Systemic therapy in gastrointestinal stromal tumors

Gastrointestinal stromal tumors(GISTs)are the most common type of soft tissue sarcoma in the gastrointestinal tract.Most GISTs have been attributed to activated gain-of-function mutations in either KIT or platelet-derived growth factor receptorα,making these molecular features essential targets for therapeutic interventions.Although surgery is the standard treatment for localized GISTs,patients often experience relapse and disease progression even after surgery.In recent years,targeted therapy has significantly improved the prognosis of patients with advanced GISTs.Imatinib mesylate,a KIT inhibitor,is the first-line treatment for advanced GISTs and has revolutionized the treatment of this disease.However,drug resistance remains a major issue with imatinib treatment,as a significant majority of patients become resistant to imatinib either after initiation or after 2–3 years of treatment.Consequently,novel tyrosine kinase inhibitors such as sunitinib,regorafenib,ripretinib,and avapritinib have been introduced to address drug resistance.Immunotherapy has emerged as a potential approach for the treatment of advanced GISTs.This review comprehensively summarizes the pathogenesis of GISTs and the development of targeted therapies and immunotherapies,provides an overview of the emergence of drug resistance in advanced GISTs,and discusses the challenges and prospects associated with the treatment of GISTs.

Ionizable drug delivery systems for efficient and selective gene therapy

Gene therapy has shown great potential to treat various diseases by repairing the abnormal gene function.However,a great challenge in bringing the nucleic acid formulations to the market is the safe and effective delivery to the specific tissues and cells.To be excited,the development of ionizable drug delivery systems(IDDSs)has promoted a great breakthrough as evidenced by the approval of the BNT162b2 vaccine for prevention of coronavirus disease 2019(COVID-19)in 2021.Compared with conventional cationic gene vectors,IDDSs can decrease the toxicity of carriers to cell membranes,and increase cellular uptake and endosomal escape of nucleic acids by their unique pH-responsive structures.Despite the progress,there remain necessary requirements for designing more efficient IDDSs for precise gene therapy.Herein,we systematically classify the IDDSs and summarize the characteristics and advantages of IDDSs in order to explore the underlying design mechanisms.The delivery mechanisms and therapeutic applications of IDDSs are comprehensively reviewed for the delivery of plasmid DNA(pDNA)and four kinds of RNA.In particular,organ selecting considerations and high-throughput screening are highlighted to explore efficiently multifunctional ionizable nanomaterials with superior gene delivery capacity.We anticipate providing references for researchers to rationally design more efficient and accurate targeted gene delivery systems in the future,and indicate ideas for developing next generation gene vectors.

Injectable hydrogel-based drug delivery systems for enhancing the efficacy of radiation therapy:A review of recent advances

Radiotherapy(RT)is a crucial treatment for cancer;however,its effectiveness is limited by adverse effects on normal tissues,radioresistance,and tumor recurrence.To overcome these challenges,hydrogels have been employed for delivery of radiosensitizers and other therapeutic agents.This review summarizes recent advancements in the application of hydrogel-based local drug delivery systems for improving the therapeutic efficacy of RT in cancer treatment.Firstly,we introduce the classification and properties of hydrogels.Next,we detail hydrogel-based platforms designed to enhance both external beam radiation therapy and brachytherapy.We also discuss hydrogels used in combination therapy involving RT and immunotherapy.Lastly,we highlight the challenges that hydrogels face in RT.By surveying the latest developments in hydrogel applications for RT,this review aims to provide insights into the development of more effective and targeted cancer therapies.

Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement

Hepatocellular carcinoma(HCC) is the most frequent form of liver cancer and the third most common cause of cancer-related death in the world. The main risk factor worldwide for this type of malignancy is chronic hepatitis caused by hepatitis B virus and hepatitis C virus infections. Advances in early detection and treatmenthave improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have revealed that there is an 8-mo median survival rate in patients, approximately 20% of whom survive one year while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy is due, among other mechanisms, to several members of the ATP-Binding Cassette protein family involved in drug transport being overexpressed. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript intends to provide further insight into the etiology and molecular mechanisms related to HCC development and the latest therapeutic approaches to treat this malignancy. The development of effective delivery systems of antitumor drugs able to target the liver parenchyma is also assessed. Finally, the prospects in the development of more efficient drug therapies to overcome multidrug resistance are also examined.

