Recent Strategies to Combat Biofilms Using Antimicrobial Agents and Therapeutic Approaches.

Biofilms are intricate bacterial assemblages that attach to diverse surfaces using an extracellular polymeric substance that protects them from the host immune system and conventional antibiotics. Biofilms cause chronic infections that result in millions of deaths around the world every year. Since the antibiotic tolerance mechanism in biofilm is different than that of the planktonic cells due to its multicellular structure, the currently available antibiotics are inadequate to treat biofilm-associated infections which have led to an immense need to find newer treatment options. Over the years, various novel antibiofilm compounds able to fight biofilms have been discovered. In this review, we have focused on the recent and intensively researched therapeutic techniques and antibiofilm agents used for biofilm treatment and grouped them according to their type and mode of action. We also discuss some therapeutic approaches that have the potential for future advancement.

The twisted structure of the rat Achilles tendon.

The rat is frequently used as a model to study the characteristics, aetiology and pathology of the Achilles tendon. However, though the structure of the human Achilles tendon has been extensively investigated, the anatomical structure of the rat Achilles tendon remains unclear, which impedes the ability to use rats to study Achilles tendinopathy. The purpose of this study was to reveal the structure of the rat Achilles tendon and to explore its similarities with the human Achilles tendon through an anatomical dissection of 80 rat Achilles tendons (40 female, 40 male). This study found that the subtendons of the rat Achilles tendon originating from the triceps surae muscle were twisted, and each subtendon also had its own torsion. The extent of these two types of torsion could be very different between rats. Alterations in this torsion may result in distinct stress fields in the Achilles tendon, which may play a critical role in the pathogenesis of Achilles tendinopathy. This study provides an important basis to support the use of rats as model animals to investigate the characteristics of the human Achilles tendon and Achilles tendinopathy.

The mitral regurgitation effects of cardiac structure and function in left ventricular noncompaction.

This study evaluated the effects of mitral regurgitation (MR) on cardiac structure and function in left ventricular noncompaction (LVNC) patients. The clinical and cardiovascular magnetic resonance (CMR) data for 182 patients with noncompaction or hypertrabeculation from three institutes were retrospectively included. We analyzed the difference in left ventricular geometry, cardiac function between LVNC patients with and without MR. The results showed that patients with MR had a worse New York Heart Association (NYHA) class and a higher incidence of arrhythmia (P < 0.05). MR occurred in 48.2% of LVNC patients. Compared to LVNC patients without MR, the two-dimensional sphericity index, maximum/minimum end-diastolic ratio and longitudinal shortening in LVNC patients with MR were lower (P < 0.05), and the peak longitudinal strain (PLS) of the global and segmental myocardium were obviously reduced (P < 0.05). No significant difference was found in strain in LVNC patients with different degree of MR; end diastolic volume, end systolic volume, and global PLS were statistically associated with MR and NYHA class (P < 0.05), but the non-compacted to compacted myocardium ratio had no significant correlation with them. In conclusion, the presence of MR is common in LVNC patients. LVNC patients with MR feature more severe morphological and functional changes. Hypertrabeculation is not an important factor affecting structure and function at the heart failure stage.

Method for Ferrite Nanomaterials-Mediated Cellular Magnetic Hyperthermia.

Magnetic hyperthermia (MH) mediated by magnetic nanoparticles is one of the most promising antitumor modalities. The past several decades have witnessed great progress for MH antitumor therapy in scientific trials and clinic applications since it was initially advanced by Gilchrist et al. The ultimate object of MH in vivo is to efficiently kill cancer cells, and hence, it is of great importance to develop an optimized cellular MH method to evaluate the therapeutic efficiency in vitro. In this study, we systematically studied the considerable affecting factors of cancer cell-killing efficiency during the cellular MH process, including the region of cell vessel positioned inside the alternating magnetic field copper coil, the magnetic field amplitude, the types of cancer cells, etc. Taking all these into account, we introduced a method for standardizing the cellular MH process to evaluate the cell-killing efficiency.

Iron nanoparticles augmented chemodynamic effect by alternative magnetic field for wound disinfection and healing.

