A NOVEL FAMILY OF MEDICINAL NANOPARTICLES TO PROMOTE

A NOVEL FAMILY OF MEDICINAL NANOPARTICLES TO PROMOTE THE MAGNETIC ISOTOPE EFFECT FOR PHARMACOLOGICAL PURPOSES Dmitry A. Kuznetsov Vladimir 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

THE CREATINE KINASE ACTIVE SITE NANOTOPOLOGY

The rate of ATP formation by mitochondria (A) and by creatine kinase (B) as a function of magnesium isotope intact mitochondria subjected to a selective blockade of oxidative phosphorylation by 1 -methylnicotine amide. A B The yield of ATP is given in mmole/g total protein

ION – RADICAL PAIRS FORMATION (SINGLET – TRIPLET PATH SHIFT) MECHANISM OF THE 25 Mg MAGNETIC ISOTOPE EFFECT EXPRESSED IN A BIOLOGICAL PHOSPHORYLATION PRECESSES (Mt-CK)

THE CK CATALYTIC SITE NANOTOPOLOGY IMPACT ONTO THE REAGENTS ELECTRON DENSITY OVERLAP A combined systemic solution of both Schroedinger and Poissone equations processed

The GPK reaction ion-radical mechanism

A phosphorylation rate expressed as the yield (Y) of -[32 P]ATP produced by 1 mg of pure enzyme per 1 min related to the ATP synthesis rate (Y 0) directed by enzyme sample with a natural abundance of Mg 2+ isotopes as a function of 25 Mg content in CK active sites.

Buckminsterfullerene(C 60)-2 -(butadiene-1 -yl)-tetra(o- -aminobutyryl-o-phtalyl)porphyrin PORPHYLLERENE – MC 16

PMC 16 CATIONITE PROPERTIES AND THE NANOCLUSTERS FORMATION AS A FUNCTION OF p. H 14. 8 nm 10. 2 nm 6. 4 nm 4. 7 nm 3. 2 nm 1. 15 nm p. H Blue arrow shows the iron-dextrane sphere exclusion limit , portion of the total PMC 16 magnesium

THE EFFECT OF A PMC 16 – TARGETED DELIVERY OF Mg 2+ ON THE DOXORUBICIN (DXR) PRE – SUPPRESSED ATP PRODUCTION IN RAT MYOCARDIUM 0. 8 DL 50 DXR, i. v. , 6 hrs → PMC 16, i. v. , 6 hrs

CK Relative Activity SYNERGISM OF THE MITOCHONDRIAL MATRIX CK ACTIVITY, MAGNESIUM CATIONS INFLUX AND THE FREE PROTONS EXCESS DEGREE Mg 2 + Inf lux ss Free xce ns E o Prot The isolated rat myocardium mitochondria tested. Yellow / Red stands for the spinless / spin Mg isotopes ratio.

SYNERGISM OF THE ATP YIELD, OXYGEN CONSUMPTION AND THE Mg 2+ INFLUX IN THE PERFUSED ISOLATED RABBIT HEART MUSCLE TISSUE A ATP yield, Y/Yo B O 2 O Con sum ptio n 2+ Mg lux Inf A – Zero spin magnesium test 2 Con sum ptio n 2+ Mg lux Inf B – Magnetic magnesium test

ELECTRON TRANSMITTING MICROPHOTOGRAMS OF THE RAT MYOCARDIOCYTIC PERINUCLEAR AREAS A C B D A, C – PMC 16 related hypoxia preventing effect B – Inhalation oxygen deficiency hypoxia model D – Intact myocardium

PMC 16 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-6 A) images C, d – Confocal scanning microscopy

PMC 16 nanoclusters immobilized on acetyl cellulose membrane a – LCM, p. H 7. 00 b – LCM, p. H 8. 40 c – AFM, p. H 8. 80

A HIGHLY SELECTIVE TRAGETING OF PMC 16 NANOPARTICELS TOWARDS THE RAT HEART MUSCLE IN A COURSE OF THE LONG – TERM ADMINISTRATION OF AN EXTRA LOW DRUG DOSAGE

NOTE: DXR, 20 mg/kg/24 hrs, i. v. : MNA, 10 mg/kg/24 hrs, i. v. :

CONCLUSIONS PORPHYRINE ADDUCTS OF FULLERENE C 60, A NEW FAMILY OF MEDICINAL NANOPARTICLES TO MEET THE FOLLOWING EXPECTATIONS: • Tissue-selective targeted delivery of 25 Mg 2+ paramagnetics • • • to the porphyrin-signaling cell compartments in myocardium and, to a lesser degree, lymphocytes The 25 Mg 2+-related magnetic isotope effect to promote a local and fast, jump-up increase of ATP production, even in the tissue oxygen deplete of any sort Smart nanoparticles behavior while in Mt-membrane, i. e. a gradual 25 Mg 2+ release that occurs exclusively in response to the tissue hypoxia-caused metabolic acidosis Low toxic, safe, efficient and completely eliminable (C 60 clearing / porphyrin metabolizing) agents, all suitable for either short or long term administration schemes