Camptothecin-based nanodrug delivery systems

The drug camptothecin has a wide range of antitumor effects in cancers including gastric cancer,rectal and colon cancer,liver cancer,and lung cancer.Camptothecin-based drugs inhibit topoisomerase 1(Topo 1),leading to destruction of DNA,and are currently being used as important chemotherapeutic agents in clinical antitumor treatment.However,the main obstacle associated with cancer therapy is represented by systemic toxicity of conventional anticancer drugs and their low accumulation at the tumor site.In addition,low bioavailability,poor water solubility,and other shortcomings hinder their anticancer activity.Different from traditional pharmaceutical preparations,nanotechnology-dependent nanopharmaceutical preparations have become one of the main strategies for different countries worldwide to overcome drug development problems.In this review,we summarized the current hotspots and discussed a variety of camptothecin-based nanodrugs for cancer therapy.We hope that through this review,more efficient drug delivery systems could be designed with potential applications in clinical cancer therapy.

Network systems biology for targeted cancer therapies

The era of targeted cancer therapies has arrived.However,due to the complexity of biological systems,the current progress is far from enough.From biological network modeling to structural/dynamic network analysis,network systems biology provides unique insight into the potential mechanisms underlying the growth and progression of cancer cells.It has also introduced great changes into the research paradigm of cancer-associated drug discovery and drug resistance.

Highly Selective Photodynamic Therapy with a Short Drug-Light Interval Using a Cytotoxic Photosensitizer Porphyrus Envelope for Drug-Resistant Prostate Cancer Cells

Background: Photodynamic therapy (PDT) is a less invasive cancer treatment using photochemical reactions induced by light irradiation to a photosensitizer (PS). Highly selective PDT with fast accumulation of the PS in target site might be a promising treatment option for drug-resistant prostate cancer facing high incidence rate of elderly men who have no effective treatment options and require a minimally invasive treatment. Hemagglutinating virus of Japan envelope (HVJ-E) allows selective and fast drug delivery to the drug-resistant prostate cancer cells via rapid cell membrane fusion. PS named porphyrus envelope (PE) has been developed by insertion of lipidated protoporphyrin IX (PpIX lipid) into HVJ-E. In this study, we investigated the optimal conditions for PE preparation and laser irradiation for highly selective PDT using PE with a short drug-light interval. Materials and Methods: Human hormon refractory prostate cancer cell line PC-3 and human normal prostate epithelial cell line PNT2 were cultured. PpIX lipid uptake and cytotoxicity of PDT in the cells incubated with PE for 10 min were evaluated by measuring fluorescence intensity and by using a cell counting reagent 24 h after PDT, respectively. Results: PpIX lipid uptake and cytotoxicity of PDT were increased with PpIX lipid concentration. Cytotoxicity of PDT using PE was more than 9 times as strong as that with PpIX lipid and PpIX induced by 5-aminolevulinic acid. Much stronger cytotoxicity was induced in PC-3 cells than PNT2 cells with the ratio of cell death rate for cancer to normal cells up to 4.64 ± 0.09. Conclusions: Fast PS delivery with HVJ-E allows highly selective PDT with a short drug-light interval. Therefore, PDT using PE has a potential to shorten treatment period and reduce side effects of PDT.

系统性红斑狼疮患者应用靶向B细胞治疗后发生中枢神经系统病变文献病例分析

目的探讨系统性红斑狼疮(SLE)患者经靶向B淋巴细胞生物制剂治疗后发生中枢神经系统不良反应的临床特征。方法检索国内外相关数据库(截至2023年5月),收集系统性红斑狼疮患者经贝利尤单抗、利妥昔单抗治疗后发生中枢神经系统病变的病例报告类文献,提取患者的基本信息、贝利尤单抗或利妥昔单抗用药情况(用法用量、单用或联用、联用方案等)、中枢神经系统病变发生时间、临床表现、影像学特征、临床治疗及转归等,并进行描述统计分析。结果检索到进行性多灶性脑白质病(PML)患者14例,发病年龄(50.71±11.45)岁;可逆性后部脑病综合征(PRES)患者24例,发病年龄(30.67±14.93)岁。纳入有详细病例报道的患者共7例,7例患者均未合并HIV感染、恶性肿瘤及其他自身免疫性疾病。7例患者均经磁共振检查确诊,均未行脑组织活检。临床表现:癫痫5例,视物模糊或视力丧失3例,构音障碍或失语2例,头痛2例,昏迷1例,血压升高4例。最终7例患者中1例死亡。结论应用靶向B细胞治疗后,SLE患者中枢神经系统副作用多发生在疾病活动期且合并使用其他免疫抑制剂时。患者的临床表现容易与神经精神狼疮混淆,导致病情延误,提示在使用靶向B细胞生物制剂治疗时,应评估SLE患者发生中枢神经系统副作用的潜在风险。