Utilizing the iron-carrying nanomaterials for Fenton chemistry mediation to catalyze decomposition of hydrogen peroxide and generate toxic hydroxyl radical (OH) has drawn much attention in antimicrobial therapy field. However, these nanomaterials are usually with unsatisfactory catalytic efficacy and lack of the capacity to modulate the catalytic activity, which may give the bacteria opportunity in developing resistance against the antibacterial treatment. Herein, we systematically investigated the influence of alternating magnetic field (AMF) on the catalytic activity and antibacterial efficiency of the amorphous iron nanoparticles (AIronNPs). With rapidly ionized and the AMF augmented chemodynamic effect, the AIronNPs can convert low concentration of H2O2 into more OH, the possible mechanism might be attributed to the accelerated ferrous iron ions releasing with AMF exposure. As a proof of concept, the AIronNPs and AMF synergetic antibacterial system have shown excellent broad-spectrum antimicrobial properties, 91.89% antibacterial efficiency is shown toward Escherichia coli and 92.65% toward Staphylococcus aureus. It also facilitated the formation of granulation tissue and accelerated wound healing on in vivo infected model, whereas AIronNPs alone have limited effect. We believe this work will broaden the thoughts for spatiotemporally manipulating the catalytic activity of nanomaterials and advance the development of magnetic nano-antibiotics in the antibacterial field.

Women Are at a Higher Risk of Chronic Metabolic Diseases Compared to Men With Increasing Body Mass Index in China.

Background: Chronic non-communicable diseases are the major causes of mortality in the world. However, few studies have investigated the association between multi-categories BMI and chronic diseases from perspective of sex stratification. This study aimed to investigate the risk of chronic diseases at different BMI levels, and to further explore whether BMI-health risk associations differ by sex. Methods: In total, 21,134 participants aged 19-65 years (60.4% men) from the Tianjin People's Hospital, Tianjin Union Medical Center-Health Management Center were recruited for this cross-sectional study. Sex-specific percentiles of BMI were calculated and divided into 11 categories according to the 2000 CDC growth charts. Health-related indicators, such as hyperglycemia, hypertension, non-alcoholic fatty liver diseases (NAFLD), hyperuricemia, etc., were used as dependent variables in this study. Statistical differences were tested by unpaired Mann-Whitney U-test and chi-squared test. Logistic regression models were used to examine the associations between BMI and health-related indicators. Results: The risk of hyperglycemia (OR: 1.67, 95%CI: 1.23-2.29), NAFLD (OR: 2.22, 95%CI: 1.74-2.85), hypertriglyceridemia (OR: 1.65, 95%CI: 1.28-2.12), and hyperuricemia (OR: 1.39, 95%CI: 1.12-1.72) in men began to increase significantly when BMI was in the range of 22.59-23.89 kg/m2. However, in women, the risk of hyperglycemia (OR: 3.02, 95%CI: 1.25-8.98) and hyperuricemia (OR: 1.94, 95%CI: 1.26-3.05) began to increase significantly when BMI was in the range of 22.76-23.62 kg/m2, and the risk of NAFLD (OR: 5.48, 95%CI: 2.49-14.47) began to increase significantly when BMI was in the range of 21.08-21.97 kg/m2. Besides, at the same BMI level, the risk of diseases in women were significantly higher than that in men, especially when BMI > 25 kg/m2. Conclusion: In the Chinese population, the risk of chronic diseases in women were significantly higher than that in men at the same BMI level, especially when BMI was >25 kg/m2. In addition, the risk of chronic diseases began to increase significantly when BMI was >21.97 kg/m2 in women and 23.89 kg/m2 in men. The results indicated that women should be more alert to the risk of chronic diseases caused by the increase of BMI than men.

Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy.

