Codelivery of anti-CD47 antibody and chlorin e6 using a dual pH-sensitive nanodrug for photodynamic immunotherapy of osteosarcoma

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis.Immunotherapy has shown great potential in the treatment of osteosarcoma.However,the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment.The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment.Here,we prepared a dual pH-sensitive nanocarrier,loaded with the photosensitizer Chlorin e6(Ce6)and CD47 monoclonal antibodies(aCD47),to deliver synergistic photodynamic and immunotherapy of osteosarcoma.On laser irradiation,Ce6 can generate reactive oxygen species(ROS)to kill cancer cells directly and induces immunogenic tumor cell death(ICD),which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47.Moreover,both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages,promote antigen presentation,and eventually induce T lymphocyte-mediated antitumor immunity.Overall,the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma,which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.

Intratympanic injection of hydrogel nanodrug for the prevention and treatment of sensorineural hearing loss

Safe and efficient drug delivery to the inner ear has always been the focus of prevention and treatment of sensorineural deafness.The rapid development of nanodrug delivery systems based on hydrogel has provided a new opportunity.Among them,thermo-sensitive hydrogels promote the development of new dosage form for intratympanic injection.This smart biomaterial could transform to semisolid phase when the temperature increased.Thermo-sensitive hydrogel nanodrug delivery system is expected to achieve safe,efficient,and sustained inner ear drug administration.This article introduces the key techniques and the latest progress in this field.

Tumor Microenvironment Cascade‑Responsive Nanodrug with Self‑Targeting Activation and ROS Regeneration for Synergistic Oxidation‑Chemotherapy

Carrier-free nanodrug with exceptionally high drug payload has attracted increasing attentions.Herein,we construct a pH/ROS cascade-responsive nanodrug which could achieve tumor acidity-triggered targeting activation followed by circularly amplified ROS-triggered drug release via positive-feedback loop.The di-selenide-bridged prodrug synthesized from vitamin E succinate and methotrexate(MTX)self-assembles into nanoparticles(VSeM);decorating acidity-cleavable PEG onto VSeM surface temporarily shields the targeting ability of MTX to evade immune clearance and consequently elongate circulation time.Upon reaching tumor sites,acidity-triggered detachment of PEG results in targeting recovery to enhance tumor cell uptake.Afterward,the VSeM could be dissociated in response to intracellular ROS to trigger VES/MTX release;then the released VES could produce extra ROS to accelerate the collapse of VSeM.Finally,the excessive ROS produced from VES could synergize with the released MTX to efficiently suppress tumor growth via orchestrated oxidation-chemotherapy.Our study provides a novel strategy to engineer cascade-responsive nanodrug for synergistic cancer treatment.

An orally administered bacterial membrane protein nanodrug ameliorates doxorubicin cardiotoxicity through alleviating impaired intestinal barrier

The cardiotoxicity caused by Dox chemotherapy represents a significant limitation to its clinical application and is a major cause of late death in patients undergoing chemotherapy.Currently,there are no effective treatments available.Our analysis of 295 clinical samples from 132 chemotherapy patients and 163 individuals undergoing physical examination revealed a strong positive correlation between intestinal barrier injury and the development of cardiotoxicity in chemotherapy patients.We developed a novel orally available and intestinal targeting protein nanodrug by assembling membrane protein Amuc_1100(obtained from intestinal bacteria Akkermansia muciniphila),fluorinated polyetherimide,and hyaluronic acid.The protein nanodrug demonstrated favorable stability against hydrolysis compared with free Amuc_1100.The in vivo results demonstrated that the protein nanodrug can alleviate Dox-induced cardiac toxicity by improving gut microbiota,increasing the proportion of short-chain fatty acid-producing bacteria from the Lachnospiraceae family,and further enhancing the levels of butyrate and pentanoic acids,ultimately regulating the homeostasis repair of lymphocytes in the spleen and heart.Therefore,we believe that the integrity of the intestinal barrier plays an important role in the development of chemotherapy-induced cardiotoxicity.Protective interventions targeting the intestinal barrier may hold promise as a general clinical treatment regimen for reducing Dox-induced cardiotoxicity.