基于中药单体构建的环境响应型纳米递药系统在肿瘤治疗中的研究进展

中药单体对肿瘤具有一定的疗效,但其低靶向性、难以在肿瘤部位聚集等不足限制了其应用。环境响应型纳米递药系统作为一种新型药物递送方式,具有靶向性递药、减少药物毒副作用、环境响应性释放等优势,在肿瘤治疗中得到广泛应用。该文通过查阅并整理相关文献,从中药单体治疗肿瘤的概况、环境响应型中药单体纳米递药系统的分类以及其在肿瘤治疗中的应用3个方面进行概括总结,旨在为解决中药单体治疗肿瘤的局限性提供思路。

零维纳米碳基靶向药物递送系统在肿瘤治疗中的研究进展(综述)

【目的】零维纳米碳基靶向药物递送系统是以具有良好稳定性和生物相容性的纳米碳材料作为药物载体,担载药物、基因以及靶向组分构建的药物递送复合体,在肿瘤治疗领域具有重要的应用价值。【方法】对零维纳米碳基药物载体的结构、靶向药物递送系统的构建及其在化学治疗、基因治疗和诊疗一体化中的应用进行综述。首先,对零维纳米碳材料进行分类。其次,从靶向修饰和药物担载两个方面总结纳米碳基靶向药物递送系统的构建策略。最后,对零维纳米碳基靶向药物递送系统的应用进展进行综述,进而给出其目前在肿瘤治疗中所面临的问题。【结论】为零维纳米碳基靶间药物递送系统在生物医学领域的广泛应用提供可借鉴的理论和实践经验。

靶向药物制剂研究进展

由于分子生物学、细胞生物学、材料科学等学科的飞速发展,靶向药物制剂成为近年来的研究热点。与普通药物制剂相比,靶向药物制剂可以选择性地提高靶组织中药物浓度,有效降低药物对正常组织的毒副作用,是一种较理想的给药方式。纳米材料以其在动物体内优越的性能受到更多的关注。纳米晶体在靶向药物制剂中的应用与发展有效改善了难溶性药物的开发瓶颈,在药物递送系统中发挥着不可或缺的作用。该文简要综述靶向制剂特点、分类,以及纳米晶体在药学领域的应用,可为靶向药物制剂的研究提供参考。

基于纳米技术的药物递送系统在肝细胞癌治疗中的研究进展

原发性肝癌是消化系统最常见的恶性肿瘤之一,其中肝细胞癌(HCC)占90%以上。早期HCC以手术切除为主,且预后较好,然而因HCC起病隐匿,绝大多数患者确诊时已进展至中晚期,手术治疗效果较差,而非手术治疗方式因为普遍存在不良反应大,肿瘤选择性低等问题,疗效也不理想,所以目前中晚期HCC治疗仍是临床工作的难点。纳米粒(NP)尺寸小、比表面积大,具有多种独特的理化性质,成为输送药物、基因及细胞活性因子等治疗剂的潜在载体。纳米递送系统以NP为载体,通过功能化修饰,从时间、空间及剂量上调控药物、基因及细胞活性因子等在体内的代谢及转化,在HCC治疗中展现出巨大的潜力。本文主要介绍了几种常见纳米递送系统,包括有机纳米载体、无机纳米载体、外泌体等在HCC治疗中的现状和优势,总结了基于NP的纳米载体治疗HCC的机制,为新型纳米递送系统的研发提供参考。