Magnetic hyperthermia (MH) has been introduced clinically as an alternative approach for the focal treatment of tumors. MH utilizes the heat generated by the magnetic nanoparticles (MNPs) when subjected to an alternating magnetic field (AMF). It has become an important topic in the nanomedical field due to their multitudes of advantages towards effective antitumor therapy such as high biosafety, deep tissue penetration, and targeted selective tumor killing. However, in order for MH to progress and to realize its paramount potential as an alternative choice for cancer treatment, tremendous challenges have to be overcome. Thus, the efficiency of MH therapy needs enhancement. In its recent 60-year of history, the field of MH has focused primarily on heating using MNPs for therapeutic applications. Increasing the thermal conversion efficiency of MNPs is the fundamental strategy for improving therapeutic efficacy. Recently, emerging experimental evidence indicates that MNPs-MH produces nano-scale heat effects without macroscopic temperature rise. A deep understanding of the effect of this localized induction heat for the destruction of subcellular/cellular structures further supports the efficacy of MH in improving therapeutic therapy. In this review, the currently available strategies for improving the antitumor therapeutic efficacy of MNPs-MH will be discussed. Firstly, the recent advancements in engineering MNP size, composition, shape, and surface to significantly improve their energy dissipation rates will be explored. Secondly, the latest studies depicting the effect of local induction heat for selectively disrupting cells/intracellular structures will be examined. Thirdly, strategies to enhance the therapeutics by combining MH therapy with chemotherapy, radiotherapy, immunotherapy, photothermal/photodynamic therapy (PDT), and gene therapy will be reviewed. Lastly, the prospect and significant challenges in MH-based antitumor therapy will be discussed. This review is to provide a comprehensive understanding of MH for improving antitumor therapeutic efficacy, which would be of utmost benefit towards guiding the users and for the future development of MNPs-MH towards successful application in medicine.

In situ forming gelatin/hyaluronic acid hydrogel for tissue sealing and hemostasis.

Fibrin glue has been widely used as a surgical sealing and hemostatic agent. Its application is restricted due to poor tissue adhesion and low mechanical strength. To develop better tissue sealant and hemostatic agent, this study prepared the injectable hydrogels by chemically cross-linking gelatin (G) with or without hyaluronic acid (HA) in situ at a mild condition. The rheological analysis, Fourier transform infrared spectroscopy, swelling, proteolytic degradation, biocompatibility, tissue sealing, and hemostatic ability of the hydrogels were investigated. It was found that the chemical cross-linking rapidly formed in both self-crosslinking gelatin (sc-G) and gelatin/hyaluronate acid (G/HA) hydrogels. The hydrogels could be degraded by trypsin and had a desirable biocompatibility. The tissue sealing ability of the hydrogels was superior to fibrin glue. Furthermore, the G/HA hydrogel had similar hemostatic performance as fibrin glue, and was better than that of gelatin hydrogel. The results in the study indicated that the G/HA hydrogel could be used in clinic as a tissue sealant or surgical hemostat.

Ellipsoidal magnetite nanoparticles: a new member of the magnetic-vortex nanoparticles family for efficient magnetic hyperthermia.

The development of magnetic iron oxide nanoparticles with novel topological magnetic domain structures, such as the vortex-domain structure, is a promising strategy for improving the application performance of conventional superparamagnetic iron oxides while maintaining their good biocompatibility. Here, we fabricated a new kind of magnetic-vortex nanoparticles, i.e., ellipsoidal magnetite nanoparticles (EMPs), for cancer magnetic hyperthermia. The magnetization configurations and switching behaviours of the EMPs were analyzed by analytical simulations and Lorentz TEM, demonstrating the magnetic vortex structures of both single and coupled EMPs. The EMP treatment of 4T1 cells exposed to an alternating magnetic field (AMF) induced a significant decrease in the cell viability by ∼51.5%, which indicated a much higher cytotoxic effect in comparison with commercial superparamagnetic iron oxides (Resovist, ∼12.0%). In addition, the in vivo high efficacy of 4T1 breast tumor inhibition was also achieved by using EMP-mediated magnetic hyperthermia. Our results not only provide a new type of magnetic-vortex nanoparticles for efficient hyperthermia but also enrich the family of magnetic iron oxide nanoparticles for various biomedical applications.

Accurate identification of myocardial viability after myocardial infarction with novel manganese chelate-based MR imaging.

