Chimeric nanoparticles for targeting mitochondria in cancer cells.

Aman Bajpai,Shalini Pandey,Nakshi Nayan Desai,Sudipta Basu,Bhaskar Datta,Chinmayee Shukla

doi:10.1039/d1na00644d

Aman Bajpai, Shalini Pandey + Show 4 more

Open Access

https://doi.org/10.1039/d1na00644d

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Abstract

Mitochondrial dysfunction is implicated in myriad diseases, including cancer. Subsequently, targeting mitochondrial DNA (mt-DNA) in cancer cells has emerged as an unorthodox strategy for anti-cancer therapy. However, approaches targeting only one component of the mitochondrial “central dogma” can be evaded by cancer cells through various mechanisms. To address this, herein, we have engineered mitochondria-targeting cholesterol-based chimeric nanoparticles (mt-CNPs) consisting of cisplatin, camptothecin, and tigecycline, which can simultaneously impair mt-DNA, mitochondrial topoisomerase I (mt-Top1), and mitochondrial ribosomes. mt-CNPs were characterized as being positively charged, spherical in shape, and 187 nm in diameter. Confocal microscopy confirmed that mt-CNPs efficiently localized into the mitochondria of A549 lung cancer cells within 6 h, followed by mitochondrial morphology damage and the subsequent generation of reactive oxygen species (ROS). mt-CNPs showed remarkable cancer-cell killing abilities compared to free-drug combinations in A549 (lung), HeLa (cervical), and MCF7 (breast) cancer cells. These mitochondria-targeting lipidic chimeric nanoparticles could be explored further to impair multiple targets in mitochondria, helping researchers to gain an understanding of mitochondrial translational and transcriptional machinery and to develop new strategies for cancer therapy.

Highlights

Confocal microscopy confirmed that mitochondria-targeting cholesterol-based chimeric nanoparticles (mt-CNPs) efficiently localized into the mitochondria of A549 lung cancer cells within 6 h, followed by mitochondrial morphology damage and the subsequent generation of reactive oxygen species (ROS). mt-CNPs showed remarkable cancer-cell killing abilities compared to free-drug combinations in A549, HeLa, and MCF7 cancer cells
Cholesterol was chosen for the development of mitochondriatargeting chimeric nanoparticles due to its biocompatibility and as it is one of the major components of cell membranes
We have synthesized a cholesterol–cisplatin conjugate (4) and cholesterol–triphenylphosphine conjugate (5) using previously reported methods and these were characterized via standard spectroscopic techniques.[27,28]

Summary

Introduction

Mitochondria have gained immense recognition in disease-related biomedical research due to their role in numerous signi cant biological phenomena, including metabolism, biosynthesis, cell survival/death programming, signalling pathways, and so on.[1,2,3,4] targeting and perturbing mitochondrial functionality in a diseased state like cancer has emerged as a novel therapeutic strategy.[5,6,7] Fascinatingly, mitochondria contain their own set of DNA, RNA, and ribosomes for synthesizing OXPHOS-associated proteins through conserved mitochondrial transcription and translational pathways.[8,9,10] impairing mitochondrial “central dogma” in relation to the routing of small molecules has been found to help improve therapeutic outcomes and overcome drug resistance.[11,12] the selective targeting of mitochondria in the cellular milieu of cancer cells is still a dauntingDue to their vast potential as drug delivery vehicles, nanomaterials have been explored as a way to deliver DNA-damaging drugs into the mitochondria of cancer cells for improved therapeutic efficacy.[17,18,19,20,21,22] mitochondrial machinery for the repair of DNA damage can evade the effects of nanoparticlemediated mitochondrial DNA damage.[23,24] As a result, it is crucial to impair multiple mitochondrial transcriptional and translational components simultaneously to obtain enhanced effects. Confocal microscopy confirmed that mt-CNPs efficiently localized into the mitochondria of A549 lung cancer cells within 6 h, followed by mitochondrial morphology damage and the subsequent generation of reactive oxygen species (ROS). Paper positively charged mt-CNPs successfully homed in on the mitochondria of A549 lung cancer cells within 3 h, leading to mitochondrial morphology disruption followed by the generation of reactive oxygen species (ROS).

Results

Conclusion