肾癌靶向治疗研究热点与前沿的文献计量学分析

目的通过文献计量学研究展示肾癌靶向治疗领域的现状、热点和前沿,为探索新的靶向策略提供参考。方法在Web of Science数据库核心合集(Web of Science Core Collection,WoSCC)中检索2009-2022年发表的相关文献1718篇及其记录的信息,采用Citespace、R及Scimago Graphica软件进行文献计量学分析与可视化。结果美国出版物数量(414篇,24.10%)、出版物引用次数(20302次)及中介中心性(betweenness centrality,BC)(0.45)排名第1,对研究的贡献最大。美国印第安纳大学的CHENG L是最多产的研究人员(22篇),斯隆凯特琳癌症中心为研究产量最多的机构(38篇),Cancers为刊发研究最多的期刊(56篇)。目前的研究热点主要包括血管生成、肿瘤微环境(tumor microenvironment,TME)、靶向药物释放系统等。上皮间充质转换(epithelial-mesenchymal transition,EMT)、免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)、肿瘤侵袭与扩散是该领域的研究前沿,正在不断发展。结论本项文献计量分析为肾癌靶向治疗的研究趋势,为相关热点及新兴前沿提供重要见解。本研究为寻求合作者的研究人员提供了有用的资源,并为未来研究提供参考。

载喜树碱抗氧化纳米药物传递系统用于肿瘤治疗的研究进展

喜树碱及其衍生物能够与DNA拓扑异构酶形成复合物,从而抑制DNA复制和RNA合成,阻止肿瘤生长,因此在肿瘤治疗方面具有巨大潜力。然而,这种化合物具有结构不稳定、溶解性差、毒性较大等缺点,限制了其在临床上的应用。使用纳米技术可以有效地增强喜树碱的水溶性和稳定性,从而提高其治疗效果。同时,抗氧化药物可以消除肿瘤微环境中氧化应激产生的大量活性氧,从而发挥抗氧化作用并抑制肿瘤生长。因此,将抗氧化纳米材料作为喜树碱的运输载体,形成载喜树碱的抗氧化纳米制剂,有望为肿瘤治疗提供抗氧化和抗肿瘤的联合治疗效果。本文主要对载喜树碱的抗氧化纳米药物传递系统的研究进展进行了综述。

多载药纳米递药系统用于提高多西紫杉醇抗肿瘤疗效的研究进展

目的对多西紫杉醇与其他抗癌药物共载药纳米递药系统在肿瘤治疗中的作用机制进行综述,旨在为以多西紫杉醇为代表的化疗药物共载药纳米递药系统研究提供一定的参考。方法以“多西紫杉醇”、“联合治疗”、“纳米递药系统”、“肿瘤”等检索词对国内外文献进行查阅,总结多西紫杉醇与其他药物共载药纳米递药系统对肿瘤的治疗效果,并对其治疗机制进行归纳。结果多西紫杉醇属于典型的紫杉烷类抗肿瘤药物,在临床中,多西紫杉醇对多种恶性肿瘤具有显著的治疗效果。然而,现有多西紫杉醇注射剂由于其组织特异性差、使用有机溶剂增溶、易产生耐药性等原因,一定程度上影响其抗肿瘤疗效的发挥及产生一定的不良反应。将其他药物与多西紫杉醇联用是提高多西紫杉醇抗肿瘤效果、克服其耐药性和减少其不良反应的一种有效方法。然而,将多种药物简单物理混合所构建的制剂尚不能解决多西紫杉醇制剂现有的缺陷;而借助于纳米递药系统,可以有效克服以上缺陷。结论今后应深度挖掘纳米递药系统在共载抗肿瘤药物递送方面的意义,促使以多西紫杉醇为代表的化疗药物共载药在肿瘤治疗方面取得更大的进展。

原位水凝胶作为联合递药系统在肿瘤治疗中的研究进展

原位水凝胶因其具有生物相容性、环境敏感性、高稳定性、可注射性等优点,成了医药领域的研究热点。由于原位水凝胶独特的相转变性质,它能够在给药部位实现药物在局部的持续释放。此外,原位水凝胶还可以将多种治疗手段(如化疗、光热疗法、光动力疗法、基因疗法和免疫疗法等)结合使用,以实现肿瘤的联合治疗。本文综述了近年来原位水凝胶作为联合递药系统在肿瘤治疗中的研究进展和发展前景。

