Poly(2-oxazoline)-magnetite NanoFerrogels: Magnetic field responsive theranostic platform for cancer drug delivery and imaging.

Combining diagnosis and treatment approaches in one entity is the goal of theranostics for cancer therapy. Magnetic nanoparticles have been extensively used as contrast agents for nuclear magnetic resonance imaging as well as drug carriers and remote actuation agents. Poly(2-oxazoline)-based polymeric micelles, which have been shown to efficiently solubilize hydrophobic drugs and drug combinations, have high loading capacity (above 40% w/w) for paclitaxel. In this study, we report the development of novel theranostic system, NanoFerrogels, which is designed to capitalize on the magnetic nanoparticle properties as imaging agents and the poly(2-oxazoline)-based micelles as drug loading compartment. We developed six formulations with magnetic nanoparticle content of 0.3%-12% (w/w), with the z-average sizes of 85-130 nm and ξ-potential of 2.7-28.3 mV. The release profiles of paclitaxel from NanoFerrogels were notably dependent on the degree of dopamine grafting on poly(2-oxazoline)-based micelles. Paclitaxel loaded NanoFerrogels showed efficacy against three breast cancer lines which was comparable to free paclitaxel. They also showed improved tumor and lymph node accumulation and signal reduction in vivo (2.7% in tumor; 8.5% in lymph node) compared to clinically approved imaging agent ferumoxytol (FERAHEME®) 24 h after administration. NanoFerrogels responded to super-low frequency alternating current magnetic field (50 kA m-1, 50 Hz) which accelerated drug release from paclitaxel-loaded NanoFerrogels or caused death of cells loaded with NanoFerrogels. These proof-of-concept experiments demonstrate that NanoFerrogels have potential as remotely actuated theranostic platform for cancer diagnosis and treatment.

Correction to "Luteinizing Hormone Releasing Hormone-Targeted Cisplatin-Loaded Magnetite Nanoclusters for Simultaneous MR Imaging and Chemotherapy of Ovarian Cancer".

[This corrects the article PMC10317193.].

Magnetic liposome design for drug release systems responsive to super-low frequency alternating current magnetic field (AC MF).

HYPOTHESIS: Magnetic liposomes are shown to release the entrapped dye once modulated by low frequency AC MF. The mechanism and effectiveness of MF application should depend on lipid composition, magnetic nanoparticles (MNPs) properties, temperature and field parameters. EXPERIMENTS: The study was performed using liposomes of various lipid composition and embedded hydrophobic MNPs. The liposomes structural changes were studied by the transmission electron microscopy (TEM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and the leakage was monitored by the fluorescent dye release. FINDINGS: Magnetic liposomes exposure to the AC MF resulted in the clustering of the MNPs in the membranes and disruption of the lipid packaging. Addition of cholesterol diminished the dye release from the saturated lipid-based liposomes. Replacement of the saturated lipid for unsaturated one also decreased the dye release. The dye release depended on the strength, but not the frequency of the field. Thus, the oscillating motion of MNPs in AC MF ruptures the gel phase membranes of saturated lipids. As the temperature increases the disruption also increases. In the liquid crystalline membranes formed by unsaturated lipids the deformations and defects created by mechanical motion of the MNPs are more likely to heal and results in decreased release.

Remote Actuation of Magnetic Nanoparticles For Cancer Cell Selective Treatment Through Cytoskeletal Disruption.

Motion of micron and sub-micron size magnetic particles in alternating magnetic fields can activate mechanosensitive cellular functions or physically destruct cancer cells. However, such effects are usually observed with relatively large magnetic particles (>250 nm) that would be difficult if at all possible to deliver to remote sites in the body to treat disease. Here we show a completely new mechanism of selective toxicity of superparamagnetic nanoparticles (SMNP) of 7 to 8 nm in diameter to cancer cells. These particles are coated by block copolymers, which facilitates their entry into the cells and clustering in the lysosomes, where they are then magneto-mechanically actuated by remotely applied alternating current (AC) magnetic fields of very low frequency (50 Hz). Such fields and treatments are safe for surrounding tissues but produce cytoskeletal disruption and subsequent death of cancer cells while leaving healthy cells intact.

