Working Together: The Combined Application of a Magnetic Field and Penetratin for the Delivery of Magnetic Nanoparticles to Cells in 3D

Abstract

Nanoparticles (NPs) are currently being developed as vehicles for in vivo drug delivery. Two of the biggest barriers facing this therapy are the site-specific targeting and consequent cellular uptake of drug-loaded NPs(1). In vitro studies in 2D cell cultures have shown that an external magnetic field (MF) and functionalization with cell-penetrating peptides (CPPs) have the capacity to overcome these barriers. This study aimed to investigate if the potential of these techniques, which has been reported in 2D, can be successfully applied to cells growing in a 3D environment. As such, this study provides a more realistic assessment of how these techniques might perform in future clinical settings. The effect of a MF and/or penetratin attachment on the uptake of 100 and 200 nm fluorescent iron oxide magnetic NPs (mNPs) into a fibroblast-seeded 3D collagen gel was quantified by inductively coupled plasma mass spectrometry. The most suitable mNP species was further investigated by fluorescence microscopy, histology, confocal microscopy, and TEM. Results show that gel mNP uptake occurred on average twice as fast in the presence of a MF and up to three times faster with penetratin attachment. In addition, a MF increased the distance of mNP travel through the gel, while penetratin increased mNP cell localization. This work is one of the first to demonstrate that MFs and CPPs can be effectively translated for use in 3D systems and, if applied together, will make excellent partners to achieve therapeutic drug delivery in vivo.

The influence of particle size and static magnetic fields on the uptake of magnetic nanoparticles into three dimensional cell‐seeded collagen gel cultures

“…Child et al recently demonstrated, using a type I collagen gel culture system, an increased mNP (200 nm) uptake in the presence of a magnetic field, as well as a five-order magnitude increase in depth penetration. 17 Previous research has shown a size dependent NP response when a magnetic field was used, thus this study extends this work to investigate the most favorable mNP size in terms of uptake into a 3D tissue equivalent model, in order to optimize potential mNP use in a clinical situation.…”

“…Gels were prepared using the method previously developed by our group. 17 The following preparation method was used for making three gels. Quantities were increased depending on how many gels were required for each experiment.…”

“…After the appropriate incubation period, samples were processed for ICP-MS as described previously. 17 Briefly, 75 mL of the residing solution was removed and added to 1 mL of distilled water in 50 mL tube. Each well was washed with 100 mL of distilled water and added to an allocated tube.…”

“…15,16 However, as NPs would need to cross membrane barriers and enter into 3D tissue to be effective, more recent investigations have progressed to the use of cell-seeded scaffolds, such as collagen gels; to recreate three-dimensional (3D) models of cells in a tissue environment. 17 The movement of NPs through these more complex, fibrous networks is far less predictable than movement through liquids such as culture medium, which move at a constant rate proportional to fluid viscosity. 18 The study presented here has investigated the effect of a static magnetic field on mNPs entering a tissue equivalent model.…”

Hybrid Collagenase Nanocapsules for Enhanced Nanocarrier Penetration in Tumoral Tissues

“…6 Different strategies have been postulated in order to overcome this limitation. Thus, the nanocarrier surface decoration with cell penetrating peptides (CPP) in combination with magnetic field guidance 7 and even the use of self-propelled devices have been described to achieve a higher penetration in 3D tissues. 8 A simpler approach consists in the local administration of proteolytic enzymes prior to the nanocarrier treatment, which has demonstrated a significant nanoparticle penetration enhancement within the tumoral tissue.…”