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Enhancement Mitochondrial Apoptosis in Breast Cancer Cells by Paclitaxel-Triphenylphosphonium Conjugate in Dna Aptamer Modified Nanoparticles Publisher



Esfandyarimanesh M1 ; Mohammadi A1, 2 ; Atyabi F1, 3 ; Ebrahimi SM4 ; Shahmoradi E5 ; Amini M6 ; Mirzaie ZH1 ; Ghahremani MH7 ; Dinarvand R1, 3
Authors
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Authors Affiliations
  1. 1. Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical, Sciences, Tehran, Iran
  3. 3. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  4. 4. Department of Chemistry, Sari Branch, Islamic Azad University, Sari, Iran
  5. 5. Department of Chemical Engineering, Sharif University of Technology, Tehran, Iran
  6. 6. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  7. 7. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Source: Journal of Drug Delivery Science and Technology Published:2019


Abstract

Mitochondria is a major regulator of inducing tumor apoptosis and it is as a prime target for chemotherapy. Anticancers need to access specific tumor cells and also pass through different barriers such as outer and inner membranes of mitochondria. Targeted accumulation of paclitaxel (PTX) within the mitochondria was achieved by direct conjugation of PTX with triphenylphosphonium (TPP) as a mitochondrial membrane-permeable cation. PTX-TPP prodrug was synthesized by pH-sensitive ester bond between the hydroxyl function of PTX and the carboxylic function of TPP. This ester bond is only cleaved by the mitochondrial aldehyde dehydrogenase. Prodrug was loaded in the albumin nanoparticles by nab-technology. The surface aptamer modification of nanoparticles was done by MUC1 DNA aptamer in order to targeting of tumor cells overexpressing MUC1. The yield of PTX-TPP conjugation was 81% and the particle size of final nanoparticles was 139 nm. The aptamer-modified nanoparticles significantly increased the cellular uptake to 99.9%, and demonstrated good mitochondrial uptake in the confocal fluorescence images leading to apoptosis of MCF-7 breast cancer cells. Early apoptosis and late apoptotic/necrotic phase of cells after 24 h were 26.4% and 25.3%, respectively, compared to 5.27% and 4.74% for free PTX. The targeted nanoparticles exhibited the superior in vitro anticancer efficacy of up to 17.8 fold higher than free PTX after 72 h. This multi-targeting strategy induced the mitochondrial apoptosis to killing tumor cells. © 2019 Elsevier B.V.