Folate-Targeted PEGylated Magnetoliposomes for Hyperthermia-Mediated Controlled Release of Doxorubicin

Emílio R Cintra; Tacio G Hayasaki; Ailton A Sousa-Junior; Artur C G Silva; Marize C Valadares; Andris F Bakuzis; Sebastião A Mendanha; Eliana M Lima

doi:10.3389/fphar.2022.854430

Folate-Targeted PEGylated Magnetoliposomes for Hyperthermia-Mediated Controlled Release of Doxorubicin

Front Pharmacol. 2022 Mar 21:13:854430. doi: 10.3389/fphar.2022.854430. eCollection 2022.

Authors

Affiliations

¹ FarmaTec-Laboratory of Pharmaceutical Technology, School of Pharmacy, Federal University of Goias, Goiania, Brazil.
² Toxin-Laboratory of Education and Research in In Vitro Toxicology, School of Pharmacy, Federal University of Goias, Goiania, Brazil.
³ Physics Institute, Federal University of Goias, Goiania, Brazil.
⁴ CNanoMed-Nanomedicine Integrated Research Center, Federal University of Goias, Goiania, Brazil.

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent commonly used for the treatment of solid tumors. However, the cardiotoxicity associated with its prolonged use prevents further adherence and therapeutic efficacy. By encapsulating DOX within a PEGylated liposome, Doxil^® considerably decreased DOX cardiotoxicity. By using thermally sensitive lysolipids in its bilayer composition, ThermoDox^® implemented a heat-induced controlled release of DOX. However, both ThermoDox^® and Doxil^® rely on their passive retention in tumors, depending on their half-lives in blood. Moreover, ThermoDox^® ordinarily depend on invasive radiofrequency-generating metallic probes for local heating. In this study, we prepare, characterize, and evaluate the antitumoral capabilities of DOX-loaded folate-targeted PEGylated magnetoliposomes (DFPML). Unlike ThermoDox^®, DOX delivery via DFPML is mediated by the heat released through dynamic hysteresis losses from magnetothermal converting systems composed by MnFe₂O₄ nanoparticles (NPs) under AC magnetic field excitation-a non-invasive technique designated magnetic hyperthermia (MHT). Moreover, DFPML dismisses the use of thermally sensitive lysolipids, allowing the use of simpler and cheaper alternative lipids. MnFe₂O₄ NPs and DFPML are fully characterized in terms of their size, morphology, polydispersion, magnetic, and magnetothermal properties. About 50% of the DOX load is released from DFPML after 30 min under MHT conditions. Being folate-targeted, in vitro DFPML antitumoral activity is higher (IC₅₀ ≈ 1 μg/ml) for folate receptor-overexpressing B16F10 murine melanoma cells, compared to MCF7 human breast adenocarcinoma cells (IC₅₀ ≈ 4 μg/ml). Taken together, our results indicate that DFPML are strong candidates for folate-targeted anticancer therapies based on DOX controlled release.

Keywords: B16F10; MCF7; doxorubicin; folic acid; magnetic hyperthermia; magnetoliposomes.