Methotrexate-Lactoferrin Targeted Exemestane Cubosomes for Synergistic Breast Cancer Therapy

Sarah Mokhtar; Sherine N Khattab; Kadria A Elkhodairy; Mohamed Teleb; Adnan A Bekhit; Ahmed O Elzoghby; Marwa A Sallam

doi:10.3389/fchem.2022.847573

Methotrexate-Lactoferrin Targeted Exemestane Cubosomes for Synergistic Breast Cancer Therapy

Front Chem. 2022 Mar 22:10:847573. doi: 10.3389/fchem.2022.847573. eCollection 2022.

Authors

Sarah Mokhtar^{1

2}, Sherine N Khattab³, Kadria A Elkhodairy^{1

2}, Mohamed Teleb^{1

4}, Adnan A Bekhit^{1

4

5}, Ahmed O Elzoghby^{1

2}, Marwa A Sallam²

Affiliations

¹ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
² Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
³ Chemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
⁵ Pharmacy Program, Allied Health Department, College of Health and Sport Sciences, University of Bahrain, Al-Manamah, Bahrain.

Abstract

While the treatment regimen of certain types of breast cancer involves a combination of hormonal therapy and chemotherapy, the outcomes are limited due to the difference in the pharmacokinetics of both treatment agents that hinders their simultaneous and selective delivery to the cancer cells. Herein, we report a hybrid carrier system for the simultaneous targeted delivery of aromatase inhibitor exemestane (EXE) and methotrexate (MTX). EXE was physically loaded within liquid crystalline nanoparticles (LCNPs), while MTX was chemically conjugated to lactoferrin (Lf) by carbodiimide reaction. The anionic EXE-loaded LCNPs were then coated by the cationic MTX-Lf conjugate via electrostatic interactions. The Lf-targeted dual drug-loaded LCNPs exhibited a particle size of 143.6 ± 3.24 nm with a polydispersity index of 0.180. It showed excellent drug loading with an EXE encapsulation efficiency of 95% and an MTX conjugation efficiency of 33.33%. EXE and MTX showed synergistic effect against the MCF-7 breast cancer cell line with a combination index (CI) of 0.342. Furthermore, the Lf-targeted dual drug-loaded LCNPs demonstrated superior synergistic cytotoxic activity with a combination index (CI) of 0.242 and a dose reduction index (DRI) of 34.14 and 4.7 for EXE and MTX, respectively. Cellular uptake studies demonstrated higher cellular uptake of Lf-targeted LCNPs into MCF-7 cancer cells than non-targeted LCNPs after 4 and 24 h. Collectively, the targeted dual drug-loaded LCNPs are a promising candidate offering combinational hormonal therapy/chemotherapy for breast cancer.

Keywords: breast cancer; cubosomes; exemestane; lactoferrin; methotrexate.