Influence of Triphenylphosphonium (TPP) Cation Hydrophobization with Phospholipids on Cellular Toxicity and Mitochondrial Selectivity

Villanueva, Diana Guzman

doi:10.15226/2374-6866/2/1/00121

Cited by 8 publications

(10 citation statements)

References 18 publications

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“…This result is consistent with previously published data 16, 39, 46 . Bielski et al found that conjugating TPP onto poly(amidoamine) (PAMAM) dendrimer nanocarriers increased both cellular internalization and mitochondrial targeting in the human lung adenocarcinoma cell line, A549 16 .…”

Section: Resultssupporting

confidence: 94%

“…Whilst TPP is a desirable agent to include into particulate formulations designed to target mitochondria, excessive TPP accumulation in mitochondria is arguably toxic to cells 45, 46 . Examples of toxic effects include the inhibition of the mitochondrial electron transport chain and inducing mitochondrial proton leakage 45 .…”

Section: Resultsmentioning

confidence: 99%

“…Bielski et al found that conjugating TPP onto poly(amidoamine) (PAMAM) dendrimer nanocarriers increased both cellular internalization and mitochondrial targeting in the human lung adenocarcinoma cell line, A549 16 . Guzman-Villaneuva et al (2015) reported that TPP-liposomes had higher cellular uptake than liposomes without surface-conjugated TPP 46 .…”

Section: Resultsmentioning

confidence: 99%

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Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

Wongrakpanich

Morris

Geary

et al. 2017

International Journal of Pharmaceutics

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An excess of calcium (Ca2+) influx into mitochondria during mitochondrial re-energization is one of the causes of myocardial cell death during ischemic/reperfusion injury. This overload of Ca2+ triggers the mitochondrial permeability transition pore (mPTP) opening which leads to programmed cell death. During the ischemic/reperfusion stage, the activated Ca2+/calmodulin-dependent protein kinase II (CaMKII) enzyme is responsible for Ca2+ influx. To reduce CaMKII-related cell death, sub-micron particles composed of poly(lactic-co-glycolic acid) (PLGA), loaded with a CaMKII inhibitor peptide were fabricated. The CaMKII inhibitor peptide-loaded (CIP) particles were coated with a mitochondria targeting moiety, triphenylphosphonium cation (TPP), which allowed the particles to accumulate and release the peptide inside mitochondria to inhibit CaMKII activity. The fluorescently labeled TPP-CIP were taken up by mitochondria and successfully reduced ROS caused by Isoprenaline (ISO) in a differentiated rat cardiomyocyte-like cell line. When cells were treated with TPP-CIP prior ISO exposure, they maintained mitochondrial membrane potential. The TPP-CIP protected cells from ISO-induced ROS production and decreased mitochondrial membrane potential. Thus, TPP-CIP have the potential to be used in protection against ischemia/reperfusion injury.

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Section: Resultssupporting

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

Wongrakpanich

Morris

Geary

et al. 2017

International Journal of Pharmaceutics

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“…A few known mitochondria‐targeting delivery moieties exhibit cationic and lipophilic properties, and as such are attracted to the negatively charged microenvironment of the mitochondrial matrix. These include, for example, dequalinium (DQA) and triphenylphosphonium (TPP) . TPP conjugated to peptide nucleic acids (PNA) was shown to target mitochondria and suppress mtDNA in cell culture but not in in‐vivo model .…”

Section: Introductionmentioning

confidence: 99%

“…These include, for example, dequalinium (DQA) [30][31][32] and triphenylphosphonium (TPP). [33][34][35] TPP conjugated to peptide nucleic acids (PNA) was shown to target mitochondria and suppress mtDNA in cell culture but not in in-vivo model. 36 Mitochondrial penetrating peptides (MPPs), short peptides consisting of hydrophobic and cationic amino acids, developed by Horton et al were also found to accumulate in the mitochondria of living cells.…”

Section: Introductionmentioning

confidence: 99%

Oligonucleotide loaded polypeptide‐peptide nanoparticles towards mitochondrial‐targeted delivery

Cohen-Erez

Harduf

Rapaport

2019

Polymers for Advanced Techs

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Nanoparticles (NPs) consisting of biodegradable and biocompatible polymers may have the ability to deliver a cargo to specific tissue, cell type, and organelle. Various diseases, which are linked to mitochondrial genome (mtDNA) mutations and have no effective treatments, may be approached by gene therapy strategies. In this study, we adapted the recently developed mitochondria delivering polypeptide‐peptide nanoparticles (PoP‐NPs) system to carry an oligonucleotide cargo to the proximity of the mitochondria. PoP‐NPs are formulated by self‐assembly of the negatively charged polypeptide, poly gamma glutamic acid (γ‐PGA), with an amphiphilic and cationic β‐sheet peptide (PFK). Here, we show that PFK interacts favorably with oligonucleotides and thereby enables the formation of DNA‐loaded PoP‐NPs (DNA‐PoP‐NPs). DNA‐PoP‐NPs could be assembled with different peptide to oligonucleotide (N/P) ratios, and their targeting to the proximity of mitochondria in cell culture could be facilitated through NPs coating with PFK peptide.

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Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

Wang,

Jin,

Xie

et al. 2023

J. Med. Chem.

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Fungal infections present a growing global public health concern, necessitating the development of novel antifungal drugs. However, many potential antifungals, particularly the expelled potential active agents (EPAAs), are often underestimated owing to their limitations in cellular entry or expulsion by efflux pumps. Herein, we identified 68 EPAAs out of 2322 candidates with activity against a Candida albicans efflux pump-deficient strain and no inhibitory activity against the wild-type strain. Using a novel conjugation strategy involving benzamidine (BM) as a mitochondrion-targeting warhead, we successfully converted EPAAs into potent antifungals against various urgent-threat azole-resistantCandida strains. Among the obtained EPAA-BM conjugates, IS-2-BM (11) exhibited excellent antifungal activities and induced negligible drug resistance. Furthermore, IS-2-BM prevented biofilm formation, eradicated mature biofilms, and exhibited excellent therapeutic effects in a murine model of systemic candidiasis. These findings provide a promising strategy for increasing the possibilities of discovering more antifungals.

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Influence of Triphenylphosphonium (TPP) Cation Hydrophobization with Phospholipids on Cellular Toxicity and Mitochondrial Selectivity

Cited by 8 publications

References 18 publications

Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

Surface-modified particles loaded with CaMKII inhibitor protect cardiac cells against mitochondrial injury

Oligonucleotide loaded polypeptide‐peptide nanoparticles towards mitochondrial‐targeted delivery

Benzamidine Conjugation Converts Expelled Potential Active Agents into Antifungals against Drug-Resistant Fungi

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