The Curie temperature: a key playmaker in self-regulated temperature hyperthermia.

The Curie temperature is an important thermo-characteristic of magnetic materials, which causes a phase transition from ferromagnetic to paramagnetic by changing the spontaneous re-arrangement of their spins (intrinsic magnetic mechanism) due to an increase in temperature. The self-control-temperature (SCT) leads to the conversion of ferro/ferrimagnetic materials to paramagnetic materials, which can extend the temperature-based applications of these materials from industrial nanotechnology to the biomedical field. In this case, magnetic induction hyperthermia (MIH) with self-control-temperature has been proposed as a physical thermo-therapeutic method for killing cancer tumors in a biologically safe environment. Specifically, the thermal source of MIH is magnetic nanoparticles (MNPs), and thus their biocompatibility and Curie temperature are two important properties, where the former is required for their clinical application, while the latter acts as a switch to automatically control the temperature of MIH. In this review, we focus on the Curie temperature of magnetic materials and provide a complete overview beginning with basic magnetism and its inevitable relation with Curie's law, theoretical prediction and experimental measurement of the Curie temperature. Furthermore, we discuss the significance, evolution from different types of alloys to ferrites and impact of the shape, size, and concentration of particles on the Curie temperature considering the proposed SCT-based MIH together with their biocompatibility. Also, we highlight the thermal efficiency of MNPs in destroying tumor cells and the significance of a low Curie temperature. Finally, the challenges, concluding remarks, and future perspectives in promoting self-control-temperature based MIH to clinical application are discussed.

CT/MR detectable magnetic microspheres for self-regulating temperature hyperthermia and transcatheter arterial chemoembolization.

The embolic microspheres containing magnetic nanoparticles and anti-tumor drugs have been proposed for transcatheter arterial chemoembolization (TACE). However, this technique still suffers the poor control of hyperthermia temperature and drug release behavior. Herein, the magnetic microspheres based on low Curie temperature superparamagnetic iron oxide nanoparticles are developed by emulsification cross-linking of gelatin, genipin, and sodium alginate. The magnetic microspheres can self-regulate the hyperthermia temperature at around 50°C, un-necessitating any temperature control facilities. The magnetic microspheres can load doxorubicin hydrochloride and the loaded drug can be released in a controllable way by using an alternating magnetic field. Cytocompatibility and hemolysis evaluations confirm the non-cytotoxicity and negligible hemolysis of magnetic microspheres. The embolization model on rabbit auricular artery demonstrates that the magnetic microspheres can occlude the targeted blood vessel and are visualized under CT/MR imaging. All these findings suggest that the prepared magnetic microspheres could be used as the embolic agent in TACE. STATEMENT OF SIGNIFICANCE: The existing magnetic embolic microspheres suffer the poor control of hyperthermia temperature and drug release behavior in TACE. In this work, we developed the magnetic embolic microspheres based on superparamagnetic iron oxide nanoparticles with a low Curie temperature. Upon the application of alternating magnetic field, the embolic microspheres can self-regulate the hyperthermia temperature at around 50°C and the drug loaded in the microspheres can be released in a somewhat controllable manner. The embolic microspheres are also detectable to both CT and MR. These characteristics enable the developed microspheres to simultaneously realize self-regulating temperature hyperthermia, on-demand drug release, embolization, and CT/MR imaging.

The heating efficiency of magnetic nanoparticles under an alternating magnetic field.

Hysteresis loss and relaxation loss are the two dominant heating mechanisms of magnetic nanoparticles (MNPs) in an alternating magnetic field (AMF). In magnetic induction hyperthermia, heating efficiency is one of the crucial factors. It is proposed that the MNPs with a dominant heating mechanism of relaxation loss will exhibit a higher heating efficiency. However, the relative experiments supporting the proposal is still absent due to the difficulty of obtaining the MNPs with the same components and similar morphology but different dominant heating mechanism. Here, the post-processing method of calcination is employed to change the cation distribution of the MNPs (Fe3O4 and Zn0.54Co0.46Cr0.6Fe1.4O4), so as to obtain the MNPs with similar morphology but different dominant heating mechanism. The magnetic heating experiments were conducted to examine the heating efficiency. The results suggest that the MNPs with relaxation loss have a higher heating efficiency under the investigated AMF.

Identification of thiophene-benzenesulfonamide derivatives for the treatment of multidrug-resistant tuberculosis.

A series of thiophene-benzenesulfonamide derivatives was designed and synthesized by exploring the structure-activity relationship of lead compounds 2,3-disubstituted thiophenes 25a and 297F as antituberculosis agents, which displayed potent antimycobacterial activity against drug-susceptible and clinically isolated drug-resistant tuberculosis. In particular, compound 17b, which had improved activity (minimum inhibitory concentration of 0.023 µg/mL) compared with the lead compounds, displayed good intracellular antimycobacterial activity in macrophages with a reduction of 1.29 log10 CFU. A druggability evaluation indicated that compound 17b had favorable hepatocyte stability, low cytotoxicity, and low hERG channel inhibition. Moreover, compound 17b exhibited modest in vivo efficacy in an acute mouse model of tuberculosis. In addition, the molecular docking study elucidated the binding mode of compound 17b in the active site of DprE1. Therefore, compound 17b may be a promising antituberculosis lead for further research.

