Biotin receptor-targeting nanogels loaded with methotrexate for enhanced antitumor efficacy in triple-negative breast cancer in vitro and in vivo models

Abstract

High-dose methotrexate (MTX) chemotherapeutic applications confront drug specificity and pharmacokinetic challenges, which can be overcome by utilizing targeted drug delivery systems. In the present study, biotin-PEG conjugated nanogels of carboxymethyl polyethyleneimine (Biotin-PEG-CMPEI) were developed for active targeted delivery of MTX in triple negative breast cancer (TNBC). TEM and DLS analyses revealed uniform, discrete, and spherical particles with a mean hydrodynamic diameter of about 100 nm and ζ-potential of + 15 mV (pH = 7.4). Biotin-PEG-CMPEI nanogels exhibited a zero-order MTX release kinetics at pH = 7.5 and a swelling-controlled release at pH = 5.5. In 4 T1 cells treated with the MTX-loaded Biotin-PEG-CMPEI, the IC₅₀ was reduced by about 10 folds compared to the free drug, while the unloaded nanogels showed no significant toxicity. In the model mice, the group treated with the MTX-loaded Biotin-PEG-CMPEI had a lower tumor volume and mortality rate animal model when compared to free drug. Additionally, histopathological analyses showed that the group treated with the MTX-loaded nanogels had less lung metastasis and glomerular damage caused by MTX. Overall, the MTX-loaded Biotin-PEG-CMPEI targeted directly against overexpressed biotin receptors in TNBC have been shown to improve the MTX safety and therapeutic efficacy.

Keywords: Allograft animal model; Biotin; Methotrexate; Nanogels; Targeted delivery; Triple negative breast cancer.