Green self-assembled lactoferrin carboxymethyl cellulose nanogels for synergistic chemo/herbal breast cancer therapy

Mai A Atallah; Marwa A Sallam; Mona A Abdelmoneem; Mohamed Teleb; Kadria A Elkhodairy; Adnan A Bekhit; Asmaa F Khafaga; Ahmed E Noreldin; Ahmed O Elzoghby; Sherine N Khattab

doi:10.1016/j.colsurfb.2022.112657

Green self-assembled lactoferrin carboxymethyl cellulose nanogels for synergistic chemo/herbal breast cancer therapy

Colloids Surf B Biointerfaces. 2022 Sep:217:112657. doi: 10.1016/j.colsurfb.2022.112657. Epub 2022 Jun 24.

Authors

Affiliations

¹ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
² Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
³ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Pharmaceutics, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt.
⁴ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
⁵ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Pharmacy Program, Allied Health Department, College of Health and Sport Sciences, University of Bahrain, P.O. Box 32038, Kingdom of Bahrain.
⁶ Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, Egypt.
⁷ Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhur University, Damanhur, Egypt.
⁸ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt. Electronic address: ahmed_elzoghby@alexu.edu.eg.
⁹ Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21321, Egypt. Electronic address: sherinekhattab@alexu.edu.eg.

PMID: 35803031
DOI: 10.1016/j.colsurfb.2022.112657

Abstract

The current treatment protocols for breast cancer have shifted from single agent therapies to combinatorial approaches that offer synergistic efficacies and reduced side effects. Self-assembled nanogels comprising natural polysaccharides and functional proteins provide an intelligent platform for the targeted co-delivery of therapeutic molecules. Herein, we report the fabrication of self-assembled nanogels utilizing hydrophilic biocompatible proteins, lactoferrin (Lf), and polysaccharide carboxy methyl cellulose (CMC), for the combined delivery of the antimetabolite pemetrexed (PMT) and the herbal polyphenol honokiol (HK). PMT was conjugated to LF via an amide bond. The conjugate was then electrostatically assembled into CMC under optimized conditions to form nanogels (Lf-CMC NGs). An inclusion complex of HK with hydroxypropyl-β-cyclodextrin was then encapsulated in the prepared Lf-CMC NGs with an entrapment efficiency of 66.67%. The dual drug-loaded cross-linked Lf-CMC NGs exhibited a particle size of 193.4 nm and zeta potential of - 34.5 mV and showed a sustained release profile for both drugs. PMT/HK-loaded Lf-CMC NGs were successfully taken up by MDA-MB-231 breast cancer cells and demonstrated superior in vitro cytotoxicity, as elucidated by a low combination index value (CI=0.17) and a higher dose reduction index (DRI) compared to those of the free drugs. An in vivo antitumor study using an Ehrlich ascites tumor (EAT) mouse model revealed the robust efficacy of PMT/HK-loaded Lf-CMC NGs in inhibiting tumor growth, which was ascribed to the reduced expression level of VEGF-1, elevated protein expression level of caspase-3, and suppressed Ki-67 protein level in the tumor tissue (P ˂0.05). In conclusion, our green fabricated self-assembled dual-loaded nanogels offer a promising biocompatible strategy for targeted combinatorial breast cancer therapy.

Keywords: Carboxymethyl cellulose; Honokiol; Hydroxypropyl β-cyclodextrin inclusion complex; Lactoferrin; Pemetrexed.

MeSH terms

Animals
Breast Neoplasms / drug therapy
Carboxymethylcellulose Sodium*
Drug Carriers / chemistry
Green Chemistry Technology
Lactoferrin / chemistry
Mice
Nanogels*
Particle Size
Pemetrexed
Phytotherapy*

Substances

Drug Carriers
Nanogels
Pemetrexed
Lactoferrin
Carboxymethylcellulose Sodium