Mitochondrial delivery of doxorubicin by triphenylphosphonium-functionalized hyperbranched nanocarriers results in rapid and severe cytotoxicity.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Physical Chemistry, IAMPPNM, NCSR "Demokritos", Patriarchou Gregoriou & Neapoleos, 15310, Ag. Paraskevi, Attiki, Greece, theo@chem.demokritos.gr.
Theodossis A
TA
Theodossiou
Zili
Z
Sideratou
Maria E
ME
Katsarou
Dimitris
D
Tsiourvas
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D006801:Humans; D007097:Imines / Q000737:chemistry; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011095:Polyethylenes / Q000737:chemistry; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D007097:Imines; D009943:Organophosphorus Compounds; D011095:Polyethylenes; C505405:poly(ethylene imine); D004317:Doxorubicin