MnO_(2)纳米材料的制备以及在药物递送中的研究进展

构建多模式纳米药物体系是提高抗肿瘤靶向性治疗效果的有效手段之一,能够克服传统化疗单一模式的局限性,并降低对人体的毒副作用。二氧化锰(MnO_(2))作为过渡金属氧化物,因其性质优越已广泛应用于生物医学领域,尤其是在调节肿瘤微环境方面更显示出了独特的优势。总结了应用于抗癌领域中MnO_(2)纳米材料的制备方法;阐述了MnO_(2)纳米材料在肿瘤微环境调节以及药物递送系统中的应用;最后,展望了MnO_(2)纳米材料在构建抗肿瘤药物体系及其在抗癌应用中的发展方向以及面临的挑战。

A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus

Tripterygium wilfordii Hook F(TWHF)is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus(SLE),with triptolide(TP)as its main active ingredient.However,its side effects also induced by TP,especially hepatotoxicity and reproductive toxicity,largely limit its application in a subset of patients.Monoclonal antibodies(mAbs)developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens,such as CD19,have failed in clinical trials,partly due to their poor efficacy in consuming B cells.Here,we report the development of a rationally designed antibody‒drug conjugate(ADC),CD19 mAb-TP conjugate,to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb.The CD19 mAb-TP conjugate,which was named ADC-TP,selectively depleted B cell subsets both in vitro and in vivo and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP.Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE,providing a feasible method for improving the current agents used for treating SLE.

人造外泌体治疗心肌梗死:应用现状及前景

背景:心肌梗死是目前最严重的心血管疾病之一,现有的临床治疗方案如溶栓治疗、经皮冠状动脉介入治疗和冠状动脉旁路移植术均无法完全恢复缺血造成的心肌损伤。干细胞来源的外泌体治疗心肌梗死是近年来的研究热点,但天然来源的外泌体产量少,获取难度大、耗时长、归巢效果不佳等限制了其临床应用。在这种情况下,构建人造外泌体作为天然外泌体的替代品已成为解决上述问题的有效策略。目的:阐述人造外泌体在治疗心肌梗死中的研究现状,将其分为半人造和全人造两种设计模式,就两种模式的研究进展及存在的问题展开讨论,最后对其在未来的临床应用做出评价和展望。方法:以“人造外泌体,心肌梗死,工程化”为中文检索词,以“artificial exosome,hybrid exosome,myocardial infarction,nanoparticle,drug delivery system”为英文检索词,检索PubMed和中国知网数据库的相关文献。检索时限重点为2017年1月至2022年12月,同时纳入部分经典远期文献。通过阅读文题和摘要进行初步筛选;排除重复性研究、低质量期刊及内容不相关的文献,最后纳入73篇文献进行综述。结果与结论:(1)通过半人造改造外泌体的方式,不论是靶向肽段的修饰、生物膜的杂交或是磁力物质的辅助,均改善了传统的外泌体疗法靶向性不足、驻留率低、易被网状内皮系统所清除等缺陷,提高了传统外泌体治疗心肌梗死的效率,但是这些改造策略存在修饰效率不明确、医学伦理以及生物毒性等方面的问题。(2)全人造仿生外泌体相对于外泌体的改造,其设计自由度较高,可以解决天然来源外泌体提取存储难度高、规模化生产局限等问题,然而全人造外泌体的改造策略目前仍缺少可靠的临床前数据支持与生物安全性的检测,尚未形成规模化生产所需的标准化流程,因此在应用到临床以前,作为替代天然外泌体的人造外泌体方案仍需要科研人员进行持续深入研究。

纳米药物递释系统在胃癌治疗中的研究进展

胃癌是最常见的消化道肿瘤之一,发病率居第五位,死亡率居第三位。手术依然是唯一可能治愈胃癌的方法,然而,即便接受根治性切除,绝大多数患者仍然出现肿瘤复发,5年生存率仅为30%。辅助化疗在胃癌术后治疗中起主导作用,化疗虽然可以进一步提高胃癌患者生存,但其副反应发生率高、且需全身多次反复给药。针对传统化疗存在的弊端,开发缓释化疗制剂成为肿瘤治疗领域的热点,其中纳米药物递释系统在缓释化疗方面具有明显的优势。本文对胃癌治疗中纳米药物递释系统的研究进展进行综述。