In Vitro Setup for Determination of Nanoparticle-Mediated Magnetic Cell and Drug Accumulation in Tumor Spheroids under Flow Conditions

Abstract

Superparamagnetic iron oxide nanoparticles (SPIONs) are used in nanomedicine as transporter systems for therapeutic cargos, or to magnetize cells to make them magnetically guidable. In cancer treatment, the site-directed delivery of chemotherapeutics or immune effector cells to the tumor can increase the therapeutic efficacy in the target region, and simultaneously reduce toxic side-effects in the rest of the body. To enable the transfer of new methods, such as the nanoparticle-mediated transport from bench to bedside, suitable experimental setups must be developed. In vivo, the SPIONs or SPION-loaded cells must be applied into the blood stream, to finally reach the tumor: consequently, targeting and treatment efficacy should be analyzed under conditions which are as close to in vivo as possible. Here, we established an in vitro method, including tumor spheroids placed in a chamber system under the influence of a magnetic field, and adapted to a peristaltic pump, to mimic the blood flow. This enabled us to analyze the magnetic capture and antitumor effects of magnetically targeted mitoxantrone and immune cells under dynamic conditions. We showed that the magnetic nanoparticle-mediated accumulation increased the anti-tumor effects, and reduced the unspecific distribution of both mitoxantrone and cells. Especially for nanomedical research, investigation of the site-specific targeting of particles, cells or drugs under circulation is important. We conclude that our in vitro setup improves the screening process of nanomedical candidates for cancer treatment.

An in silico model of the capturing of magnetic nanoparticles in tumour spheroids in the presence of flow

“…The smaller the magnet, the harder it is to capture nanoparticles at the top of the domain. The maximum magnetic flux density is ♣B♣ max = µ 0 ♣H♣ max = 300 mT, which is of the same order of magnitude as the magnetic flux density in our experimental setup (Behr et al, 2022). The maximum magnetic force in the domain is of the order of pN, which is larger than the values estimated in Pálovics and Rencz (2022) but on a similar order of magnitude.…”

“…Motivated by a recent experimental test setup (Behr et al, 2022), we presented a computational model for the magnetic capture of nanoparticles in a flow chamber with a tumour spheroid. Our continuum approach for the transport of the nanoparticles based on the Smoluchowski advection-diffusion equation includes the advection by the fluid flow and the magnetophoresis by the external magnetic field.…”

“…The experimental setup is sketched in Fig. 1a and described in detail in Behr et al (2022). Therefore, we only give a brief summary below.…”

“…To study the magnetic capturing of nanoparticles in tumour spheroids in the presence of flow, we use a simplified in vitro test setup: a tumour spheroid is placed in a flow chamber with a magnet underneath to capture the nanoparticles, as presented by Behr et al (2022). We retain the essential characteristics and transport barriers of the tumour microenvironment while reducing the complexity of the in vivo scenario to a controlled and monitorable setup.…”

Tumor Models and Drug Targeting In Vitro—Where Are We Today? Where Do We Go from Here?

“…After intra-arterial application, SPIONs can be navigated to the tumor region by using an external magnet (magnetic drug targeting). Behr et al [ 26 ] have now established an in vitro system with which to analyze the magnetic accumulation of drug-loaded SPIONs or SPION-loaded cells and their effects on tumor spheroids. For this purpose, spheroids were placed in a chamber system under the influence of a magnetic field and connected to a peristaltic pump to simulate blood flow.…”