Supramolecular self-assembly of EGCG-selenomethionine nanodrug for treating osteoarthritis

Osteoarthritis(OA)has emerged as a significant health concern among the elderly population,with increasing attention paid to ferroptosis-induced OA in recent years.However,the prolonged use of nonsteroidal anti-inflammatory drugs or corticosteroids can lead to a series of side effects and limited therapeutic efficacy.This study aimed to employ the Mannich condensation reaction between epigallocatechin-3-gallate(EGCG)and selenomethionine(SeMet)to efficiently synthesize polyphenol-based nanodrugs in aqueous media for treating OA.Molecular biology experiments demonstrated that EGCG-based nanodrugs(ES NDs)could effectively reduce glutathione peroxidase 4(GPX4)inactivation,abnormal Fe2+accumulation,and lipid peroxidation induced by oxidative stress,which ameliorated the metabolic disorder of chondrocytes and other multiple pathological processes triggered by ferroptosis.Moreover,imaging and histopathological analysis of the destabilization of the medial meniscus model in mice confirmed that ES NDs exhibiting significant therapeutic effects in relieving OA.The intra-articular delivery of ES NDs represents a promising approach for treating OA and other joint inflammatory diseases.

Twins-like nanodrugs synchronously transport in blood and coalesce inside tumors for sensitive ultrasound imaging and triggerable penetrative drug delivery

Nanodrugs capable of aggregating in the tumor microenvironment(TME)have demonstrated great efficiency in improving the therapeutic outcome.Among vari-ous approaches,the strategy utilizing electrostatic interaction as a driving force to achieve intratumor aggregation of nanodrugs has attracted great attention.However,the great difference between the two nanodrugs with varied physicochemical prop-erties makes their synchronous transport in blood circulation and equal-opportunity tumor uptake impossible,which significantly detracts from the beneficial effects of nanodrug aggregation inside tumors.We herein propose a new strategy to construct a pair of extremely similar nanodrugs,referred to as“twins-like nanodrugs(TLNs)”,which have identical physicochemical properties including the same morphology,size,and electroneutrality to render them the same blood circulation time and tumor entrance.The 1:1 mixture of TLNs(TLNs-Mix)intravenously injected into a mouse model efficiently accumulates in tumor sites and then transfers to oppositely charged nanodrugs for electrostatic interaction-driven coalescence via responding to matrix metalloproteinase-2(MMP-2)enriched in tumor.In addition to enhanced tumor retention,the thus-formed micron-sized aggregates show high echo intensity essen-tial for ultrasound imaging as well as ultrasound-triggered penetrative drug delivery.Owing to their distinctive features,the TLNs-Mix carrying sonosensitizer,immune adjuvant,and ultrasound contrast agent exert potent sonodynamic immunotherapy against hypovascular hepatoma,demonstrating their great potential in treating solid malignancies.

高价值专利影响因素分析及主题挖掘——以纳米药物领域为例

挖掘高价值专利影响因素及主题有利于政府和企业进行前瞻性专利战略部署,对抢占技术先机、赢取竞争优势具有积极意义。文章首先依托专利数据,采用因子分析法计算专利综合价值评分,依据二八原则筛选高价值专利;然后对专利指标及其分类标签进行特征分析、差异性分析和回归分析,探究影响专利价值的因素;最后使用BERTopic主题模型挖掘高价值专利主题。选取“纳米药物”专利数据进行实证分析,结果表明该方法能有效探究出专利价值的强影响因素,筛选出的高价值专利与其他方法获得结果高度一致。

Role of targeting ferroptosis as a component of combination therapy in combating drug resistance in colorectal cancer

Colorectal cancer(CRC)is a form of cancer that is often resistant to chemotherapy,targeted therapy,radiotherapy,and immunotherapy due to its genomic instability and inflammatory tumor microenvironment.Ferroptosis,a type of non-apoptotic cell death,is characterized by the accumulation of iron and the oxidation of lipids.Studies have revealed that the levels of reactive oxygen species and glutathione in CRC cells are significantly lower than those in healthy colon cells.Erastin has emerged as a promising candidate for CRC treatment by diminishing stemness and chemoresistance.Moreover,the gut,responsible for regulating iron absorption and release,could influence CRC susceptibility through iron metabolism modulation.Investigation into ferroptosis offers new insights into CRC pathogenesis and clinical management,potentially revolutionizing treatment approaches for therapy-resistant cancers.

