Biodegradable polyelectrolyte/magnetite capsules for MR imaging and magnetic targeting of tumors

Abstract

Rationale: The tireless research for effective drug delivery approaches is prompted by poor target tissue penetration and limited selectivity against diseased cells. To overcome these issues, various nano- and micro-carriers have been developed so far, but some of them are characterized by slow degradation time, thus hampering repeated drug administrations. The aim of this study was to pursue a selective delivery of magnetic biodegradable polyelectrolyte capsules in a mouse breast cancer model, using an external magnetic field. Methods: Four different kinds of magnetic polyelectrolyte capsules were fabricated via layer-by-layer assembly of biodegradable polymers on calcium carbonate templates. Magnetite nanoparticles were embedded either into the capsules' shell (sample S) or both into the shell and the inner volume of the capsules (samples C n S, where n is the number of nanoparticle loading cycles). Samples were first characterized in terms of their relaxometric and photosedimentometric properties. In vitro magnetic resonance imaging (MRI) experiments, carried out on RAW 264.7 cells, allowed the selection of two lead samples that proceeded for the in vivo testing on a mouse breast cancer model. In the set of in vivo experiments, an external magnet was applied for 1 hour following the intravenous injection of the capsules to improve their delivery to tumor, and MRI scans were acquired at different time points post administration. Results: All samples were considered non-cytotoxic as they provided more than 76% viability of RAW 264.7 cells upon 2 h incubation. Sample S appeared to be the most efficient in terms of T 2 -MRI contrast, but the less sensitive to external magnet navigation, since no difference in MRI signal with and without the magnet was observed. On the other side, sample C 6 S was efficiently delivered to the tumor tissue, with a three-fold T 2 -MRI contrast enhancement upon the external magnet application. The effective magnetic targeting of C 6 S capsules was also confirmed by the reduction in T 2 -MRI contrast in spleen if compared with the untreated with magnet mice values, and the presence of dense and clustered iron aggregates in tumor histology sections even 48 h after the magnetic targeting. Conclusion: The highlighted strategy of magnetic biodegradable polyelectrolyte capsules' design allows for the development of an efficient drug delivery system, which through an MRI-guided externally controlled navigation may lead to a significant improvement of the anticancer chemotherapy performance.

Biopolymer-Based Multilayer Capsules and Beads Made via Templating: Advantages, Hurdles and Perspectives

“…Functionalisation of PEMCs with nanoparticles serves similar purposes. Magnetic nanoparticles were embedded into the multilayer shell for increased accumulation at the target site, within DS/pARG capsules, for example [174,240]. For instance, Fe 3 O 4 and doxorubicin-loaded PR-carboxymethylcellulose PEMCs showed greater efficacy against doxorubicin-resistant HeLa cells in mice, resulting in greater apoptotic effects in tumour cells.…”

“…The authors attributed this to the controlled in vivo distribution of doxorubicin, which was controlled via an external magnetic field [241]. This gives scope for magnetic bio-capsules to be used in theranostics, both as drug delivery vehicles and contrast agents [240]. Superparamagnetic iron oxide nanoparticles were also adsorbed onto CaCO 3 -templated DS/pARG multilayer capsules through replacing a negatively charged layer.…”

Designing Functionalized Polyelectrolyte Microcapsules for Cancer Treatment

“…The method of layer-by-layer adsorption of polyelectrolytes used for the formation of the polymer shell allows magnetic [21,22] and fluorescent semiconductor [10,13,23] nanoparticles and other fluorescent labels [24] to be incorporated into the shell, thus ensuring magnetic resonance or fluorescence imaging of the MCs. These polyelectrolyte structures can be efficiently optically encoded with fluorescent semiconductor nanocrystals (quantum dots (QDs)) [23,25].…”

Effect of Size on Magnetic Polyelectrolyte Microcapsules Behavior: Biodistribution, Circulation Time, Interactions with Blood Cells and Immune System

“…The main parameters, in terms of the safety and efficiency of drug delivery systems, are their load capacity, biocompatibility, biodegradability [6], sensitivity to external stimuli [4], duration of their circulation in the vascular system [7], and their ability to avoid the host's immune system stimulation. Although the above parameters are crucial for successful targeted drug delivery, the carrier size can also play an important role.…”

“…One of the most commonly used combinations of biocompatible and biodegradable polymers for LbL assembly is polyarginine (Parg)/dextran sulfate (DS), indicated by the tremendous number of articles published in the last decade [6,7,10,11,[14][15][16]. However, despite the profound interest in magnetic Parg/DS microcapsules, the cytotoxicity, hemotoxicity, and systemic side effects induced by their application have not been properly studied to date.…”