We developed a novel manganese (Mn2+ ) chelate for magnetic resonance imaging (MRI) assessment of myocardial viability in acute and chronic myocardial infarct (MI) models, and compared it with Gadolinium-based delay enhancement MRI (Gd3+ -DEMRI) and histology. MI was induced in 14 rabbits by permanent occlusion of the left circumflex coronary artery. Gd3+ -DEMRI and Mn2+ chelate-based delayed enhancement MRI (Mn2+ chelate-DEMRI) were performed at 7 days (acute MI, n = 8) or 8 weeks (chronic MI, n = 6) after surgery with sequential injection of 0.15 mmol/kg Gd3+ and Mn2+ chelate. The biodistribution of Mn2+ in tissues and blood was measured at 1.5 and 24 h. Blood pressure, heart rate (HR), left ventricular (LV) function, and infarct fraction (IF) were analyzed, and IF was compared with the histology. The Mn2+ chelate group maintained a stable hemodynamic status during experiment. For acute and chronic MI, all rabbits survived without significant differences in HR or LV function before and after injection of Mn2+ chelate or Gd3+ (p > 0.05). Mn2+ chelate mainly accumulated in the kidney, liver, spleen, and heart at 1.5 h, with low tissue uptake and urine residue at 24 h after injection. In the acute MI group, there was no significant difference in IF between Mn2+ chelate-DEMRI and histology (22.92 ± 2.21% vs. 21.79 ± 2.25%, respectively, p = 0.87), while Gd3+ -DEMRI overestimated IF, as compared with histology (24.54 ± 1.73%, p = 0.04). In the chronic MI group, there was no significant difference in IF between the Mn2+ chelate-DEMRI, Gd3+ -DEMRI, and histology (29.50 ± 11.39%, 29.95 ± 9.40%, and 29.00 ± 10.44%, respectively, p > 0.05), and all three were well correlated (r = 0.92-0.96, p < 0.01). We conclude that the use of Mn2+ chelate-DEMRI is reliable for MI visualization and identifies acute MI more accurately than Gd3+ -DEMRI.

Magnetic Hydrogel with Optimally Adaptive Functions for Breast Cancer Recurrence Prevention.

Engineering biocompatible hydrogels using functional nanoparticles has attracted considerable attention because of their uniquely appealing cooperative effects that can enable multimodality imaging and treatment with improved efficacy against serious diseases. However, the effects of high-content nanoparticle dopants on the rheological properties of hydrogels frequently lead to an unsatisfactory therapeutic result, which is particularly notable in the design of magnetic hydrogel formulations for cancer therapy. Herein is reported a novel magnetic hydrogel functionalized by ferromagnetic vortex-domain iron oxide (FVIOs) with optimally adaptive functions for prevention of breast cancer recurrence. The FVIOs can perfectly incorporate into the dynamic hydrogel networks with an extremely low concentration (0.6 mg mL-1 ), 17 times lower than that of conventional superparamagnetic iron oxide nanoparticles with sufficient heating capacity. Such magnetic hydrogels exhibit high inductive heating and remarkable rheological properties simultaneously. Moreover, the self-healing, self-conformal ability, controlled release of loaded doxorubicin, biodegradation, and pH-responsiveness of the magnetic hydrogel project their efficient sustainable therapeutic ability. In vivo postoperative treatment has further demonstrated the high efficacy of FVIO-based magnetic hydrogels, as evidenced by the significant suppression of the local tumor recurrences compared to chemotherapy or hyperthermia alone. This unique magnetic hydrogel formulation with optimally adaptive functions shows strong potential in preventing relapses of various cancers.

In situ injectable hyaluronic acid/gelatin hydrogel for hemorrhage control.

Tissue sealants are used for hemorrhage control which is imperative in many surgical procedures. It is a highly challenging task to obtain the ideal tissue sealant. Only a few commercially tissue sealants are available to be used for internal tissue or organ hemorrhage control. This study introduced two in situ injectable hydrogels for hemorrhage control: self-crosslinking gelatin (sc-G) hydrogel and hyaluronic acid/gelatin (HA/G) hydrogel. They were prepared on the tissue surface in situ and characterized by rheological analysis, stability, cytotoxicity, and bursting strength test. The hemostatic ability of the hydrogels was evaluated in a liver-bleeding rat model. The sc-G and HA/G hydrogels gelled around 90 s and 50 s, respectively. They were preferable for cell attachment and proliferation. The bursting strengths of both hydrogels exceeded that of fibrin glue. The hemostatic ability of HA/G hydrogel was better than that of sc-G hydrogel, and was same as that of fibrin glue. The HA/G hydrogel could be used as a tissue sealant for hemorrhage control in clinic.

