A multifunctional nanoplatform for improving microwave hyperthermia by a combination therapy of vessel disruptive agent and immune modulator.

Microwave (MW) hyperthermia is one of the safest and most efficient minimally invasive tumor treatment methods, it is restricted by the bottlenecks of the heat sink effect and ineffective immune activation. Herein, a multifunctional nano platform with the load of nano immune modulator bimetallic metal-organic framework (BM), tumor vessel destructive agent and prodrug for gas production is developed for improving MW hyperthermia. Specifically, the combretastatin A4 phosphate (CA4P) was a vessel destructive agent to reduce MW heat loss by destructing the tumor blood vessel. Moreover, the as designed BM can scavenge the endogenic reactive oxygen species, which is conducive to hydrogen sulfide gas (H2S) that produced by bismuth sulfide (Bi2S3) to activate immune cells. Our in vivo experimental results demonstrate the destruction of tumor blood vessels coupled with the activated immune system results in the remarkable antitumor effect. This study provides an efficient strategy to improve MW hyperthermia by a combination of vasculature-targeting therapy with systemic immunity.

High Biocompatible Poly(lactic-co-glycolic acid)-Based Nanosensitizer With Magnetic Resonance Imaging Capacity for Tumor Targeted Microwave Hyperthermia and Chemotherapy.

Microwave (MW) hyperthermia has been widely studied in tumor therapy, while the lack of specificity, and the potential toxicity induced by instability or difficulty in degradation of existed MW thermal sensitizers still limits the application. Herein, a new biocompatible Poly(lactic-co-glycolic acid) (PLGA)-based nanosensitizer of Dtxl-Gd@PLGA-PEG-TPP (DGPPT) with capacities of magnetic resonance (MR) imaging and mitochondrial targeting for MW hyperthermia combined with chemotherapy was constructed via a double emulsion solvent evaporation method. The modified TPP significantly enhanced the specificity of sensitizer for targeting mitochondria, a heat-sensitive energy supply plant in cells. Thus the MW thermal damage induced by the loaded Gd in PLGA nanospheres was also strengthened. Together, the system could also achieve MR imaging due to the existence of Gd. In addition, the encapsulated Dtxl performed the chemotherapy of inhibiting mitochondrial function for assisting with MW hyperthermia. In vivo experiments demonstrated that PLGA had high biocompatibility that no obvious damage occurred even the dose was up to 200 mg/kg. Meanwhile, DGPPT+MW representing the combination of mitochondrial targeting and MW hyperthermia-chemotherapy has also been proved to shrink tumor size effectively. This study provides a new direction for building biosafe and multifunctional MW sensitizer with active targeting ability to impede tumor growth.

Fe(III)-Chelated Polydopamine Nanoparticles for Synergistic Tumor Therapies of Enhanced Photothermal Ablation and Antitumor Immune Activation.

Both the low energy density of near-infrared (NIR) photothermal conversion during treatment and the recurrence and metastasis after local treatment have been the main obstacles and conundrums in polydopamine-mediated tumor photothermal therapy (PTT). Herein, On the basis of the enhancement of NIR absorption by ligand to metal charge transfer (LMCT) in transition-metal complexes and the activation of antitumor immunity by an appropriate concentration of Fe(III) ions, Fe(III)-chelated PDA nanoparticles (Fe-PDA NPs) with high loading and responsive release of iron ions were synthesized through a prechelation-polymerization method. First, Fe(III) chelated with the catechol groups in DA to form a mono-dopa-Fe(III) chelate, and then the polymerization of dopamine was initiated under alkaline conditions. The results revealed that the mono-dopa-Fe(III) chelate was still the main form of the Fe ion existing in Fe-PDA and was able to greatly enhance the light absorption behaviors of PDA in NIR, resulting a superior photothermal conversion ability (η = 55.5%). Moreover, the existence of Fe(III) also gave Fe-PDA a T1-weighted MRI contrast-enhancement performance (r1 = 7.668 mM-1 s-1) and it would enable the accurate ablation of primary tumors in vivo with Fe-PDA under NIR irradiation by means of the guidance of MRI and thermal imaging. Furthermore, Fe-PDA exhibited better H2O2-responsive biodegradability in comparison to PDA and easily released Fe ions in tumors, which could effectively promote the tumor-associated macrophage (TAM) repolarization to the M1 mode. TAM repolarization combined with the immunogenic cell death (ICD) induced by PTT could effectively enhance the efficacy of immunotherapy, preventing tumor recurrence and metastasis. The design of Fe-PDA nanoparticles should provide more inspiration for structural and functional improvements of melanin-based materials in tumor suppression.

