Cocrystal formation of betulinic acid and ascorbic acid: Synthesis, physico-chemical assessment, antioxidant, and antiproliferative activity

Mirela Nicolov, Roxana M. Ghiulai, Mirela Voicu, Marius Mioc, Adina Octavia Duse, Roxana Roman, Rita Ambrus, Istvan Zupko, Elena Alina Moaca, Dorina E. Coricovac, Claudia Farcas, Roxana Marcela Racoviceanu, Corina Danciu, Cristina Adriana Dehelean, Codruta Soica

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1 Citation (Scopus)

Abstract

Betulinic acid (BA) was demonstrated to be a very promising anticancer agent against various tumor cell lines such as breast, colon, lung, and brain. Despite its strong cytotoxic effect, betulinic acid exhibits low water solubility, feature that is reflected in its poor bioavailability. To overcome these drawbacks, numerous strategies were conducted to improve its physicochemical and pharmacokinetic profile, among which cocrystalization emerged as a promising approach. Thus, our work consisted in obtaining slowly grown cocrystals of BA and ascorbic acid (BA+VitC) in isopropyl alcohol obtained in a hydrothermal experiment. The newly formed cocrystals were characterized by physico-chemical methods such asSEM, DSC, XRPD, and FT-IR spectroscopy demonstrating BA+VitC cocrystal formation while their antioxidant activity revealed an additive antioxidant effect. To investigate the biological effect, BA+VitC cocrystals were tested on HaCat (immortalized human keratinocytes), B164A5 and B16F0 (murine melanoma), MCF7 and MDA-MB-231 (human breast cancer), and HeLa (cervical cancer) cell lines. Results of BA upon the tested tumor cell lines, after co-crystallization with vitamin C, indicated a superior cytotoxic effect with the preservation of a good selectivity index assumably due to an improved BA water solubility and consequently an optimized bioavailability.

Original languageEnglish
Article number92
JournalFrontiers in Chemistry
Volume7
Issue numberFEB
DOIs
Publication statusPublished - Jan 1 2019

Keywords

  • Antioxidant activity
  • Antiproliferative activity
  • Betulinic acid
  • Cocrystal
  • Vitamin C

ASJC Scopus subject areas

  • Chemistry(all)

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    Nicolov, M., Ghiulai, R. M., Voicu, M., Mioc, M., Duse, A. O., Roman, R., Ambrus, R., Zupko, I., Moaca, E. A., Coricovac, D. E., Farcas, C., Racoviceanu, R. M., Danciu, C., Dehelean, C. A., & Soica, C. (2019). Cocrystal formation of betulinic acid and ascorbic acid: Synthesis, physico-chemical assessment, antioxidant, and antiproliferative activity. Frontiers in Chemistry, 7(FEB), [92]. https://doi.org/10.3389/fchem.2019.00092