Magnetic hydrogel with long in situ retention time for self-regulating temperature hyperthermia.

Aim: Magnetic hydrogels (MHGs) have been proposed to avoid the redistribution and loss of magnetic nanoparticles (MNPs) when administrated by intratumoral injection. However, the requirement of complex cooling systems and temperature monitoring systems still hinder the clinical application of MHGs. This study investigates the feasibility of developing an MHG to realize the self-regulation of hyperthermia temperature. Methods: The MHG was developed by dispersing the MNPs with self-regulating temperature property into the temperature-sensitive hydrogel through physical crosslinking. The MHG's gelation temperature was tested by measuring the storage modulus and loss modulus on a rotational rheometer. The biocompatibility of the MHG and MNPs was characterized by CCK-8 assay against HaCaT cells. The in vivo magnetic heating property was examined through monitoring the temperature in the MHG on mice back upon the application of the alternating magnetic field (400 ± 5 Oe, 100 ± 5 kHz) every week for successive six weeks. Results: The gelation temperature of the MHG falls in 28.4°C-37.4°C. At in vivo applied concentration of 80 mg/mL, the MHG exhibits over 80% cell viability after 72 h, significantly higher than 50% cell viability of the MNPs (p<0.001). The MHG's stable magnetic hyperthermia temperatures in vivo are in the range of 43.4°C-43.8°C. Conclusions: The developed MHG can be injected using a syringe and will solidify upon body temperature. The biocompatibility is improved after the MNPs being made into MHG. The MHG can self-regulate the temperature for six weeks, exhibiting application potential for self-regulating temperature hyperthermia.

Onion-structure bionic hydrogel capsules based on chitosan for regulating doxorubicin release.

Inspired by the multilayer structure of onion, herein, a novel strategy to prepare bionic multilayer hydrogel capsules for inhibiting burst release of doxorubicin (DOX) is reported. The bionic multilayer hydrogel capsules are prepared by the ionotropic crosslinking method. Compared with monolayer hydrogel capsules, the multilayer hydrogel capsules can largely homogenize the distribution of DOX and suppress the concentration gradient of DOX between the outermost hydrogel layer and external environment and the dense cuticular membranes of capsules can restrict the migration and diffusion of DOX. As a result, a significant inhibition of the burst release of DOX can be achieved. Moreover, the bionic multilayer hydrogel capsules demonstrate pH sensitivity and good biocompatibility to human epidermal keratinocyte (HaCaT) cells. This work opens up a new horizon in the burst release of biomaterial-based hydrogels for drug delivery system.

Novel nanoparticles with Cr3+ substituted ferrite for self-regulating temperature hyperthermia.

For hyperthermia to be used under clinical conditions for cancer therapeutics the temperature regulation needs to be precise and accurately controllable. In the case of the metal nanoparticles used for such activities, a high coercivity is a prerequisite in order to couple more energy in a single heating cycle for efficient and faster differential heating. The chemically stable Co-Zn ferrite nanoparticles have typically not been used in such self-regulating hyperthermia temperature applications to date due to their low Curie temperature usually accompanied by a poor coercivity. The latter physical property limitation under clinically applied magnetic field conditions (frequency: 100 kHz, intensity: 200 Oe) restricts the transfer of a reasonable heat energy, and thus limits the hyperthermia efficiency. Here, we report a novel Cr3+ substituted Co-Zn ferrite (Zn0.54Co0.46Cr0.6Fe1.4O4), whose Curie temperature and coercivity values are 45.7 °C and 174 Oe, respectively. Under clinically acceptable magnetic field conditions, the temperature of these nanoparticle suspensions can be self-regulated to 44.0 °C and, most importantly with a specific absorption rate (SAR) of 774 W kg-1, which is two-fold higher than the SAR standard for magnetic nanoparticles used in hyperthermia (300 W kg-1). The evaluation of the in vitro cytotoxicity of the nanoparticles reports a low toxicity, which points to a novel set of magnetic nanoparticles for use in self-regulating hyperthermia.

Preclinical evaluations of peptide-conjugate vaccines targeting the antigenic domain-2 of glycoprotein B of human cytomegalovirus.

The Antigenic Domain 2 (AD-2) is a short region near the N-terminus of glycoprotein B of human cytomegalovirus (HCMV). AD-2 has been shown to contain linear epitopes that are targets for neutralizing monoclonal antibodies from human subjects with natural HCMV infection. However, AD-2 appears to be masked by the adjacent immunodominant AD-1 region. We assessed a serum panel from HCMV-seropositive individuals and found a wide range of antibody titers to AD-2; these did not correlate to serum neutralization. To expose potential epitopes in AD-2, we constructed a series of AD-2 peptide-conjugate vaccines. Mice were immunized 3 times and produced high and sustained antibody titers to AD-2 peptides, but neutralization was weak even after a single boost with whole HCMV virions. Rabbits were likewise immunized with AD-2 peptide vaccines, and produced a robust antibody response, but neutralization was inferior to a recombinant gB vaccine with an oil-in-water adjuvant. These results highlight the challenges of developing a peptide-based vaccine specific to the HCMV gB AD-2 region.