A Smart Hyperthermia Nanofiber-Platform-Enabled Sustained Release of Doxorubicin and 17AAG for Synergistic Cancer Therapy

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.     

System control-mediated drug delivery towards complex systems via nanodiamond carriers

Cells represent the basic units of life and contain an intertwined network of signaling and regulatory circuitries that drive the processes of life. These processes include the mediation of mechano-sensation, onset of and protection against disease, inflammation, and others. In the network of bio-complex systems, each pathway interacts nonlinearly with others through different molecular intermediates. As a result, specific functionalities can not be simply linked to the cellular molecules in isolation. A complex system generally possesses very rich information content that can be characterized by the following features: (i) they contain a large number of building blocks; (ii) their interactions among building blocks and with their environment; (iii) they display organization without an external organizing principle being applied; and (iv) they exhibit adaptability and robustness. These properties account for the innate intelligence of biology and its ability to regulate its homeostatic behavior. However, this same complexity underlies, in cancer for example, challenges towards disease management, as the addressing of singular pathways with therapeutic compounds is not sufficient. Therefore, combinatorial therapy often serves as a key strategy towards tumor suppression. Because iterative searching for optimized therapeutic combinations is indeed a daunting, if not preclusive task, we introduce the feedback system control (FSC) scheme, which may serve as a clinically relevant approach, provided a translational approach towards drug delivery is employed. Due to their innate biocompatibility, which has been comprehensively observed, as well as their ability to delivery virtually any type of therapeutic in a sustained fashion due to their unique surface properties, nanodiamonds may serve as a foundation for nano-enabled combinatorial therapy.     

Fluorescent magnetic nanoparticle-labeled mesenchymal stem cells for targeted imaging and hyperthermia therapy of in vivo gastric cancer

How to find early gastric cancer cells in vivo is a great challenge for the diagnosis and therapy of gastric cancer. This study is aimed at investigating the feasibility of using fluorescent magnetic nanoparticle (FMNP)-labeled mesenchymal stem cells (MSCs) to realize targeted imaging and hyperthermia therapy of in vivo gastric cancer. The primary cultured mouse marrow MSCs were labeled with amino-modified FMNPs then intravenously injected into mouse model with subcutaneous gastric tumor, and then, the in vivo distribution of FMNP-labeled MSCs was observed by using fluorescence imaging system and magnetic resonance imaging system. After FMNP-labeled MSCs arrived in local tumor tissues, subcutaneous tumor tissues in nude mice were treated under external alternating magnetic field. The possible mechanism of MSCs targeting gastric cancer was investigated by using a micro-multiwell chemotaxis chamber assay. Results show that MSCs were labeled with FMNPs efficiently and kept stable fluorescent signal and magnetic properties within 14 days, FMNP-labeled MSCs could target and image in vivo gastric cancer cells after being intravenously injected for 14 days, FMNP-labeled MSCs could significantly inhibit the growth of in vivo gastric cancer because of hyperthermia effects, and CCL19/CCR7 and CXCL12/CXCR4 axis loops may play key roles in the targeting of MSCs to in vivo gastric cancer. In conclusion, FMNP-labeled MSCs could target in vivo gastric cancer cells and have great potential in applications such as imaging, diagnosis, and hyperthermia therapy of early gastric cancer in the near future.     

In Silico Study on Tumor-Size-Dependent Thermal Profiles inside an Anthropomorphic Female Breast Phantom Subjected to Multi-Dipole Antenna Array

