Highly Reproducible Hyperthermia Response in Water, Agar, and Cellular Environment by Discretely PEGylated Magnetite Nanoparticles

Abstract

Local heat generation from magnetic nanoparticles (MNPs) exposed to alternating magnetic fields can revolutionize cancer treatment. However, the application of MNPs as anticancer agents is limited by serious drawbacks. Foremost among these are the fast uptake and biodegradation of MNPs by cells and the unpredictable magnetic behavior of the MNPs when they accumulate within or around cells and tissues. In fact, several studies have reported that the heating power of MNPs is severely reduced in the cellular environment, probably due to a combination of increased viscosity and strong NP agglomeration. Herein, we present an optimized protocol to coat magnetite (Fe 3 O 4 ) NPs larger than 20 nm (FM-NPs) with high molecular weight PEG molecules that avoid collective coatings, prevent the formation of large clusters of NPs and keep constant their high heating performance in environments with very different ionic strengths and viscosities (distilled water, physiological solutions, agar and cell culture media). The great reproducibility and reliability of the heating capacity of this FM-NP@PEG system in such different environments has been confirmed by AC magnetometry and by more conventional calorimetric measurements. The explanation of this behavior has been shown to lie in preserving as much as possible the magnetic single domain-type behavior of nearly isolated NPs. In vitro endocytosis experiments in a colon cancer-derived cell line indicate that FM-NP@PEG formulations with PEGs of higher molecular weight (20 kDa) are more resistant to endocytosis than formulations with smaller PEGs (5 kDa), showing quite large uptake mean-life (τ > 5 h) in comparison with other NP systems. The in vitro magnetic hyperthermia was performed at 21 mT and 650 kHz during 1 h in a pre-endocytosis stage and complete cell death was achieved 48 h posthyperthermia. These optimal FM-NP@PEG formulations with high resistance to endocytosis and predictable magnetic response will aid the progress and accuracy of the emerging era of theranostics.

Exploring the potential of the dynamic hysteresis loops via high field, high frequency and temperature adjustable AC magnetometer for magnetic hyperthermia characterization

“…AC magnetometry has also allowed to correlate the shape of the MNPs and their hyperthermia performance [30], or to clarify why the heating power of MNPs tends to fall in cellular enviroments [31]. In addition, AC magnetometry studies have made possible the development of new coating strategies to keep constant the heating performance of MNPs in media with different viscosities and ionic strength [32].…”

Disentangling local heat contributions in interacting magnetic nanoparticles

“…Firstly, substantial differences between in-vivo and in-vitro heating properties are reported in the literature. 11,12 One of the important reasons for this is that within a tumor magnetic nanoparticles can form aggregated (strongly-interacting) fractal structures, 13 whereas in the lab they are in well-dispersed stable fluid suspensions. Secondly, the intricately-entwined effects of particle properties and experimental protocols on MNH heating (even for homogeneously distributed samples) become further complex when aggregation occurs.…”

Shaping Up Zn-Doped Magnetite Nanoparticles from Mono- and Bimetallic Oleates: The Impact of Zn Content, Fe Vacancies, and Morphology on Magnetic Hyperthermia Performance

“…First, to make the Zn x Fe 3– x O 4 samples hydrophilic and colloidally stable in physiological solutions, samples were coated using the PMAO-PEG copolymer (see Section 4 and Table S7 in the Supporting Information) following a previously published protocol that minimizes collective coatings. 29 Sample Zn 0.1 -24 was functionalized using 10 kDa PEG, and samples Zn 0.1 -34, Zn 0.1 -48, and Zn 0.25 -39, which are composed of larger NPs, were coated using longer PEG molecules (20 kDa) to better counterbalance the dipolar interaction among NPs. Due to the small size of the NPs forming the Zn 0.15 -10 sample and, thus, its low potential as a magnetothermal actuator, from here on, this sample will no longer be a part of the discussion.…”

“…AC hysteresis loops of samples composed of single crystals (Zn 0.1 -48@PEG, Zn 0.1 -24@PEG, Zn 0.1 -34@PEG), in Figure 8 , are similar to those obtained in pure magnetite FM-NPs prepared following a similar synthetic route. 29 , 55 , 56 Importantly, these loops are typical of nearly isolated magnetic single domains whose easy axes are oriented at random relative to the externally applied AC magnetic field. In consequence, the Stoner–Wohlfarth-based approach 57 fits reasonably with most of the hysteresis loops presented in Figure 8 d(123).…”