Д.А.Кузнецев. Университет им.Н.И.Пирогова(РГМУ)
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Transcript of Д.А.Кузнецев. Университет им.Н.И.Пирогова(РГМУ)
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A NOVEL FAMILY OF MEDICINAL NANOPARTICLES TO PROMOTE THE MAGNETIC ISOTOPE EFFECT FOR PHARMACOLOGICAL PURPOSES
Dmitry A. KuznetsovVladimir P. Chekhonin
N.N. Semenov Institute for Chemical Physics, Russian Academy of Sciences, Moscow, Russia
Department of Medicinal Nanobiotechnology, N.I. Pirogov Russian State Medical University, Moscow, Russia
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THE CREATINE KINASE ACTIVE SITE NANOTOPOLOGY
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1.0
25
24 26
The rate of ATP formation by mitochondria (A) and by creatine kinase (B) as a function of magnesium isotope
The yield of ATP is given in mmole/g total protein
intact mitochondria
mitochondria subjected to a selective blockade of oxidative phosphorylation by 1-methylnicotine amide.
A B
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ION – RADICAL PAIRS FORMATION
(SINGLET – TRIPLET PATH SHIFT)
MECHANISM
OF THE 25Mg MAGNETIC ISOTOPE EFFECT
EXPRESSED
IN A BIOLOGICAL PHOSPHORYLATION
PRECESSES
(Mt-CK)
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THE CK CATALYTIC SITE NANOTOPOLOGY IMPACT ONTO THE CK CATALYTIC SITE NANOTOPOLOGY IMPACT ONTO THE REAGENTS ELECTRON DENSITY OVERLAPTHE REAGENTS ELECTRON DENSITY OVERLAP
A combined systemic solution of both Schroedinger and Poissone equations processed
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The GPK reaction ion-radical mechanism
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A phosphorylation rate expressed as the yield (Y) of -[32P]ATP produced by 1 mg of pure enzyme per 1 min related to the ATP synthesis rate (Y0) directed by enzyme sample with a natural
abundance of Mg2+ isotopes as a function of 25Mg content in CK active sites.
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Buckminsterfullerene(C60)-2-(butadiene-1-yl)--tetra(o--aminobutyryl-o-phtalyl)porphyrin
PORPHYLLERENE – MC16
N
N
N
N
Fe
COO- -OOC
-OOCCOO-
COO-
COO-
-OOC
-OOC
CH2
CHH2N
CH2
-OOC
H2C
HC NH2
CH2
COO-
CH2
HC NH2
CH2
COO-
CH2
CHH2N
CH2
-OOC
Mg2+
Mg2+2
2
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PMC16 CATIONITE PROPERTIES AND THE NANOCLUSTERS FORMATION PMC16 CATIONITE PROPERTIES AND THE NANOCLUSTERS FORMATION AS A FUNCTION OF pHAS A FUNCTION OF pH
Blue arrow shows the iron-dextrane sphere exclusion limit
1.15nm
14.8nm
6.4nm
10.2nm
3.2nm4.7nm
pH
, portion of the total PMC16 magnesium
Blue arrow shows the iron-dextrane sphere exclusion limit
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THE EFFECT OF A PMC16 – TARGETED DELIVERY OF THE EFFECT OF A PMC16 – TARGETED DELIVERY OF MgMg2+2+ ON THE DOXORUBICIN (DXR) PRE – SUPPRESSED ON THE DOXORUBICIN (DXR) PRE – SUPPRESSED ATP PRODUCTION IN RAT MYOCARDIUMATP PRODUCTION IN RAT MYOCARDIUM
0.8 DL50 DXR, i.v., 6 hrs → PMC16, i.v., 6 hrs
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CK
Rela
tive A
ctiv
ity
Mg 2+InfluxFree Protons Excess
SYNERGISM OF THE MITOCHONDRIAL MATRIX CK ACTIVITY, MAGNESIUM CATIONS INFLUX AND THE
FREE PROTONS EXCESS DEGREE
The isolated rat myocardium mitochondria tested.
