Abstract
It is a challenge to eradicate tumor cells while sparing normal cells. We used magnetoelectric nanoparticles (MENs) to control drug delivery and release. The physics is due to electric-field interactions (i) between MENs and a drug and (ii) between drug-loaded MENs and cells. MENs distinguish cancer cells from normal cells through the membrane’s electric properties; cancer cells have a significantly smaller threshold field to induce electroporation. In vitro and in vivo studies (nude mice with SKOV-3 xenografts) showed that (i) drug (paclitaxel (PTX)) could be attached to MENs (30-nm CoFe2O4@BaTiO3 nanostructures) through surface functionalization to avoid its premature release, (ii) drug-loaded MENs could be delivered into cancer cells via application of a d.c. field (~100 Oe), and (iii) the drug could be released off MENs on demand via application of an a.c. field (~50 Oe, 100 Hz). The cell lysate content was measured with scanning probe microscopy and spectrophotometry. MENs and control ferromagnetic and polymer nanoparticles conjugated with HER2-neu antibodies, all loaded with PTX were weekly administrated intravenously. Only the mice treated with PTX-loaded MENs (15/200 μg) in a field for three months were completely cured, as confirmed through infrared imaging and post-euthanasia histology studies via energy-dispersive spectroscopy and immunohistochemistry.
Highlights
Administrated nanoparticles have been shown to passively accumulate in a number of tumors because of the enhanced permeability and retention (EPR) effect due to the high leakiness of tumor blood vessels and the lack of a lymphatic system[17,18,19,20]
The proposed mechanism of drug delivery by magnetoelectric nanoparticles (MENs) can be applied to any cancer; for the sake of simplicity, this study has focused on ovarian cancer (OC), which is characteristically metastatic (Stage III) at the time of diagnosis[44,45]
This comprehensive study included (i) in vitro analyses to investigate the underlying physics of the MEN-based mechanism to deliver and release a drug into cancer cells via application of external d.c. and a.c. magnetic fields, respectively, and (ii) in vivo measurements on mice with inhibited immune system bearing SKOV-3 human ovarian carcinoma xenografts to test the hypothesis on animals
Summary
Administrated nanoparticles have been shown to passively accumulate in a number of tumors because of the enhanced permeability and retention (EPR) effect due to the high leakiness of tumor blood vessels and the lack of a lymphatic system[17,18,19,20]. Despite the great potential of the nanoparticle delivery, a significant problem remains to ensure that the drug is not prematurely released in the plasma or interstitial space but is released at an appropriate rate once at the intended site, e.g. into the cancer cell cytoplasm[27] To address this problem, nanoparticles have been formulated to allow for triggering drug release by externally applied temperature[28,29], ultrasound[30,31], intracellular pH32, intracellular enzymes[33,34], or the tumor microenvironment[35]. Using NDD systems to control retention and specific delivery of the drug remains a major open question in cancer treatment This combined in vitro and in vivo study shows how a class of multiferroic nanostructures known as magnetoelectric nanoparticles (MENs) can be used to enable externally controlled high-specificity targeted delivery and release of therapeutic loads on demand. This nanotechnology, especially with the use of PTX, could be straightforwardly extended to breast cancer, lung cancer, and pancreatic cancers, among others
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