肿瘤微环境响应型NO递送系统及其用于肿瘤联合治疗的研究进展

NO气体治疗是近年来飞速发展的一种新兴的肿瘤治疗方式,因其“绿色”的优点而备受纳米医学的关注.NO气体分子可以作为肿瘤细胞毒性剂和凋亡诱导剂,其治疗效果主要与NO的局部浓度和分布有关.因此,如何维持合适的NO浓度、控制NO的胞内释放、实现NO的精准递送和减少NO的全身毒性,是实现高效NO气体治疗亟需解决的关键科学问题.此外, NO分子还能破坏线粒体并减少ATP的产生,进而能增敏包括化疗在内的其他治疗方法,实现高效的协同治疗.基于这一研究热点,本综述重点介绍了多种刺激响应型NO纳米递送系统,并归纳总结了NO气体治疗与其他抗肿瘤疗法的联合使用策略.     

刺激响应型纳米载体在肿瘤诊疗中的研究进展

刺激响应型纳米载体是通过对外界刺激响应而产生相应结构或理化性质变化的纳米智能载药体系,具有避免药物过早泄露,提高病灶药物浓度的特点,目前已成为肿瘤诊断和治疗领域的研究热点,广泛用于控制药物的呈递和释放.本文从温度、磁场、超声、光、pH等外源和内源刺激角度,阐述了智能响应型纳米载体近年来在肿瘤诊疗领域的研究进展.     

酸敏感离子通道研究进展

组织酸化是生理和病理下常见的现象.神经元可以通过酸敏感的离子通道（ASICs）来感受细胞周围的pH值的降低.ASICs属于NaC/DEG家族的一个成员.目前,已发现了6个ASICs亚基,它们在外周和中枢神经系统中广泛表达,其同聚体和异聚体通道有着各种不同的电生理学特性.ASICs在机体感觉尤其是痛觉中起着至关重要的作用.     

口服抗癌药物纳米载体的研究进展

实现抗癌药物的口服给药,对于癌症的化疗及患者的生活会有很大的方便性。但大多数抗癌药物直接口服给药时,由于受到胃肠道的屏蔽作用导致生物利用度降低,所以寻找一种有效的药物载体,对于实现抗癌药物的口服给药是至关重要的。纳米技术的出现,带动了纳米药物载体的发展,使得抗癌药物的口服给药有了很大的突破。对不同材料,主要包括合成高分子材料、天然高分子材料作为口服抗癌药物载体的特点以及体内体外的研究结果进行回顾和综述。     

pH敏感纳米药物载体在肿瘤治疗中的应用研究

pH敏感的纳米递药系统能有效利用其纳米尺寸以及敏感的连接键响应生物体内外不同的刺激,并通过在肿瘤部位选择性释药、增加药物的蓄积、减少药物在血液循环过程中的渗漏以及减轻毒副作用等方式提高药物生物利用度。根据肿瘤组织内不同的pH值构建多种刺激-响应型纳米载药系统是肿瘤治疗领域的发展趋势。本文综述了pH敏感的纳米药物载体在肿瘤治疗领域的研究与进展,以期为今后相关内容的深入研究提供借鉴。     

新型纳米靶向给药系统载体材料的设计

新型纳米靶向给药系统的研究与开发对于难治愈性疾病（尤其是肿瘤）的治疗具有重大意义,而其发展很大程度上取决于载体材料 的设计。构思巧妙、设计合理的载体材料能使载体实现靶向功能,将药物定位浓集于病灶部位,并最大限度地发挥高效低毒的作用。基于 不同的靶向策略,包括被动靶向、主动靶向和响应肿瘤微环境的靶向,综述了近年来一些新型纳米载体材料的设计,为新型纳米靶向给药 系统的研究提供参考。     

酸敏感离子通道外源性配体研究进展

酸敏感离子通道(ASICs)属于上皮 Na+ 通道/退化蛋白超家族,对细胞外 H+ 浓度变化敏感,其受多种外源性配体调控,产生 不同生理和病理学效应。越来越多研究发现,ASICs 参与脑缺血、炎症、肿瘤等具有酸化改变的病理过程。简介 ASICs 的结构及其配体 作用位点以及各亚基的组织分布和电生理特性,主要对各类 ASICs 外源性配体的研究进展作一综述。     

可控释放纳米载体在癌症治疗中的研究进展

癌症治疗的靶向分子药物的设计与构建,是目前生物医学领域的研究前沿热点之一。靶向药物载体的构建,是通过药物直接加载靶向生物分子或者利用载体自身特性,使化疗药物可以到达并富集在特定组织,所以也被称为"分子火车"。纳米药物的研究已经从单靶向发展到多靶向,实现从单一功能到多功能的应用。单纯的被动释放药物的载体颗粒在复杂的细胞微环境中缺乏精确治疗。因此通过构建带有可控释放特性的纳米药物载体,不仅能有效的提高药物在靶向部位的药物浓度,加强药效,而且还能降低对非靶向组织的毒副作用,提高纳米药物的安全性。常用的控制纳米药物释放的方式包括pH响应,酶响应,光响应,磁响应等。本文主要介绍构建可控药物释放纳米载体的研究进展。     

