Mitochondrial Delivery of Doxorubicin by Triphenylphosphonium-Functionalized Hyperbranched Nanocarriers Results in Rapid and Severe Cytotoxicity
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- Theodossiou, T.A., Sideratou, Z., Katsarou, M.E. et al. Pharm Res (2013) 30: 2832. doi:10.1007/s11095-013-1111-7
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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.
KEY WORDScytotoxicity doxorubicin hyperbranched poly(ethylene imine) mitochondrial drug delivery triphenylphosphonium
Adenine nucleotide translocator
Atractyloside potassium salt
Carbonyl cyanide 3-chlorophenylhydrazone
Dynamic light scattering
Enhanced permeability and retention
Electron transport chain
Fetal bovine serum
Nω-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