Abstract
In this study, poly(isobutylene-alt-maleic anhydride) (PMA)-coated spinel ferrite (MFe2O4, where M = Fe, Co, Ni, or Zn) nanoparticles (NPs) were developed as carriers of the anticancer drugs doxorubicin (DOX) and methotrexate (MTX). Physical characterizations confirmed the formation of pure cubic structures (14–22 nm) with magnetic properties. Drug-loaded NPs exhibited tumor specificity with significantly higher (p < 0.005) drug release in an acidic environment (pH 5.5). The nanoparticles were highly colloidal (zeta potential = −35 to −26 mV) in deionized water, phosphate buffer saline (PBS), and sodium borate buffer (SBB). They showed elevated and dose-dependent cytotoxicity in vitro compared to free drug controls. The IC50 values ranged from 0.81 to 3.97 μg/mL for HepG2 and HT144 cells, whereas IC50 values for normal lymphocytes were 10 to 35 times higher (18.35–43.04 µg/mL). Cobalt ferrite (CFO) and zinc ferrite (ZFO) NPs were highly genotoxic (p < 0.05) in cancer cell lines. The nanoparticles caused cytotoxicity via oxidative stress, causing DNA damage and activation of p53-mediated cell cycle arrest (significantly elevated expression, p < 0.005, majorly G1 and G2/M arrest) and apoptosis. Cytotoxicity testing in 3D spheroids showed significant (p < 0.05) reduction in spheroid diameter and up to 74 ± 8.9% of cell death after two weeks. In addition, they also inhibited multidrug resistance (MDR) pump activity in both cell lines suggesting effectivity in MDR cancers. Among the tested MFe2O4 NPs, CFO nanocarriers were the most favorable for targeted cancer therapy due to excellent magnetic, colloidal, cytotoxic, and biocompatible aspects. However, detailed mechanistic, in vivo cytotoxicity, and magnetic-field-assisted studies are required to fully exploit these nanocarriers in therapeutic applications.
Highlights
Cancer is the second leading cause of death and, as such, it is a global health concern [1]
The selected area electron diffraction (SAED) images explain the position of the crystalline system upon diffraction
Distinct bands of 180 bp were visualized on a 2% agarose gel, which indicates shearing of DNA as a result of apoptosis in treated cells. These findings indicated that drugloaded NPs cause cytotoxicity in cancer cells via oxidative stress leading to apoptosis and DNA fragmentation
Summary
Cancer is the second leading cause of death and, as such, it is a global health concern [1]. It is caused by uncontrolled cell proliferation, reduced cell death rate, or both [2]. Conventional treatment strategies for cancer, including surgery, radiotherapy, and chemotherapy, lack the ability to selectively target neoplastic tissue, which results in systemic toxicity [3]. For these reasons, the focus of the field was transferred to nanomedicine which enables targeted therapy and reduces side effects of conventional therapeutic agents [4]. The targeting of specific tumor tissue is achieved by an increased biodistribution process known as enhanced permeability and retention (EPR) effect [7]
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