酸敏感离子通道与脑梗死

急性脑梗死约占全部脑卒中的70%,病死率和致残率高,且极易复发。但目前针对急性脑梗死在时间窗内溶栓、抗凝等治疗手段不能从根本上切实有效地修复受损脑组织,且伴有出血等风险。寻找脑梗死形成发展的原因并予以治疗迫在眉睫。酸中毒是引起缺血性脑损伤的重要机制。大量实验研究表明,酸中毒能加重神经元的缺血性损伤,且其梗死面积与酸中毒的程度直接相关。但缺血产生的酸中毒如何引起神经元损伤的确切机制尚不明确。最近研究发现酸中毒能激活一种在中枢及周围神经中广泛存在的膜通道,即酸敏感离子通道,它对Ca^2＋通透,能引起细胞内Ca^2＋超载,同时能激活胞内酶引起细胞内蛋白质、脂类及核酸的降解,加重缺血后脑损伤。本文就酸敏感离子通道1a与脑梗死做一综述。     

Glucose and pH dual-responsive concanavalin A based microhydrogels for insulin delivery

Glucose and pH dual-responsive microhydrogels based on concanavalin A (Con A) were prepared and used for insulin delivery. The combination of the specific saccharide-binding affinity of Con A and the cationic groups of N-(2-(dimethylamino) ethyl)-methacrylamide (DMAEMA) led to dual-responsive systems. SEM, fluorescence microscopy and particle size analysis showed that the obtained microhydrogels had a dense surface morphology and an average size of 38 μm. The in vitro insulin release study revealed that the microhydrogels could quickly respond to the changes of glucose concentrations in the medium and small change in pH value of the environment. The kinetics of insulin release was analyzed by using empirical equation and the apparent diffusion coefficient was calculated according to a solution of Fick's second law. The released insulin was proved to remain active. The result suggested that this microhydrogel might find potential applications for self-regulated insulin delivery, actuators and separation systems with sensitivity to glucose.     

Tumor‐stroma interactions differentially alter drug sensitivity based on the origin of stromal cells

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large‐scale coculture assay optimized to measure drug‐induced cell death, we identify tumor–stroma interactions that modulate drug sensitivity. Our data show that the chemo‐insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor–stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.     

白桦脂酸的研究进展

白桦脂酸是一种五环三萜酸,存在于多种天然植物,特别是白桦树皮中,毒性低,安全指数高。近年来发现白桦脂酸具有抗肿瘤、抗HIV、抗炎、抗菌、抗疟疾等多种生物活性,特别是在抗黑色素瘤与抗HIV方面具有突出的表现,从而引起了人们极大的研究兴趣。对白桦脂酸的来源和生物活性进行了简要综述。     

Radiation crosslinked psyllium and polyacrylic acid based hydrogels for use in colon specific drug delivery

In order to utilize the psyllium husk, a medicinally important natural polysaccharide, to develop the hydrogels meant for the drug delivery, we have prepared psyllium and polyacrylic acid based polymeric networks by radiation-induced crosslinked copolymerization. Polymeric networks (hydrogels) thus formed were characterized with SEMs, FTIR and swelling studies. Swelling behavior of the hydrogels was studied as a function of monomer concentration in the hydrogels and temperature, pH and [NaCl] of the swelling medium. This paper discusses the swelling kinetics of the hydrogels and release dynamics of anticancer model drug 5-fluorouracil from the hydrogels for the evaluation of swelling and drug release mechanisms. It has been observed from the release dynamics of drug that diffusion exponent ‘n’ have 0.7, 0.8 and 0.7 values and gel characteristics constant ‘k’ have 9.13 × 10⁻³, 6.22 × 10⁻³ and 9.01 × 10⁻³ values for the release of 5-fluorouracil, respectively, in distilled water, pH 2.2 buffer and pH 7.4 buffer. The values of the diffusion exponent show that the release of drug from drug-loaded hydrogels has occurred through Non-Fickian diffusion mechanism. It has also been observed from the swelling and release of drug in the different pH buffer that the polymer matrix is pH responsive and can be exploited for the delivery of anticancer drug to the colon.     

外泌体环状RNA在肿瘤微环境中的研究进展

外泌体是细胞分泌的30～150 nm的细胞外囊泡,在肿瘤微环境(tumor microenvironment,TME)中介导细胞间通讯.环状RNA (circular RNA,circRNAs)是一类由前体mRNA (precursor mRNA,pre-mRNA)反向剪接生成的非编码RNA(non-coding RNA,ncRNA),在外泌体中富集且表达稳定.本文主要讨论外泌体起源和circRNAs在外泌体中的分选调控机制,阐述外泌体circRNAs在肿瘤微环境各个阶段中的作用与机制,包括血管生成、EMT、耐药等.最后,本文探讨外泌体circRNAs作为肿瘤标志物和治疗靶点的临床应用前景与价值.     