刺激响应型智能纳米递药系统的研究进展

开发高效、绿色农药制剂以最大限度地减少化学残留和环境污染,对于确保粮食和生态安全至关重要。纳米技术的发展为农业绿色农药制剂的创制提供了策略,科研人员设计了一系列针对病虫草害引发的病理环境和体外物理刺激的智能响应型金属或无机纳米载体,该类载体可以通过响应动植物体内pH、活性氧(reactive oxygen species, ROS)、氧化还原条件等内源性变化或者温度、光照等外部刺激,来实现药物的精准可控释放,并提高对病虫草害的防治效率。本文从内源性刺激响应、外源性刺激响应和多重刺激响应3个方面综述了当前农业领域智能响应型纳米递药系统的研究进展,对智能响应型纳米递药系统的功能设计、作用特点及效果进行了介绍,以期为农药/核酸类药物及其递送系统的研究提供参考。未来智能响应型纳米递药系统将会作为一种有前途的方式,提高药剂的利用率,实现药剂的靶向释放。

纳米药物递送系统:胰腺癌靶向策略的新选择

胰腺导管腺癌(PDAC)是一类进展迅速、早期诊断困难的恶性消化系统实体肿瘤,多数患者就诊时已失去根治性手术切除机会。PDAC组织中的多种细胞成分和非细胞成分组成复杂的调控网络,共同塑造了代谢异常的肿瘤微环境,导致临床化疗和免疫治疗等效果受限。纳米技术的发展为PDAC的高效药物递送和精准靶向治疗提供了新思路。本文从靶向肿瘤细胞与肿瘤微环境两个方面,综述了近年来基于纳米药物递送系统的PDAC治疗策略,并总结了本团队在相关领域的研究进展,为胰腺癌的治疗提供参考。

Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy:From intrinsic physicochemical properties to external modification

The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability,simple preparation method,and offering“all-in-one”functional platform features.However,the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey,which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment.In this review,we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy,including optimizing the intrinsic physicochemical properties and external modification.Finally,the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented.We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.

EGCG-PLGA纳米粒子减轻心肌缺血损伤的作用及机制研究

目的:构建基于聚乳酸—羟基乙酸共聚物(PLGA)纳米粒子的表没食子儿茶素没食子酸酯(EGCG)药物递送系统,研究其对心肌缺血损伤的作用及机制。方法:改进现有EGCG-PLGA纳米粒子(E-P-NPs)制备工艺,以透射电镜观察所制备的E-PNPs形态,并测量聚合物分散性指数、Zeta电位、纳米粒径和载药率,进行纳米粒表征;以荧光标记法观察心肌细胞对纳米粒子的摄取情况。体外建立心肌细胞缺氧模型,体内建立小鼠急性心肌缺血损伤模型,检测不同浓度E-P-NPs对细胞活力、细胞凋亡、心肌肌钙蛋白I(cTn-I)水平及Bcl-2、Caspase9、Bax表达的影响。结果:E-P-NPs呈圆球形,多分散性指数(PDI)为0.285,平均粒径193.5 nm,电位-28.7 m V,载药率9.23%,可被心肌细胞摄取。体内、外实验研究均表明,E-P-NPs可剂量依赖性地增强心肌细胞活力,降低c Tn-I水平,降低凋亡率,上调Bcl-2蛋白表达,下调Caspase9、Bax蛋白表达,抑制细胞凋亡;E-P-NPs对缺血心肌的保护作用优于EGCG。结论:E-P-NPs粒径分布较集中,均一性较好,可通过抑制凋亡减轻心肌缺血损伤,且能使EGCG更好地发挥药效。

