Nanoarchitectures of Folate-Functionalized Highly Monodispersed Ce–Tb Doped Core@Shell Nanorods for Targeted and Enhanced Chemotherapy of Human Cervical and Triple-Negative Breast Carcinoma

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Abstract
The high incidence, aggressiveness, and chemo-refractory nature of cervical and triple-negative breast cancers (TNBC) warrant the development of targeted chemotherapy strategies for improving their therapeutic outcomes. The present study reports the design and preparation of highly monodispersed, biocompatible, and hemocompatible Ce–Tb-doped core@shell NaGdF4:20Ce@NaGdF4:5Tb (CS) nanorods prepared by a thermolysis process with an aim to enhance drug accumulation and site-specific chemotherapy in two aggressive drug-resistant human cancer cell lines, namely, cervical and TNBC. The nanorods were coated with silica to impart aqueous dispersibility, followed by covalent conjugation with folic acid, enabling their application in the site-specific delivery of anticancer drug, doxorubicin hydrochloride (DOX). MTT assay suggested a dose- and time-dependent enhancement in DOX-induced cytotoxicity of DOX-loaded CS (CS@Si-NH2–FA-DOX) in folate receptor overexpressing cervical (KB) and TNBC (MDA MB-231) cells in comparison to normal human mammary epithelial cells (MCF 10A) and human lung fibroblast cells (WI26VA4). IC50 values of CS@Si-NH2–FA-DOX were found to be ∼10–40-fold lower in KB and MDA MB-231 compared to normal cell lines, corroborating highly cancer-specific chemotherapeutic efficacy. The enhanced anticancer efficacy of CS@Si-NH2–FA-DOX was further supported by ∼3–5-fold higher intracellular uptake in both KB and MDA MB-231 cells in comparison to free DOX, as investigated by flow cytometry analysis. Pertinently, confocal studies validated that CS@Si-NH2–FA-DOX are able to deliver DOX to its intracellular target, i.e., nucleus, resulting in a significant enhancement of cytotoxicity as compared to free DOX. Furthermore, pretreatment of KB cells with pan caspase inhibitor, Z-VAD-fmk, showed significantly higher (∼2-fold) rescue after treatment with CS@Si-NH2–FA-DOX as compared to free DOX, suggesting a higher induction of apoptotic cell death by CS@Si-NH2–FA-DOX. Thus, CS@Si-NH2–FA-DOX nanorods are promising to be used as a nanodelivery vehicle for targeted chemotherapy and also for circumventing the chemo-resistance associated with cervical and TNBC cancers.

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