Research Paper

Pharmaceutical Research

, Volume 30, Issue 11, pp 2832-2842

First online:

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

  • Theodossis A. TheodossiouAffiliated withDepartment of Physical Chemistry, IAMPPNM, NCSR “Demokritos” Email author 
  • , Zili SideratouAffiliated withDepartment of Physical Chemistry, IAMPPNM, NCSR “Demokritos”
  • , Maria E. KatsarouAffiliated withDepartment of Physical Chemistry, IAMPPNM, NCSR “Demokritos”
  • , Dimitris TsiourvasAffiliated withDepartment of Physical Chemistry, IAMPPNM, NCSR “Demokritos”

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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