Yellow / Red stands for the spinless / spin Mg isotopes ratio.
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SYNERGISM OF THE ATP YIELD, OXYGEN CONSUMPTION AND THE Mg2+ INFLUX IN THE PERFUSED ISOLATED
RABBIT HEART MUSCLE TISSUEA
TP y
ield
, Y/Y
o
O2
ConsumptionMg2+ Influx
ATP y
ield
, Y/Y
o
O2
ConsumptionMg2+ Influx
A B
A – Zero spin magnesium test B – Magnetic magnesium test
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A
D
B
C
ELECTRON TRANSMITTING MICROPHOTOGRAMS OF THE RAT MYOCARDIOCYTIC PERINUCLEAR AREAS
A, C – PMC16 related hypoxia preventing effect
B – Inhalation oxygen deficiency hypoxia model
D – Intact myocardium
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PMC16 CLUSTER POSITIONING INSIDE THE RAT MYOCARDIOCYTIC MITOCHONDRIAL MEMBRANE IN
METABOLIC ACIDOSIS (a, c) AND IN NORMAL CONDITIONS (b, d)
a, b – Laser contrast (Nanofinder-S-6A) images
C, d – Confocal scanning microscopy
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PMC16 nanoclusters immobilized on acetyl cellulose membrane
a – LCM, pH 7.00b – LCM, pH 8.40c – AFM, pH 8.80
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A HIGHLY SELECTIVE TRAGETING OF PMC16 NANOPARTICELS A HIGHLY SELECTIVE TRAGETING OF PMC16 NANOPARTICELS TOWARDS THE RAT HEART MUSCLE IN A COURSE OF THE LONG – TERM TOWARDS THE RAT HEART MUSCLE IN A COURSE OF THE LONG – TERM ADMINISTRATION OF AN EXTRA LOW DRUG DOSAGEADMINISTRATION OF AN EXTRA LOW DRUG DOSAGE
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NOTE: DXR, 20 mg/kg/24 hrs, i.v.:
MNA, 10 mg/kg/24 hrs, i.v.:
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CONCLUSIONSCONCLUSIONSPORPHYRINE ADDUCTS OF FULLERENE CPORPHYRINE ADDUCTS OF FULLERENE C6060, , A NEW FAMILY OF MEDICINAL NANOPARTICLES A NEW FAMILY OF MEDICINAL NANOPARTICLES TO MEET THE FOLLOWING EXPECTATIONS:TO MEET THE FOLLOWING EXPECTATIONS:
• Tissue-selective targeted delivery of Tissue-selective targeted delivery of 2525MgMg2+2+ paramagnetics paramagnetics to the porphyrin-signaling cell compartments in to the porphyrin-signaling cell compartments in myocardiummyocardium and, to a lesser degree, and, to a lesser degree, lymphocyteslymphocytes
• The The 2525MgMg2+2+-related magnetic isotope effect to promote a -related magnetic isotope effect to promote a local and fast, jump-up increase of ATP production, even in local and fast, jump-up increase of ATP production, even in the tissue oxygen deplete of any sortthe tissue oxygen deplete of any sort
• Smart nanoparticles behavior while in Mt-membrane, Smart nanoparticles behavior while in Mt-membrane, i.e.i.e. a a gradual gradual 2525MgMg2+ 2+ release that occurs exclusively in response release that occurs exclusively in response to the tissue hypoxia-caused metabolic acidosisto the tissue hypoxia-caused metabolic acidosis
• Low toxic, safe, efficient and completely eliminable (CLow toxic, safe, efficient and completely eliminable (C6060--clearing / porphyrin metabolizing) agents, all suitable for clearing / porphyrin metabolizing) agents, all suitable for either short or long term administration schemeseither short or long term administration schemes