Non‐viral gene delivery for cancer immunotherapy

Recent decades have witnessed the revolutionary development of cancer immunotherapies, which boost cancer‐specific immune responses for long‐term tumor regression. However, immunotherapy still has limitations, including off‐target side effects, long processing times and limited patient responses. These disadvantages of current immunotherapy are being addressed by improving our understanding of the immune system, as well as by establishing combinational approaches. Advanced biomaterials and gene delivery systems overcome some of these delivery issues, harnessing adverse effects and amplifying immunomodulatory effects, and are superior to standard formulations with respect to eliciting antitumor immunity. Nucleic acid‐based nanostructures have diverse functions, ranging from gene expression and gene regulation to pro‐inflammatory effects, as well as the ability to specifically bind different molecules. A brief overview is provided of the recent advances in the non‐viral gene delivery methods that are being used to activate cancer‐specific immune responses. Furthermore, the tumor microenvironment‐responsive synergistic strategies that modulate the immune response by targeting various signaling pathways are discussed. Nanoparticle‐based non‐viral gene delivery strategies have great potential to be implemented in the clinic for cancer immunotherapy.     

Autophagy on acid

The microenvironment of solid tumors tends to be more acidic (6.5–7.0) than surrounding normal (7.2–7.4) tissue. Chaotic vasculature, oxygen limitation and major metabolic changes all contribute to the acidic microenvironment. We have previously proposed that low extracellular pH (pHe) plays a critical role in the development and progression of solid tumors. While extracellular acidosis is toxic to most normal cells, cancer cells can adapt and survive under this harsh condition. In this study, we focused on identifying survival strategies employed by cancer cells when challenged with an acidic pHe (6.6–6.7) either acutely or for many generations. While acutely acidic cells did not grow, those acclimated over many generations grew at the same rate as control cells. We observed that these cells induce autophagy in response to acidosis both acutely and chronically, and that this adaptation appears to be necessary for survival. Inhibition of autophagy in low pH cultured cells results in cell death. Histological analysis of tumor xenografts reveals a strong correlation of LC3 protein expression in regions projected to be acidic. Furthermore, in vivo buffering experiments using sodium bicarbonate, previously shown to raise extracellular tumor pH, decreases LC3 protein expression in tumor xenografts. These data imply that autophagy can be induced by extracellular acidosis and appears to be chronically employed as a survival adaptation to acidic microenvironments.     

Autophagy on acid

The microenvironment of solid tumors tends to be more acidic (6.5–7.0) than surrounding normal (7.2–7.4) tissue. Chaotic vasculature, oxygen limitation and major metabolic changes all contribute to the acidic microenvironment. We have previously proposed that low extracellular pH (pHe) plays a critical role in the development and progression of solid tumors. While extracellular acidosis is toxic to most normal cells, cancer cells can adapt and survive under this harsh condition. In this study, we focused on identifying survival strategies employed by cancer cells when challenged with an acidic pHe (6.6–6.7) either acutely or for many generations. While acutely acidic cells did not grow, those acclimated over many generations grew at the same rate as control cells. We observed that these cells induce autophagy in response to acidosis both acutely and chronically, and that this adaptation appears to be necessary for survival. Inhibition of autophagy in low pH cultured cells results in cell death. Histological analysis of tumor xenografts reveals a strong correlation of LC3 protein expression in regions projected to be acidic. Furthermore, in vivo buffering experiments using sodium bicarbonate, previously shown to raise extracellular tumor pH, decreases LC3 protein expression in tumor xenografts. These data imply that autophagy can be induced by extracellular acidosis and appears to be chronically employed as a survival adaptation to acidic microenvironments.     

Alpha-lipoic acid increases insulin sensitivity by activating AMPK in skeletal muscle

Triglyceride accumulation in skeletal muscle contributes to insulin resistance in obesity. We recently showed that alpha-lipoic acid (ALA) reduces body weight and prevents the development of diabetes in diabetes-prone obese rats by reducing triglyceride accumulation in non-adipose tissues. AMP-activated protein kinase (AMPK) is a major regulator of cellular energy metabolism. We examined whether ALA lowers triglyceride accumulation in skeletal muscle by activating AMPK. Alpha2-AMPK activity was decreased in obese rats compared to control rats. Administration of ALA to obese rats increased insulin-stimulated glucose disposal in whole body and in skeletal muscle. ALA also increased fatty acid oxidation and activated AMPK in skeletal muscle. Adenovirus-mediated administration of dominant negative AMPK into skeletal muscle prevented the ALA-induced increases in fatty acid oxidation and insulin-stimulated glucose uptake. These results suggest that ALA-induced improvement of insulin sensitivity is mediated by activation of AMPK and reduced triglyceride accumulation in skeletal muscle.