mp9b00177_si_001.pdf (999.85 kB)
Induction of Mitochondrial Cell Death and Reversal of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium Derivative of Tocopheryl Polyethylene Glycol Succinate
journal contribution
posted on 2019-08-22, 20:48 authored by Yuvraj Singh, K. K. Durga Rao Viswanadham, Vivek K. Pawar, Jayagopal Meher, Arun Kumar Jajoriya, Ankur Omer, Swati Jaiswal, Jayant Dewangan, H. K. Bora, Poonam Singh, Srikanta Kumar Rath, Jawahar Lal, Durga Prasad Mishra, Manish Kumar ChourasiaWe
have devised a nanocarrier using “tocopheryl polyethylene
glycol succinate (TPGS) conjugated to triphenylphosphonium cation”
(TPP-TPGS) for improving the efficacy of doxorubicin hydrochloride
(DOX). Triphenylphosphonium cation (TPP) has affinity for an elevated
transmembrane potential gradient (mitochondrial), which is usually
high in cancer cells. Consequently, when tested in molecular docking
and cytotoxicity assays, TPP-TPGS, owing to its structural similarity
to mitochondrially directed anticancer compounds of the “tocopheryl
succinate” family, interferes specifically in mitochondrial
CII enzyme activity, increases intracellular oxidative stress, and
induces apoptosis in breast cancer cells. DOX loaded nanocarrier (DTPP-TPGS)
constructed using TPP-TPGS was positively charged, spherical in shape,
sized below 100 nm, and had its drug content distributed evenly. DTPP-TPGS
offers greater intracellular drug delivery due to its rapid endocytosis
and subsequent endosomal escape. DTPP-TPGS also efficiently inhibits
efflux transporter P glycoprotein (PgP), which, along with greater
cell uptake and inherent cytotoxic activity of the construction material
(TPP-TPGS), cumulatively results in 3-fold increment in anticancer
activity of DOX in resistant breast cancer cells as well as greater
induction of necroapoptosis and arrest in all phases of the cell cycle.
DTPP-TPGS after intravenous administration in Balb/C mice with breast
cancer accumulates preferentially in tumor tissue, which produces
significantly greater antitumor activity when compared to DOX solution.
Toxicity evaluation was also performed to confirm the safety of this
formulation. Overall TPP-TPGS is a promising candidate for delivery
of DOX.
History
Usage metrics
Categories
Keywords
TPPmitochondrial CII enzyme activityefflux transporter P glycoproteinTriphenylphosphonium cationanticancer activitydrug contentAnticancer Drug ResistanceTocopheryl Polyethylene Glycol Succinateanticancer compoundsDOX solutionMitochondrial Cell Deathantitumor activityintracellular drug deliverytumor tissueTPP-TPGSNanocarriers Composedsuccinateincreases intracellular oxidative stressbreast cancer cellsnanocarriercancer cellsbreast cancerToxicity evaluationDTPP-TPGStocopherylcytotoxicity assaysconstruction materialcell cycleTPGScell uptakedoxorubicin hydrochloride100 nmcytotoxic activity
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC