Construction Of Injectable Thermosensitive Magnetic Hydrogel And Its Application On Tumor Interventional Magnetic Induction Hyperthermia

Magnetic induction hyperthermia（MIH）has become a new therapeutic procedure after surgical therapy,chemotherapy and radiotherapy in current tumor treatment.Magnetic nanoparticles（MNPs）mediated MIH is to apply an alternating current magnetic field（ACMF）of sufficient strength and frequency to cause the particles to heat in tumor by the combined effects of the rotational external（Brownian）and internal（Néel）diffusion of the particle magnetic moment.The main modes of administration of tumor MIH are intravenous injection and intratumoral injection.Nevertheless,intravenously injected MNPs tend to have high accumulation in the liver and spleen,resulting in inadequate tumor accumulation for a sufficient temperature increase.For in situ localized MIH,intratumoral injection of MNPs may be technically feasible.However,the small particulate size and the high tumor osmotic pressure make MNPs easily leak out along the route of the syringe needle and escape from the tumor tissues during the long term therapeutic process.Based on this,authors are dedicated to designing magnetic hydrogels with both injectability and temperature sensitivity for solid tumor interventional MIH.Injectable thermosensitive hydrogels can be uniformly injected into tumor tissue in a minimally invasive manner without leaking or moving to the peripheral tissue,ensuring sufficient accumulation of MNPs in the tumor tissue for the effective temperature increase and eliminating the fact that the organs around the tumor are also heated when the tumor tissue is under hyperthermia.First of all,a series of Fe₃O₄ nanoparticles with different sizes（10 nm,15 nm,25 nm,37 nm,42 nm,50 nm,65 nm,80 nm,125 nm）were synthesized by adjusting the ratio of iron precursor and oleic acid using the high temperature thermal decomposition method.Ferrite nanoparticles doped with different metal elements [（Znx Fe1-x）Fe₂O₄,（Znx Mn1-x）Fe₂O₄,（Znx Co1-x）Fe₂O₄,（Znx Co1-x）Fe₂O₄@（Znx Mn1-x）Fe₂O₄] were obtained by the addition of zinc acetylacetonate,manganese acetylacetonate and cobalt acetylacetonate.It has been verified that the proper ratio of manganese-zinc doping can effectively increase the saturation magnetization value Ms of 15 nm MNPs from 85emu/g to 136 emu/g metal;The doping of cobalt significantly enhanced the coercivity of 15 nm MNPs from 1 Oe to 115 Oe at 300 K.The increase of Ms and Hc of MNPs are contribute to the effects on the Néel relaxation and Brownian relaxation as well as hysteresis loss under the ACMF,which laid a foundation for the efficient MIH.This article designed three hydrogel platforms suitable for tumor MIH at different temperatures,which are aimed at tumor thermal ablation at 60℃,tumor resection at45℃ and tumor regression at 42℃.In the first platform,an injectable and thermosensitive magnetic nanoemulsion hydrogel（MNH）containing Zn ferrite MNPs,PEG-DA,indocyanine green（ICG）and silicone oil droplets for localized magnetic thermal ablation of tumor under multimodal imaging guidance has been presented.MNH transformed into a solid-like magnetic hydrogel after injected into the tumor tissue without leakage in response to body temperature（37℃）.By applying the ACMF,the tumor achieved coagulative necrosis by MNPs induced thermal ablation.The procedure of in situ injection could be dynamically monitored by ultrasound（US）imaging,while the therapeutic process was guided and evaluated by magnetic resonance（MR）imaging and near-infrared fluorescence（NIRF）imaging.Furthermore,Zn ferrite MNPs within the MNH showed enhanced heat transformation effect at a very low MNPs dosage（Fe: 90 μg）,which is attributed to its high SAR value and local orientation in the hydrogel under the ACMF.The crosslinking among the nanoemulsion droplets further increased the heat accumulation.All these benefits caused the efficient tumor hyperthermia therapeutic outcome.For the treatment of recurring tumors after surgery,lower temperature hyperthermia is more acceptable than thermal ablation.A magnetic supramolecular hydrogel（MSH）self-assembled by PEGylated Fe₃O₄ nanoparticles and α-CD through inclusion complexation for the treatment of locoregional recurrence of cancer following primary tumor resection has been designed.DSPE-m PEG2000 with amphiphilic character was used as the stabilizing agent in the preparation of PEGylated Fe₃O₄ nanoparticles,in which the DSPE block formed the shell around the magnetic core,while the m PEG block played as the guest molecule for the crystalline inclusion complex with a cyclic oligosaccharide host molecule,α-CD.The MSH composite of hierarchical structure contained both hydrophilic and hydrophobic domains,which enabled dual loading of a hydrophobic paclitaxel（PTX）into the shell structure of PEGylated Fe₃O₄ nanoparticles and another hydrophilic Doxorubicin（DOX·HCl）into the aqueous bulk of the gel.The MSH can be easily injected to the surgical residual position through a needle due to its shear-thinning property and liquid-conformally cover any residual cancer cells on the margins or in the hollow of the cavity as it presents a magnetocaloric gel-sol transition when exposed to ACMF.Magnetically induced heating effect during the gel-sol transition procedure also afforded tumor hyperthermia treatment simultaneously.The MSH might provide a potential thermochemotherapy approach for the treatment of locoregional recurrence of cancer.The 42℃ temperature that normal tissues tolerate while tumor cells are damaged is more suitable for clinical applications.Magnetic hydrogel nanozyme（MHZ）utilizing inclusion complexation between PEGylated nanoparticles and α-CD,which can enhance tumor oxidative stress levels by generating reactive oxygen species（ROS）through nanozyme-catalyzed reactions based on tumor MIH has been developed.MHZ can be injected and diffused into the tumor tissue due to shear thinning as well as magnetocaloric phase transition properties,and magnetic heat generated by the Fe₃O₄ first gave 42℃ of hyperthermia to the tumor.Fe₃O₄ nanozyme exerted peroxidase-like properties in the acidic environment of tumor to generate hydroxyl radicals（·OH）by the Fenton reaction.The hyperthermia promoted the enzymatic activity of Fe₃O₄ nanozyme to produce more ·OH.Simultaneously,·OH further damaged the protective heat shock protein HSP 70 which highly expressed in hyperthermia to enhance the therapeutic effect of hyperthermia.This single MNPs exerted dual functions of hyperthermia and catalytic therapy to synergistically treat tumor strategy,overcoming the resistance of tumor cells to induced thermal stress without causing severe side effects to normal tissues at 42℃ hyperthermia.In summary,the injectable thermosensitive magnetic hydrogel was used to solve some of the bottleneck problems faced by current MIH.The regulation of the types,contents of MNPs in different hydrogel systems and ACMF parameters can achieve a reasonable selection of the thermotherapy dose in tumor site,reaching hyperthermia（42℃-45℃）or thermal ablation（>50℃）therapy.Futhermore,magnetic hydrogelbased MIH can be combined with chemotherapy and catalytic therapy.The designed treatment systems are more flexible and effective,which was hoped to make breakthroughs in the field of interventional MIH of solid tumor.