Luteinizing Hormone Releasing Hormone-Targeted Cisplatin-Loaded Magnetite Nanoclusters for Simultaneous MR Imaging and Chemotherapy of Ovarian Cancer.

Given the superior soft tissue contrasts obtained by MRI and the long residence times of magnetic nanoparticles (MNPs) in soft tissues, MNP-based theranostic systems are being developed for simultaneous imaging and treatment. However, development of such theranostic nanoformulations presents significant challenges of balancing the therapeutic and diagnostic functionalities in order to achieve optimum effect from both. Here we developed a simple theranostic nanoformulation based on magnetic nanoclusters (MNCs) stabilized by a bisphosphonate-modified poly(glutamic acid)-b-(ethylene glycol) block copolymer and complexed with cisplatin. The MNCs were decorated with luteinizing hormone releasing hormone (LHRH) to target LHRH receptors (LHRHr) overexpressed in ovarian cancer cells. The targeted MNCs significantly improved the uptake of the drug in cancer cells and decreased its IC50 compared to the nontargeted formulations. Also, the enhanced LHRHr-mediated uptake of the targeted MNCs resulted in enhancement in the T2-weighted negative contrast in cellular phantom gels. Taken together, the LHRH-conjugated MNCs show good potential as ovarian cancer theranostics.

VEGF-targeted magnetic nanoparticles for MRI visualization of brain tumor.

This work is focused on synthesis and characterization of targeted magnetic nanoparticles as magnetic resonance imaging (МRI) agents for in vivo visualization of gliomas. Ferric oxide (Fe3O4) cores were synthesized by thermal decomposition and coated with bovine serum albumin (BSA) to form nanoparticles with Deff of 53±9nm. The BSA was further cross-linked to improve colloidal stability. Monoclonal antibodies against vascular endothelial growth factor (mAbVEGF) were covalently conjugated to BSA through a polyethyleneglycol linker. Here we demonstrate that 1) BSA coated nanoparticles are stable and non-toxic to different cells at concentration up to 2.5mg/mL; 2) conjugation of monoclonal antibodies to nanoparticles promotes their binding to VEGF-positive glioma С6 cells in vitro; 3) targeted nanoparticles are effective in MRI visualization of the intracranial glioma. Thus, mAbVEGF-targeted BSA-coated magnetic nanoparticles are promising MRI contrast agents for glioma visualization. FROM THE CLINICAL EDITOR: This work focuses on synthesis and characterization of targeted magnetic nanoparticles as magnetic resonance imaging (МRI) agents for in vivo visualization of gliomas. The authors utilize the fact that high-grade gliomas have extensive areas of necrosis and hypoxia, which results in increased secretion of angiogenesis vascular endothelial growth factor (VEGF). Monoclonal antibodies against vascular endothelial growth factor (mAbVEGF) were covalently conjugated to crosslinked BSA coated ferric oxide (Fe3O4) nanoparticles. The results show that these targeted nanoparticles are effective in MRI visualization of the intracranial glioma and may provide a new and promising contrast agent.

Formulation design facilitates magnetic nanoparticle delivery to diseased cells and tissues.

Magnetic nanoparticles (MNPs) accumulate at disease sites with the aid of magnetic fields; biodegradable MNPs can be designed to facilitate drug delivery, influence disease diagnostics, facilitate tissue regeneration and permit protein purification. Because of their limited toxicity, MNPs are widely used in theranostics, simultaneously facilitating diagnostics and therapeutics. To realize therapeutic end points, iron oxide nanoparticle cores (5-30 nm) are encapsulated in a biocompatible polymer shell with drug cargos. Although limited, the toxic potential of MNPs parallels magnetite composition, along with shape, size and surface chemistry. Clearance is hastened by the reticuloendothelial system. To surmount translational barriers, the crystal structure, particle surface and magnetic properties of MNPs need to be optimized. With this in mind, we provide a comprehensive evaluation of advancements in MNP synthesis, functionalization and design, with an eye towards bench-to-bedside translation.