Preparation of carboxylic graphene oxide-composited polypyrrole conduits and their effect on sciatic nerve repair under electrical stimulation.

Carboxylic graphene oxide-composited polypyrrole/poly-l-lactic acid (C-GO/PPy/PLLA) films were fabricated by electrochemical deposition of C-GO-composited PPy on PLLA fibers-film, and their conductivity and tensile strength (∼4.6 S/cm and 26.4 MPa, respectively) were stably remained after the immersion of 4 weeks, due to the hydrogen bond interaction between graphene oxide's carboxylic groups and pyrrole's imino groups. Their specific surface areas of ∼57.5 m2 /g and pore volume of ∼0.02 cm3 /g were significantly larger than those of PPy/PLLA films, due to the addition of C-GO nanosheets. Then, C-GO/PPy/PLLA conducting conduit with 2 mm inner diameter was prepared to bridge 10 mm sciatic nerve defect of rats, and the direction of fiber-axis in the conduit was the same as the conduit central axis. Electrical stimulation (ES) of 1 V and 20 Hz through the conducting conduit was exerted on the defect site. The results of in vivo electrophysiological and histological evaluation indicated that, the sciatic nerve defect could be repaired in C-GO/PPy/PLLA conduit, moreover the re-innervated gastrocnemius muscle and nerve conduction in C-GO/PPy/PLLA conduit & ES group were obviously better than the conduit without ES group. The results of transmission electron microscope analysis also demonstrated that the mean thickness of myelin sheath and diameter of axon in C-GO/PPy/PLLA conduit & ES group were significantly larger than those without ES, suggesting that the repair efficiency of ES & conduit group was closer to that of autograft group. These results indicated the great potential of C-GO/PPy/PLLA with the in vivo ES in the application of sciatic nerve repair.

Mitochondria-targeted zirconium metal-organic frameworks for enhancing the efficacy of microwave thermal therapy against tumors.

Although microwave (MW) thermal therapy has been widely studied for the treatment of tumors due to its less invasiveness, recurrence of tumors is still observed because of the relatively low bioavailability of MW sensitizers. For enhancing the bioavailability of MW sensitizers, triphenyl phosphate (TPP)-conjugated and doxorubicin (DOX)-loaded porous zirconium metal-organic framework nanocubes (ZrMOF NCs) modified with polyethylene glycol (PEG), ZrMOF-PEG-TPP@DOX NCs, were prepared as a MW sensitizer with mitochondrial-targeting ability. Moreover, the mitochondria are more susceptible to heat than the tumor tissues; this leads to improved tumor cell apoptosis. The results of this study indicate that ZrMOF NCs exhibit excellent heating effects due to the increased collisions of ions in the micropores of ZrMOFs under MW irradiation. In addition, ZrMOF-PEG-TPP@DOX NCs show preferential aggregation in the mitochondria, confirmed by confocal microscopy images. In vivo MW thermal therapeutic efficacy of ZrMOF-PEG-TPP@DOX NCs + MW is also better without recurrence during treatment than that of ZrMOF-PEG@DOX NCs + MW at a similar thermal therapeutic temperature; this reveals that the mitochondrial-targeting strategy can enhance the MW thermal therapeutic efficacy. This study provides a new biosafe MW sensitizer with mitochondrial-targeting ability for enhancing the efficacy of MW thermal therapy against tumors.

Microwave-Activated Mn-Doped Zirconium Metal-Organic Framework Nanocubes for Highly Effective Combination of Microwave Dynamic and Thermal Therapies Against Cancer.

