed in the text lead to increased production of reactive oxygen species (ROS), depletion of mitochondrial DNA, increased permeability of the mitochondrial membrane, activation of Bax, suppression of Bcl-2, release of cytochrome C, and subsequent activation of Caspase 3 and Caspase 9 enzymes, which ultimately results in apoptosis (created in http://BioRender.com).