Electromagnetic hyperthermia as a potent adjuvant for conventional cancer therapies can be considered valuable in modern oncology, as its task is to thermally destroy cancer cells exposed to high-frequency electromagnetic fields. Hyperthermia treatment planning based on computer in silico simulations has the potential to improve the localized heating of breast tissues through the use of the phased-array dipole applicators. Herein, we intended to improve our understanding of temperature estimation in an anatomically accurate female breast phantom embedded with a tumor, particularly when it is exposed to an eight-element dipole antenna matrix surrounding the breast tissues. The Maxwell equations coupled with the modified Pennes’ bioheat equation was solved in the modelled breast tissues using the finite-difference time-domain (FDTD) engine. The microwave (MW) applicators around the object were modelled with shortened half-wavelength dipole antennas operating at the same 1 GHz frequency, but with different input power and phases for the dipole sources. The total input power of an eight-dipole antenna matrix was set at 8 W so that the temperature in the breast tumor did not exceed 42 °C. Finding the optimal setting for each dipole antenna from the matrix was our primary objective. Such a procedure should form the basis of any successful hyperthermia treatment planning. We applied the algorithm of multi for multi-objective optimization for the power and phases for the dipole sources in terms of maximizing the specific absorption rate (SAR) parameter inside the breast tumor while minimizing this parameter in the healthy tissues. Electro-thermal simulations were performed for tumors of different radii to confirm the reliable operation of the given optimization procedure. In the next step, thermal profiles for tumors of various sizes were calculated for the optimal parameters of dipole sources. The computed results showed that larger tumors heated better than smaller tumors; however, the procedure worked well regardless of the tumor size. This verifies the effectiveness of the applied optimization method, regardless of the various stages of breast tumor development.     

核素治疗骨转移瘤患者免疫学指标与预后的关系

目的　研究放射性核素89SrCl2 治疗骨转移瘤前后机体免疫功能变化及免疫学指标与预后关系。方法　选择经89SrCl2 治疗的患者 17例及正常对照 2 0例。分别检测治疗组治疗前、后及正常对照组CD+4、CD+8、CD+4/CD+8、TNF α和IL 2值 ,并对死亡患者与存活患者各项指标进行比较。结果　正常对照组与治疗组治疗前后各项指标差异均有显著意义 (P <0 .0 5 )。死亡患者与存活患者之间各项指标差异均有显著意义 (P <0 .0 5 )。结论　通过对CD+4、CD+8、CD+4/CD+8、TNF α及IL 2水平监测 ,为进一步选择治疗药物和治疗时机提供良好的指标     

New Therapeutic Approaches for Conjunctival Melanoma—What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells

Conjunctival melanoma (CM) accounts for 5% of all ocular melanomas and arises from malignantly transformed melanocytes in the conjunctival epithelium. Current therapies using surgical excision in combination with chemo- or cryotherapy still have high rates for recurrences and metastatic disease. Lately, novel signal transduction-targeted and immune checkpoint inhibitors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) receptor inhibitors, BRAF- or MEK-inhibitors for systemic treatment of melanoma have improved the outcome even for unresectable cutaneous melanoma, improving patient survival dramatically. The use of these therapies is now also recommended for CM; however, the immunological background of CM is barely known, underlining the need for research to better understand the immunological basics when treating CM patients with immunomodulatory therapies. Immune checkpoint inhibitors activate tumor defense by interrupting inhibitory interactions between tumor cells and T lymphocytes at the so-called checkpoints. The tumor cells exploit these inhibitory targets on T-cells that are usually used by dendritic cells (DCs). DCs are antigen-presenting cells at the forefront of immune response induction. They contribute to immune tolerance and immune defense but in the case of tumor development, immune tolerance is often prevalent. Enhancing the immune response via DCs, interfering with the lymphatic pathways during immune cell migration and tumor development and specifically targeting tumor cells is a major therapeutic opportunity for many tumor entities including CM. This review summarizes the current knowledge on the function of lymphatic vessels in tumor growth and immune cell transport and continues to compare DC subsets in CM with related melanomas, such as cutaneous melanoma and mucosal melanoma.     

Magnetic Particle Imaging: Current and Future Applications,Magnetic Nanoparticle Synthesis Methods and Safety Measures

Magnetic nanoparticles (MNPs) have a wide range of applications; an area of particular interest is magnetic particle imaging (MPI). MPI is an imaging modality that utilizes superparamagnetic iron oxide particles (SPIONs) as tracer particles to produce highly sensitive and specific images in a broad range of applications, including cardiovascular, neuroimaging, tumor imaging, magnetic hyperthermia and cellular tracking. While there are hurdles to overcome, including accessibility of products, and an understanding of safety and toxicity profiles, MPI has the potential to revolutionize research and clinical biomedical imaging. This review will explore a brief history of MPI, MNP synthesis methods, current and future applications, and safety concerns associated with this newly emerging imaging modality.     