Developing functional nanoagents for achieving the combination of microwave dynamic therapy (MDT) and microwave thermal therapy (MTT) is highly desirable due to the advantages of improving the therapeutic effect on tumors and minimizing the side effects. Metal-organic frameworks (MOFs), as emerging porous materials, exhibit many intriguing properties for application in biomedicine. Herein, new-style flexible Mn-doped zirconium metal-organic framework (Mn-ZrMOF) nanocubes (NCs) with the average size of about 60 nm were prepared easily by a one-pot hydrothermal method. Due to the strong inelastic collision of ions confined in a large number of micropores, the Mn-ZrMOF NCs were demonstrated to be an effective microwave-sensitive agent with a high thermal conversion efficiency up to 28.7%, which is the highest one of the recently reported microwave-sensitive agents. This is the first report of determining the microwave thermal conversion efficiency, which can be used to evaluate, compare, and predict the microwave sensitivity of different microwave-sensitive agents. More importantly, such Mn-ZrMOF NCs generate abundant reactive oxygen species (ROS) of hydroxyl radicals under microwave irradiation. As such, the Mn-ZrMOF NCs efficiently suppress the tumor cell growth in vivo and in vitro under mild microwave irradiation for the synergic effect of MTT and MDT. This work paves the way for developing nanoagents that are responsive to microwave irradiation, producing ROS and improving thermal effects to realize the noninvasive MTT and MDT treatment in clinics.

In Vivo Magnetic Resonance Imaging and Microwave Thermotherapy of Cancer Using Novel Chitosan Microcapsules.

Herein, we develop a novel integrated strategy for the preparation of theranostic chitosan microcapsules by encapsulating ion liquids (ILs) and Fe3O4 nanoparticles. The as-prepared chitosan/Fe3O4@IL microcapsules exhibit not only significant heating efficacy in vitro under microwave (MW) irradiation but also obvious enhancement of T2-weighted magnetic resonance (MR) imaging, besides the excellent biocompatibility in physiological environments. The chitosan/Fe3O4@IL microcapsules show ideal temperature rise and therapeutic efficiency when applied to microwave thermal therapy in vivo. Complete tumor elimination is realizing after MW irradiation at an ultralow power density (1.8 W/cm(2)), while neither the MW group nor the chitosan microcapsule group has significant influence on the tumor development. The applicability of the chitosan/Fe3O4@IL microcapsules as an efficient contrast agent for MR imaging is proved in vivo. Moreover, the result of in vivo systematic toxicity shows that chitosan/Fe3O4@IL microcapsules have no acute fatal toxicity. Our study presents an interesting type of multifunctional platform developed by chitosan microcapsule promising for imaging-guided MW thermotherapy.

Fabrication of Aligned Conducting PPy-PLLA Fiber Films and Their Electrically Controlled Guidance and Orientation for Neurites.

Electrically conductive biomaterial scaffolds have great potential in neural tissue regeneration. In this work, an aligned conductive fibrous scaffold was prepared by electrospinning PLLA on rotating collector and chemical oxidation polymerization of pyrrole (PPy) codoped with poly(glutamic acid)/dodecyl benzenesulfonic acid sodium. The characterization results of composition, structure and mechanics of fiber films show that the existence of weak polar van der Waals' force between PPy coating and PLLA fibers. The resistivity of aligned rough PPy-PLLA fiber film (about 800 nm of fiber diameter) at the perpendicular and parallel directions is 0.971 and 0.874 Ω m, respectively. Aligned rough PPy-PLLA fiber film could guide the extension of 68% PC12 neurites along the direction of fiber axis. Under electrostimulation (ES) of 100, 200, and 400 mV/cm, median neurite lengths of differentiated PC12 on aligned fiber-films are 128, 149, and 141 µm, respectively. Furthermore, under ES of 100, 200, and 400 mV/cm, the alignment rate of neurite along the electropotential direction (angle between neurite and electropotential direction ≤10°) on random fibers film are 17, 23, and 28%, respectively, and the alignment rate of neurites along the fiber axis (angle between neurite and fiber axis ≤10°) on aligned fibers film reach to 76, 83, and 79%, respectively, indicating that the combination of ES and rough conducting aligned structure could adjust the alignment of cellular neurites along the direction of the fiber axis or electropotential.

