Abstract
Advances in nanomedicine have seen the adaptation of nanoparticles (NPs) for subcellular delivery for enhanced therapeutic impact and reduced side effects. The pivotal role of the mitochondria in apoptosis and their potential as a target in cancers enables selective induction of cancer cell death. In this study, we examined the mitochondrial targeted delivery of betulinic acid (BA) by the mitochondriotropic TPP+-functionalized epigallocatechin gallate (EGCG)-capped gold NPs (AuNPs), comparing the impact of polyethylene glycol (PEG) and poly-L-lysine-graft-polyethylene glycol (PLL-g-PEG) copolymer on delivery efficacy. This included the assessment of their cellular uptake, mitochondrial localization and efficacy as therapeutic delivery platforms for BA in the human Caco-2, HeLa and MCF-7 cancer cell lines. These mitochondrial-targeted nanocomplexes demonstrated significant inhibition of cancer cell growth, with targeted nanocomplexes recording IC50 values in the range of 3.12–13.2 µM compared to that of the free BA (9.74–36.31 µM) in vitro, demonstrating the merit of mitochondrial targeting. Their mechanisms of action implicated high amplitude mitochondrial depolarization, caspases 3/7 activation, with an associated arrest at the G0/G1 phase of the cell cycle. This nano-delivery system is a potentially viable platform for mitochondrial-targeted delivery of BA and highlights mitochondrial targeting as an option in cancer therapy.
Highlights
The continuous rise in cancer-associated mortality against a backdrop of advances in drug discovery highlights the prevailing challenges of existing therapeutic interventions for cancer
Considering the potential inherent in the preferential targeting of therapeutics to intracellular sites of action to bring about improved bioavailability and therapeutic efficacy at a lower dose with tolerable side effects, we have studied the capacity of epigallocatechin gallate (EGCG)-capped, laminin receptor-avid AuNPs for mitochondrial-targeted delivery of betulinic acid (BA) in selected cancer cells in vitro
These vibrations, represented as band shifts at characteristic wavelengths in the IR spectrum are applied in the analysis of organic compounds, especially in the identification of functional groups [30]
Summary
The continuous rise in cancer-associated mortality against a backdrop of advances in drug discovery highlights the prevailing challenges of existing therapeutic interventions for cancer. The application of this concept has seen the development of nano-delivery systems engineered to target and accumulate in cancerous tissues. Their application significantly enhances drug pharmacokinetics, minimizes side effects, and improves the drug’s therapeutic index [2,4]. Recent reports revealed that nanoformulations targeted to organelles such as the mitochondria, endosome, lysosome, nucleus, ribosome and the Golgi apparatus, demonstrated efficacy in the delivery of genes, proteins and drugs, highlighting their potential application in clinical scenarios [6,7]. The central role of mitochondria in bioenergetics and apoptosis signaling has made them a focus of clinical research, and a therapeutic target for diseases in recent years. Apoptosis is a well-regulated physiological process, certain extracellular agents have been shown to modulate mitochondria function and induce apoptosis, presenting an in-road to preferentially targeting the organelle in related disease conditions [8]
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