Nanomedicine-Based Delivery Strategies for Breast Cancer Treatment and Management

Breast cancer is one of the most common types of cancer among women globally. It is caused by mutations in the estrogen/progesterone receptors and conventional treatment methods are commonly utilized. About 70–80 percent of individuals with the early-stage non-metastatic disease may be cured. Conventional treatment is far less than the optimal ratio, as demonstrated through the high mortality rate of women with this cancer. However, conventional treatment methods like surgery, radiotherapy, and chemotherapy are not as effective as expected and lead to concerns about low bioavailability, low cellular uptake, emerging resistance, and adverse toxicities. A nanomedicine-based approach is a promising alternative for breast cancer treatment. The present era is witnessing rapid advancements in nanomedicine as a platform for investigating novel therapeutic applications and modern intelligent healthcare management strategies. This paper focuses on nanomedicine-based therapeutic interventions that are becoming more widely accepted for improving treatment effectiveness and reducing undesired side effects in breast cancer patients. By evaluating the state-of-the-art tools and taking the challenges involved into consideration, various aspects of the proposed nano-enabled therapeutic approaches have been discussed in this review.     

交变磁场中Fe3O4磁流体对肿瘤组织加热作用的理论研究

磁流体在肿瘤中的扩散和能量在肿瘤中的传递是磁流体热疗中的关键过程,并直接影响到治疗的效果。本文针对这些关键过程,建立了靶区内球形肿瘤的多物理场耦合模型,并采用有限元方法,对其进行了数值求解,获得了肿瘤靶区组织的压力分布、温度分布及磁流体浓度分布。分析了扩散时间、注射点以及磁流体比吸收率等关键因素对温度分布的影响。结果表明,延长扩散时间、在注射总量一定的情况下增加注射点数及增大比吸收率,均可使肿瘤中达到细胞坏死温度的体积增大,从而提高肿瘤的治愈率。但增大比吸收率的同时也会使正常组织的温升增加。     

钙铁硅铁磁体微晶玻璃生物活性的模拟体液研究

为了研究用作温热治疗肿瘤热种子材料的钙铁硅铁磁体微晶玻璃的生物活性，试样在模拟体液中浸泡以后，用ＳＥＭ、俄昂扬电子能谱、ＦＴ－ＩＲ对其表面生成的江膜进行观察和分析，研究结果表明，试样表面的硅胶层上生成物活性。     

交变磁场中Fe3O4磁流体对肿瘤组织加热作用的理论研究

磁流体在肿瘤中的扩散和能量在肿瘤中的传递是磁流体热疗中的关键过程,并直接影响到治疗的效果。本文针对这些关键过程,建立了靶区内球形肿瘤的多物理场耦合模型,并采用有限元方法,对其进行了数值求解,获得了肿瘤靶区组织的压力分布、温度分布及磁流体浓度分布。分析了扩散时间、注射点以及磁流体比吸收率等关键因素对温度分布的影响。结果表明,延长扩散时间、在注射总量一定的情况下增加注射点数及增大比吸收率,均可使肿瘤中达到细胞坏死温度的体积增大,从而提高肿瘤的治愈率。但增大比吸收率的同时也会使正常组织的温升增加。     

Ethanol Enhances Hyperthermia-Induced Cell Death in Human Leukemia Cells

Ethanol has been shown to exhibit therapeutic properties as an ablative agent alone and in combination with thermal ablation. Ethanol may also increase sensitivity of cancer cells to certain physical and chemical antitumoral agents. The aim of our study was to assess the potential influence of nontoxic concentrations of ethanol on hyperthermia therapy, an antitumoral modality that is continuously growing and that can be combined with classical chemotherapy and radiotherapy to improve their efficiency. Human leukemia cells were included as a model in the study. The results indicated that ethanol augments the cytotoxicity of hyperthermia against U937 and HL60 cells. The therapeutic benefit of the hyperthermia/ethanol combination was associated with an increase in the percentage of apoptotic cells and activation of caspases-3, -8 and -9. Apoptosis triggered either by hyperthermia or hyperthermia/ethanol was almost completely abolished by a caspase-8 specific inhibitor, indicating that this caspase plays a main role in both conditions. The role of caspase-9 in hyperthermia treated cells acquired significance whether ethanol was present during hyperthermia since the alcohol enhanced Bid cleavage, translocation of Bax from cytosol to mitochondria, release of mitochondrial apoptogenic factors, and decreased of the levels of the anti-apoptotic factor myeloid cell leukemia-1 (Mcl-1). The enhancement effect of ethanol on hyperthermia-activated cell death was associated with a reduction in the expression of HSP70, a protein known to interfere in the activation of apoptosis at different stages. Collectively, our findings suggest that ethanol could be useful as an adjuvant in hyperthermia therapy for cancer.     