Encapsulating Ionic Liquid and Fe3O4 Nanoparticles in Gelatin Microcapsules as Microwave Susceptible Agent for MR Imaging-guided Tumor Thermotherapy.

The combination of therapies and monitoring the treatment process has become a new concept in cancer therapy. Herein, gelatin-based microcapsules have been first reported to be used as microwave (MW) susceptible agent and magnetic resonance (MR) imaging contrast agent for cancer MW thermotherapy. Using the simple coacervation methods, ionic liquid (IL) and Fe3O4 nanoparticles (NPs) were wrapped in microcapsules, and these microcapsules showed good heating efficacy in vitro under MW irradiation. The results of cell tests indicated that gelatin/IL@Fe3O4 microcapsules possessed excellent compatibility in physiological environments, and they could effectively kill cancer cells with exposure to MW. The ICR mice bearing H22 tumors treated with gelatin/IL@Fe3O4 microcapsules were obtained an outstanding MW thermotherapy efficacy with 100% tumor elimination under ultralow density irradiation (1.8 W/cm(2), 450 MHz). In addition, the applicability of the microcapsules as an efficient contrast agent for MR imaging in vivo was evident. Therefore, these multifunctional microcapsules have a great potential for MR imaging-guided MW thermotherapy.

Gelatin microcapsules for enhanced microwave tumor hyperthermia.

Local and rapid heating by microwave (MW) irradiation is important in the clinical treatment of tumors using hyperthermia. We report here a new thermo-seed technique for the highly efficient MW irradiation ablation of tumors in vivo based on gelatin microcapsules. We achieved 100% tumor elimination in a mouse model at an ultralow power of 1.8 W without any side-effects. The results of MTT assays, a hemolysis test and the histological staining of organs indicated that the gelatin microcapsules showed excellent compatibility with the physiological environment. A possible mechanism is proposed for MW hyperthermia using gelatin microcapsules. We also used gelatin microcapsules capped with CdTe quantum dots for in vivo optical imaging. Our study suggests that these microcapsules may have potential applications in imaging-guided cancer treatment.

Synergistic and sequential effects of BMP-2, bFGF and VEGF on osteogenic differentiation of rat osteoblasts.

In the present study, the effects of bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) on regulation of rat osteoblast (ROB) maturation in vitro were investigated. It was found that the proliferation, differentiation and mineralization of ROBs were all dose-dependently increased at particular times in the case of treatment with only one growth factor. To investigate the effects of combined treatment, ROBs were treated with either a single application of a relatively high dose of each growth factor, or binary/triple combined applications of relatively low doses of the growth factors. Osteogenic differentiation was significantly promoted in the triple combination treatment of BMP-2, VEGF and bFGF compared with the single or binary combination treatments. The optimal timing of the triple combination to enhance osteogenesis was also tested. When bFGF and VEGF were added in the early stage, and BMP-2 and VEGF were added in the late stage, osteogenic differentiation of ROBs could be enhanced more effectively. These results could be used to construct bone tissue engineering scaffolds that release growth factors sequentially.

Fabrication of conductive NGF-conjugated polypyrrole-poly(l-lactic acid) fibers and their effect on neurite outgrowth.

In order to fabricate a tissue scaffold with the neurotrophic and electrical activities, conductive nerve growth factor (NGF)-conjugated polypyrrole-poly(l-lactic acid) (PPy-PLLA) composite fibers were prepared by oxidation polymerization and EDC chemistry with poly-l-lysine. PPy nanoparticles (∼70nm diameter) accumulated on PLLA fiber surface to form a rough thick shell (∼200nm thickness). These NGF-conjugated PPy-PLLA fibers could support PC12 neurite outgrowth and extension. Especially, 40% and 74% increase in PC12 neurite outgrowth and extension, respectively, could be obtained under electrical stimulation of 100mV/cm voltages through the composite fibers. A mechanism for the interaction between neurite extension and the NGF-conjugated PPy-PLLA fibers under electro-stimulation was proposed, to explain the synergistic effect of the rough PPy shell, conjugated NGF and electricity on neurite outgrowth and elongation.