Nonmagnetic Hypertonic Saline-Based Implant for Breast Cancer Postsurgical Recurrence Prevention by Magnetic Field/pH-Driven Thermochemotherapy.

Magnetic-mediated hyperthermia (MMT) is emerging as one of the promising techniques, which could synergistically treat cancer along with current treatment techniques such as chemotherapy and radiotherapy and trigger on-demand release of therapeutic macromolecules. However, the low specific absorption rate and potential in vivo toxicity of magnetic nanomaterials as the MMT mediators restrict the new advancements in MMT treatment. Herein, for the first trial, the unique inductive heating property of hypertonic saline (HTS), a clinically applied solution exhibiting several physiological effects under alternative magnetic field (AMF), was systematically investigated. Though without magnetic property, due to the dipolar polarization under the electromagnetic radiation, HTS can induce enough high and rapid temperature increase upon exposure under AMF. Based on such an observation, PEG-based HTS hydrogel was fabricated for the inhibition of unwanted diffusion of ions so as to ensure the ideal temperature rise at the targeted region for a longer time. Furthermore, an anticancer drug (doxorubicin) was also incorporated into the hydrogel to achieve the magnetic field/pH stimuli-responsive drug-sustainable release as well as synergistic thermochemotherapy. The potential application of the drug-loaded HTS-PEG-injectable hydrogel for breast cancer postsurgical recurrence prevention is demonstrated. Significant in vivo suppression of two kinds of breast cancer models was achieved by the hybrid hydrogel system. This work explores a new biomedical use of clinical HTS and a promising cancer treatment protocol based on HTS-PEG hydrogel for magnetic hyperthermia combined with stimuli-responsive chemotherapy for breast cancer postsurgical recurrence prevention.

Magnetic Nanomaterials for Advanced Regenerative Medicine: The Promise and Challenges.

The recent emergence of numerous nanotechnologies is expected to facilitate the development of regenerative medicine, which is a tissue regeneration technique based on the replacement/repair of diseased tissue or organs to restore the function of lost, damaged, and aging cells in the human body. In particular, the unique magnetic properties and specific dimensions of magnetic nanomaterials make them promising innovative components capable of significantly advancing the field of tissue regeneration. Their potential applications in tissue regeneration are the focus here, beginning with the fundamentals of magnetic nanomaterials. How nanomaterials-both those that are intrinsically magnetic and those that respond to an externally applied magnetic field-can enhance the efficiency of tissue regeneration is also described. Applications including magnetically controlled cargo delivery and release, real-time visualization and tracking of transplanted cells, magnetic regulation of cell proliferation/differentiation, and magnetic activation of targeted ion channels and signal pathways involved in regeneration are highlighted, and comments on the perspectives and challenges in magnetic nanomaterial-based tissue regeneration are given.

Facile Preparation of Gold-Decorated Fe3O4 Nanoparticles for CT and MR Dual-Modal Imaging.

The development of a multifunctional nanoprobe capable of non-invasive multimodal imaging is crucial for precise tumour diagnosis. Herein, we report a facile polymer-assisted method to produce Au-Fe3O4 nanocomposites (NCPs) for the dual-modal magnetic resonance (MR) and X-ray computed tomography (CT) imaging of tumours. In this approach, amino-functionalized Au nanospheres were first obtained by surface modification of the bifunctional polymer SH-PEG-NH2. Hydrophilic and carboxyl-functionalized Fe3O4 nanoparticles were produced by phase transfer of reverse micelle oxidation in our previous work. The Au nanoparticles were conjugated with hydrophilic Fe3O4 nanoparticles through an amide reaction. The obtained Au-Fe3O4 nanocomposites display a high r2 relativity (157.92 mM-1 s-1) and a Hounsfield units (HU) value (270 HU) at Au concentration of 8 mg/mL and could be applied as nanoprobes for the dual-modal MR/CT imaging of a xenografted tumour model. Our work provides a facile method to prepare Au-Fe3O4 nanocomposites for dual-modal MR/CT imaging, and this method can be extended to prepare other multifunctional nanoparticles for multimodal bioimaging.