Mucin Glycopeptide-Protein Conjugates – Promising Antitumor Vaccine Candidates

Recent efforts towards the development of synthetic glycopeptide vaccines, which aim at the active immunization of patients against their own tumor tissues, are outlined. To achieve sufficient tumor selectivity, glycopeptides of the tandem repeat region of tumor-associated mucin, MUC1, have been synthesized. Since the endogenous structures usually exert low immunogenicity, these glycopeptide antigens, as B-cell epitopes, were conjugated with immunostimulating components. In the present short review, work is outlined in which the MUC1 B-cell epitope peptides are conjugated with bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), or tetanus toxoid (TTox). In particular, the synthetic vaccines based on tetanus toxoid induce very strong tolerance-breaking immune responses in mice. The induced antibodies of the IgG type indicate the installation of an immunological memory. In addition, these antibodies strongly bind to human breast tumor cells in culture, demonstrated by flow cytometry experiments, and also to the tumor cells in mammary carcinoma tissues.     

New insights into the heating mechanisms and self-regulating abilities of manganite perovskite nanoparticles suitable for magnetic fluid hyperthermia

The heating and self-regulating abilities of La(1-x)Sr(x)MnO(3+Δ) ferromagnetic nanoparticles for magnetic fluid hyperthermia are studied. The samples, synthesized by the Glycine Nitrate Process, present non-agglomerated particles but are partially constituted by polycrystalline nanoparticles, displaying average crystallite diameters ranging from 21 to 31 nm. The strontium content of these nanoparticles, between 0.14 and 0.39, is associated with non-stoichiometry effects in the materials, and both govern their Curie temperatures (T(C)), which range between 13 and 86 °C, respectively. Heating experiments carried out on samples suspended in an aqueous agarose gel and with different alternating magnetic fields derive unexpected maximum temperatures that cannot be explained on the basis of static magnetization data. The measurement of the thermal dependence of the specific absorption rate (SAR) of nanopowders by adiabatic magnetothermia reveals the existence of a dissipation peak just below T(C), which is assigned to a Hopkinson peak. This thermal dependence of SAR, together with a simple thermal model that considers a linear approximation for the heat power losses, is crucial to clarify the behavior observed in heating experiments and also to discuss the possibilities of the samples as self-regulating hyperthermia mediators. This analysis emphasizes that, for the correct design of a self-regulating system, the heat power losses determined by the surrounding conditions must be taken into account as well as the heating capacity of the magnetic nanoparticles.     

The Pathogenesis of Giant Condyloma Acuminatum (Buschke-Lowenstein Tumor): An Overview

Giant condyloma acuminatum, also known as Buschke-Lowenstein tumor (BLT), is a rare disease of the anogenital region. BLT is considered a locally aggressive tumor of benign histological appearance, but with the potential for destructive growth and high recurrence rates. BLT development is strongly associated with infection with low-risk human papillomaviruses (HPVs), mostly HPV-6 and -11. Immunity to HPVs plays a crucial role in the natural control of various HPV-induced lesions. Large condyloma acuminata are frequently reported in patients with primary (e.g., DOCK8 or SPINK5 deficiencies) and secondary (e.g., AIDS, solid organ transplantation) immune defects. Individuals with extensive anogenital warts, including BLT in particular, should therefore be tested for inherited or acquired immunodeficiency. Research into the genetic basis of unexplained cases is warranted. An understanding of the etiology of BLT would lead to improvements in its management. This review focuses on the role of underlying HPV infections, and human genetic and immunological determinants of BLT.     

