Development and pharmaceutical evaluation of the anticancer Anthrafuran/Cavitron complex, a prototypic parenteral drug formulation

Helen M Treshalina; Vladimir I Romanenko; Dmitry N Kaluzhny; Michael I Treshalin; Aleksey A Nikitin; Alexander S Tikhomirov; Andrey E Shchekotikhin

doi:10.1016/j.ejps.2017.09.025

Development and pharmaceutical evaluation of the anticancer Anthrafuran/Cavitron complex, a prototypic parenteral drug formulation

Eur J Pharm Sci. 2017 Nov 15:109:631-637. doi: 10.1016/j.ejps.2017.09.025. Epub 2017 Sep 18.

Authors

Helen M Treshalina¹, Vladimir I Romanenko¹, Dmitry N Kaluzhny², Michael I Treshalin³, Aleksey A Nikitin⁴, Alexander S Tikhomirov⁵, Andrey E Shchekotikhin⁶

Affiliations

¹ Federal State Budgetary Scientific Institution "N.N. Blokhin Russian Cancer Research Center" of the Ministry of Health of the Russian Federation, 24 Kashirskoye Shosse, Moscow 115478, Russia.
² Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov Street, Moscow 119991, Russia.
³ Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia.
⁴ National University of Science and Technology "MISIS", 4 Leninsky prospect, Moscow, 119991, Russia; Lomonosov Moscow State University, 1-3 Leninskiye Gory, Moscow GSP-1, 119991, Russia.
⁵ Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia.
⁶ Gause Institute of New Antibiotics, 11 B. Pirogovskaya Street, Moscow 119021, Russia; Mendeleyev University of Chemical Technology, 9 Miusskaya Square, Moscow 125190, Russia. Electronic address: instna@sovintel.ru.

PMID: 28927751
DOI: 10.1016/j.ejps.2017.09.025

Abstract

To improve the water solubility of the anticancer drug candidate LCTA-2034 (A1), we investigated the formation of complexes of this anthrax[2,3-b]furan congener with the solubilizing 2-hydroxypropyl derivative of β-cyclodextrin HP-βCD (Cavitron®). The interaction of A1 with HP-βCD resulted in the inclusion complex A1/HP-βCD in 1:1 stoichiometry. The A1/HP-βCD complex was used to develop a prototype of a lyophilised drug formulation with enhanced (>10-fold) aqueous solubility than A1 and a long-term stability. The use of HP-βCD decreased the acute toxicity of A1 by >30%. The A1/HP-βCD drug formulation as well as A1 in equal doses (5×30mg/kg) to increase the lifespan by up to 140% for mice with i.p. transplanted P388 leukaemia. Furthermore, the A1/HP-βCD formulation demonstrated a significant and reliable antitumor efficacy in a Р388/ADR drug resistant leukaemia and B16/F10 melanoma, proving a perspective of investigations of toxicology, biodistribution and pharmacokinetics.

Keywords: 2-Hydroxypropyl-β-cyclodextrin; Acute toxicity; Anthra[2,3-b]furan; Anticancer activity; Drug formulation.

MeSH terms

2-Hydroxypropyl-beta-cyclodextrin* / chemistry
2-Hydroxypropyl-beta-cyclodextrin* / pharmacology
2-Hydroxypropyl-beta-cyclodextrin* / therapeutic use
2-Hydroxypropyl-beta-cyclodextrin* / toxicity
Animals
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Antineoplastic Agents* / toxicity
Cell Survival / drug effects
Drug Resistance, Neoplasm
Female
Furans* / chemistry
Furans* / pharmacology
Furans* / therapeutic use
Furans* / toxicity
HCT116 Cells
Humans
Lethal Dose 50
Leukemia / drug therapy
Melanoma, Experimental / drug therapy
Mice, Inbred C57BL
Mice, Inbred DBA

Substances

Antineoplastic Agents
Furans
LCTA-2034
2-Hydroxypropyl-beta-cyclodextrin