Pharmaceutical Research

, Volume 30, Issue 11, pp 2832–2842 | Cite as

Mitochondrial Delivery of Doxorubicin by Triphenylphosphonium-Functionalized Hyperbranched Nanocarriers Results in Rapid and Severe Cytotoxicity

  • Theodossis A. Theodossiou
  • Zili Sideratou
  • Maria E. Katsarou
  • Dimitris Tsiourvas
Research Paper



To develop a novel hyperbranched polymer-based nanocarrier for efficient drug delivery to cell mitochondria. Also to study for the first time the cytotoxic effect of doxorubicin via mitochondria-specific delivery system.


We introduced alkyltriphenylphosphonium groups (TPP) to a poly(ethylene imine) hyperbranched polymer (PEI). We harnessed the hydrophobic assembly of these alkylTPP functionalized PEI molecules into ~100 nm diameter nanoparticles (PEI-TPP) and further encapsulated the chemotherapy agent doxorubicin (DOX), to produce the mitotropic nanoparticles PEI-TPP-DOX.


By administering PEI-TPP-DOX to human prostate carcinoma cells DU145, we found that: (i) PEI-TPP-DOX specifically localized at cell mitochondria as revealed by the inherent DOX fluorescence; (ii) in contrast to the slow apoptotic cell death incurred by DOX over the period of days at micromolar concentrations, PEI-TPP-DOX triggered rapid and severe cytotoxicity within few hours of incubation and at submicromolar incubation concentrations. This cytotoxicity was mainly found to be of a necrotic nature, not precluding autophagy related death pathways to a smaller extent.


We have elaborated a versatile mitotropic nanocarrier; furthermore, using this platform, we have developed a mitochondrial-doxorubicin formulation with exceptional cytocidal properties, even in nanomolar concentrations.


cytotoxicity doxorubicin hyperbranched poly(ethylene imine) mitochondrial drug delivery triphenylphosphonium 



Adenine nucleotide translocator


Antimycin A


Atractyloside potassium salt






Carbonyl cyanide 3-chlorophenylhydrazone


Cyclosporine A




Dynamic light scattering




Ethidium bromide


Enhanced permeability and retention


Electron transport chain


Fetal bovine serum






Lactate dehydrogenase


-nitro-L-arginine methyl ester hydrochloride




Mitochondrial permeability transition pore


Thiazolyl blue tetrazolium bromide




β-Nicotinamide adenine dinucleotide reduced disodium salt




Phosphate buffer saline


Hyperbranched poly(ethylene imine)




Reactive oxygen species




Ruthenium red




Trypan blue


Triphenylphosphonium cation




Uric acid



Supplementary material

11095_2013_1111_MOESM1_ESM.doc (1.9 mb)
ESM 1(DOC 1914 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Theodossis A. Theodossiou
    • 1
  • Zili Sideratou
    • 1
  • Maria E. Katsarou
    • 1
  • Dimitris Tsiourvas
    • 1
  1. 1.Department of Physical Chemistry, IAMPPNMNCSR “Demokritos”Ag. ParaskeviGreece

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