Induction of Mitochondrial Cell Death and Reversal
of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium
Derivative of Tocopheryl Polyethylene Glycol Succinate
Posted on 2019-08-22 - 20:48
We
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.
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Singh, Yuvraj; Viswanadham, K. K. Durga Rao; Pawar, Vivek K.; Meher, Jayagopal; Jajoriya, Arun Kumar; Omer, Ankur; et al. (2019). Induction of Mitochondrial Cell Death and Reversal
of Anticancer Drug Resistance via Nanocarriers Composed of a Triphenylphosphonium
Derivative of Tocopheryl Polyethylene Glycol Succinate. ACS Publications. Collection. https://doi.org/10.1021/acs.molpharmaceut.9b00177
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AUTHORS (14)
YS
Yuvraj Singh
KV
K. K. Durga Rao Viswanadham
VP
Vivek K. Pawar
JM
Jayagopal Meher
AJ
Arun Kumar Jajoriya
AO
Ankur Omer
SJ
Swati Jaiswal
JD
Jayant Dewangan
HB
H. K. Bora
PS
Poonam Singh
SR
Srikanta Kumar Rath
JL
Jawahar Lal
DM
Durga Prasad Mishra
MC
Manish Kumar Chourasia
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