Pushing the cycling stability limit of hierarchical metal oxide core/shell nanoarrays pseudocapacitor electrodes by nanoscale interface optimization.

Three-dimensional hierarchical metal oxide core/shell nanowire arrays (HMONAs) have become promising pseudocapacitive materials due to their integrated smart architectures. However, these core/shell nanostructures have unsatisfactory structural stability and frequently suffer destruction during their fabrication process and their charge-discharge cycles, thus limiting their application lifespan. Herein, a general strategy based on the minimization of the lattice mismatch between the shell and the backbone at the nanoscale interface has been proposed to improve the cycling stability of the HMONAs. This strategy is achieved by a facile hydrothermal pretreatment under mild acidic condition, where a selective dissolution process occurs for interface optimization. To prove the concept, three typical HMONAs, α-MnO2 nanotube@δ-MnO2 nanosheet core/shell arrays, α-MnO2 nanotube@NiO nanosheet core/shell arrays and Co3O4@MnO2 core/shell nanoarrays, were synthesized for interface optimization. It was found that these thermodynamically unstable nanostructures in the shells of HMONAs can be selectively dissolved under a hydrothermal process, leading to enhanced stability of HMONAs. The comparison study indicates that all treated HMONAs exhibit excellent capacitance retention of 93.2% (MnO2@MnO2), 94.3% (MnO2@NiO) and 95.3% (Co3O4@MnO2) after 5000 cycles, which are 22.9%, 9.3% and 20.1% higher, respectively, than those of the untreated HMONAs. Furthermore, the symmetrical supercapacitors based on treated MnO2@MnO2 nanoarrays electrodes also demonstrate 92% capacitance retention after 5000 cycles, showing better comprehensive performance than their untreated counterpart (78% capacitance retention). The general strategy of nanoscale interface optimization provides new opportunities in pushing the cycling stability limit of HMONAs.

Magnetic nanoparticles based cancer therapy: current status and applications.

Nanotechnology holds a promising potential for developing biomedical nanoplatforms in cancer therapy. The magnetic nanoparticles, which integrate uniquely appealing features of magnetic manipulation, nanoscale heat generator, localized magnetic field and enzyme-mimics, prompt the development and application of magnetic nanoparticles-based cancer medicine. Considerable success has been achieved in improving the magnetic resonance imaging (MRI) sensitivity, and the therapeutic function of the magnetic nanoparticles should be given adequate attention. This work reviews the current status and applications of magnetic nanoparticles based cancer therapy. The advantages of magnetic nanoparticles that may contribute to improved therapeutics efficacy of clinic cancer treatment are highlighted here.

Thermokinetic profile of NDM-1 and its inhibition by small carboxylic acids.

The New Delhi metallo-ß-lactamase (NDM-1) is an important clinical target for antimicrobial research, but there are insufficient clinically useful inhibitors and the details of NDM-1 enzyme catalysis remain unclear. The aim of this work is to provide a thermodynamic profile of NDM-1 catalysed hydrolysis of ß-lactams using an isothermal titration calorimetry (ITC) approach and to apply this new method to the identification of new low-molecular-weight dicarboxylic acid inhibitors. The results reveal that hydrolysis of penicillin G and imipenem by NDM-1 share the same thermodynamic features with a significant intrinsic enthalpy change and the release of one proton into solution, while NDM-1 hydrolysis of cefazolin exhibits a different mechanism with a smaller enthalpy change and the release of two protons. The inhibitory constants of four carboxylic acids are found to be in the micromolar range. The compounds pyridine-2,6-dicarboxylic acid and thiazolidine-2,4-dicarboxylic acid show the best inhibitory potency and are confirmed to inhibit NDM-1 using a clinical strain of Escherichia coli The pyridine compound is further shown to restore the susceptibility of this E. coli strain to imipenem, at an inhibitor concentration of 400 µM, while the thiazoline compound also shows a synergistic effect with imipenem. These results provide valuable information to enrich current understanding on the catalytic mechanism of NDM-1 and to aid the future optimisation of ß-lactamase inhibitors based on these scaffolds to tackle the problem of antibiotic resistance.