Hyperthermia Induces Apoptosis through Endoplasmic Reticulum and Reactive Oxygen Species in Human Osteosarcoma Cells

Osteosarcoma (OS) is a relatively rare form of cancer, but OS is the most commonly diagnosed bone cancer in children and adolescents. Chemotherapy has side effects and induces drug resistance in OS. Since an effective adjuvant therapy was insufficient for treating OS, researching novel and adequate remedies is critical. Hyperthermia can induce cell death in various cancer cells, and thus, in this study, we investigated the anticancer method of hyperthermia in human OS (U-2 OS) cells. Treatment at 43 °C for 60 min induced apoptosis in human OS cell lines, but not in primary bone cells. Furthermore, hyperthermia was associated with increases of intracellular reactive oxygen species (ROS) and caspase-3 activation in U-2 OS cells. Mitochondrial dysfunction was followed by the release of cytochrome c from the mitochondria, and was accompanied by decreased anti-apoptotic Bcl-2 and Bcl-xL, and increased pro-apoptotic proteins Bak and Bax. Hyperthermia triggered endoplasmic reticulum (ER) stress, which was characterized by changes in cytosolic calcium levels, as well as increased calpain expression and activity. In addition, cells treated with calcium chelator (BAPTA-AM) blocked hyperthermia-induced cell apoptosis in U-2 OS cells. In conclusion, hyperthermia induced cell apoptosis substantially via the ROS, ER stress, mitochondria, and caspase pathways. Thus, hyperthermia may be a novel anticancer method for treating OS.     

Twist and miR-34a Are Involved in the Generation of Tumor-Educated Myeloid-Derived Suppressor Cells

Tumors can induce the generation and accumulation of immunosuppressive cells such as myeloid-derived suppressor cells in the tumor microenvironment, contributing to tumor immunological escapes. Many studies have demonstrated that multiple factors could induce myeloid precursor cells into myeloid-derived suppressor cells, not dendritic cells. In our study, we found that tumor supernatants could induce the generation of myeloid-derived suppressor cells by disturbing the development of dendritic cells. Twist and miR-34a may regulate the effect of tumor cells inducing myeloid-derived suppressor cells via TGF-β and/or IL-10.     

铁钙硅铁磁体微晶玻璃——一种治癌生物材料

扼要叙述温热疗法治疗癌症的原理,比较详尽地介绍了关于作为温热疗法热种子的铁钙硅铁磁体微晶玻璃的组成,形成过程,结构,磁性,生物相容性及癌症试验等方面研究的最新进展。     

PEGylated copper(II)-chelated polydopamine nanocomposites for photothermal-enhanced chemodynamic therapy against tumor cells

Photothermal-enhanced chemodynamic therapy is a novel and promising strategy for effective tumor treatment. Herein, a kind of polydopamine (PDA)-based nanoplatform is reported for photothermal-enhanced chemodynamic therapy against tumor cells. PDA nanoparticles (NPs) were prepared through the self-polymerization method, which were subsequently chelated with Cu²⁺ and linked with poly(ethylene glycol) (PEG) chains, finally obtaining PDA-Cu(II)-PEG NPs. The fabricated PDA-Cu(II)-PEG NPs were uniform in shape with a narrow polydispersity. They can firstly react with glutathione (GSH) to generate Cu⁺, inducing GSH depletion meanwhile. The formed Cu⁺ could catalyze H₂O₂ to produce hydroxyl radicals (˙OH) via a Fenton-like reaction. The formed PDA-Cu(II)-PEG NPs displayed good photothermal conversion efficiency and photothermal stability. They can be internalized by 4T1 cells effectively. Under near-infrared light irradiation, PDA-Cu(II)-PEG NPs can generate hyperthermia and ˙OH for photothermal/chemodynamic therapy against tumor cells.     

温热疗法治癌材料现状

癌症是人类面临的一大医学难题,作为一种有效的治癌新方法--温热疗法正成为国际研究的热点.本文介绍了温热疗法的原理及近年来研究较多的一些温热治癌材料,其中包括:磁性微晶玻璃、低居里点铁氧体、合金热籽和磁流体,并对温热疗法治癌材料的研究发展予以展望.