AMF responsive DOX-loaded magnetic microspheres: transmembrane drug release mechanism and multimodality postsurgical treatment of breast cancer.

DOX-loaded magnetic alginate-chitosan microspheres (DM-ACMSs) were developed as a model system to evaluate alternating magnetic field (AMF)-responsive, chemo-thermal synergistic therapy for multimodality postsurgical treatment of breast cancer. This multimodality function can be achieved by the combination of DOX for chemotherapy, with superparamagnetic iron oxide nanoparticles (SPIONs) as magnetic hyperthermia agents and drug release trigger. Both moieties are encapsulated in ACMSs which also allow on-demand drug release. It is demonstrated that the optimized SPION content in DM-ACMSs is about 0.29 mg Fe, at which DM-ACMSs could exhibit the best hyperthermia performance. Under a remote AMF, DM-ACMs can quickly reach a 22.5% cumulative drug release in the tumor site within 10 min upon exposure under AMF, whereas only 0.2% DOX is released in the absence of AMF. Furthermore, a comparison study of AMF and water bath as heating source indicates that the cumulative drug release amount upon AMF exposure is twice that by water bath heating. Further analysis revealed that the AMF stimulated drug release is driven by both thermal and concentration gradient from inside to outside, which can be well-described by the coupling mechanism of mass and heat transfer using the Soret diffusion model. In vitro cytotoxicity tests on MCF-7 breast cancer cells show that the combined therapy based on DM-ACMSs leads to 95.5% cell death, about 1.5-fold and 1.1-fold higher than that of single magnetic hyperthermia or chemotherapy, respectively. The in vivo anti-tumor effect on tumor-bearing mice demonstrates that the residual tumor disappears in 12 days after chemo-thermal synergistic treatment using DM-ACMSs, and there is no recurrence in the entire experiment period (40 days) as compared to 25 days recurrence for single-modality treatment. Our results not only provide an innovative DM-ACMSs system as a stimuli-responsive, synergistic chemo-thermal therapy platform for efficient reduction in the recurrence of breast cancer, but also provide insight into the intricate interplay of the functional components in magnetic hydrogel microspheres.

Ultrasmall Ferrite Nanoparticles Synthesized via Dynamic Simultaneous Thermal Decomposition for High-Performance and Multifunctional T1 Magnetic Resonance Imaging Contrast Agent.

Large-scale synthesis of monodisperse ultrasmall metal ferrite nanoparticles as well as understanding the correlations between chemical composition and MR signal enhancement is critical for developing next-generation, ultrasensitive T1 magnetic resonance imaging (MRI) nanoprobes. Herein, taking ultrasmall MnFe2O4 nanoparticles (UMFNPs) as a model system, we report a general dynamic simultaneous thermal decomposition (DSTD) strategy for controllable synthesis of monodisperse ultrasmall metal ferrite nanoparticles with sizes smaller than 4 nm. The comparison study revealed that the DSTD using the iron-eruciate paired with a metal-oleate precursor enabled a nucleation-doping process, which is crucial for particle size and distribution control of ultrasmall metal ferrite nanoparticles. The principle of DSTD synthesis has been further confirmed by synthesizing NiFe2O4 and CoFe2O4 nanoparticles with well-controlled sizes of ∼3 nm. More significantly, the success in DSTD synthesis allows us to tune both MR and biochemical properties of magnetic iron oxide nanoprobes by adjusting their chemical composition. Beneficial from the Mn2+ dopant, the synthesized UMFNPs exhibited the highest r1 relaxivity (up to 8.43 mM-1 s-1) among the ferrite nanoparticles with similar sizes reported so far and demonstrated a multifunctional T1 MR nanoprobe for in vivo high-resolution blood pool and liver-specific MRI simultaneously. Our study provides a general strategy to synthesize ultrasmall multicomponent magnetic nanoparticles, which offers possibilities for the chemical design of a highly sensitive ultrasmall magnetic nanoparticle based T1 MRI probe for various clinical diagnosis applications.