Engineered protein nanodrug as an emerging therapeutic tool

Functional proteins are the most versatile macromolecules.They can be obtained by extraction from natural sources or by genetic engineering technologies.The outstanding selectivity,specificity,binding activity,and biocompatibility endow engineered proteins with outstanding performance for disease therapy.Nevertheless,their stability is dramatically impaired in blood circulation,hindering clinical translations.Thus,many strategies have been developed to improve the stability,efficacy,bioavailability,and productivity of therapeutic proteins for clinical applications.In this review,we summarize the recent progress in the fabrication and application of therapeutic proteins.We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly.Furthermore,we highlight their diverse applications as growth factors,nanovaccines,antibody-based drugs,bioimaging molecules,and cytokine receptor antagonists.Finally,a summary and perspective for the future development of therapeutic proteins are presented.

Local T regulatory cells depletion by an integrated nanodrug system for efficient chem-immunotherapy of tumor

T regulatory(Treg) cell is a major immunosuppressive factor that restrains the antitumor effect of immunotherapy, because it gets more after the immune activation and is hardly to be eliminated. Here, an acid-sensitive integrated nanodrug system is designed to activate antitumor immune response as well as locally deplete Treg cells with low side effect. The nanosystem is synthetized by coordinating doxorubicin(DOX) and pentoxifylline(PTX) with Zn ions, then stabilized via liposome encapsulation(denoted as DTX@Lipo). DTX@Lipo can activate antitumor immune effect by chemotherapy of DOX. Besides, the release of PTX inhibits c-Rel expression, leading to the reduction of Treg cells in tumor site. Owing to the good tumor accumulation and local drug release ability, DTX@Lipo exhibits better biosafety and convenience than traditional antibody blockade method for Treg cells depletion. According to the results of in vivo experiments, the nanodrug system can significantly increase the ratio between effector T(Teff) cells and Treg cells locally, resulting in an immunoactivated tumor microenvironment. Importantly, it exhibits significant antitumor effect when combined with PD-1 blockade therapy, providing great potential for tumor therapy.

纳米递药系统负载奥希替尼抗非小细胞肺癌的研究进展

奥希替尼是不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),用于治疗经典EGFR突变和T790M耐药突变的非小细胞肺癌(NSCLC)。然而,与其他EGFR-TKIs一样,奥希替尼不可避免地存在获得性耐药、水溶性差、肿瘤累积率低等问题,限制了其治疗效果。纳米递药系统可增加药物的溶解度和稳定性,延长药物血液循环时间,提高细胞摄取率,增加在肿瘤组织中的聚集改善药物耐药问题,已成为解决传统靶向药物弊端的有效手段。本文综述了第三代EGFR-TKI奥希替尼的作用机制,重点阐述了奥希替尼纳米递药系统抗NSCLC的研究进展,并对该领域面临的挑战和未来发展方向进行了展望。

纳米药物在心肌梗死治疗中的应用研究进展

心肌梗死是冠状动脉急性闭塞引起的严重而持久的缺血性心肌坏死,传统药物治疗靶向性较差,到达损伤区域的药物剂量不足且停留时间偏短。近年来研究显示,纳米药物实现了对病变组织的选择性靶向输送,在心肌梗死的靶向治疗中,借助其独特的理化性质,纳米载体可携带炎症因子受体、炎症信号通路抑制剂、抗氧化剂、治疗基因、特异性抗体和生长因子等到达心肌组织释放药物。纳米药物通过中和炎症因子、抑制炎症信号通路和炎症基因表达、调节巨噬细胞表型等对抗单核巨噬细胞及中性粒细胞介导的炎症损伤;通过抗氧化剂消除过氧化物的方式对抗氧化应激性损伤;通过生长因子促进心肌组织的再生和修复;通过水凝胶修复心脏电传导功能并促进心脏间充质干细胞的增殖分化。研究发现,纳米药物可保护缺血心肌组织,改善心脏功能。本文对纳米药物在心肌梗死治疗中的应用研究进展进行综述。

Advances of nanotechnology applied to cancer stem cells

Cancer stem cells(CSCs)are a small proportion of the cells that exist in cancer tissues.They are considered to be the culprit of tumor genesis,development,drug resistance,metastasis and recurrence because of their self-renewal,proliferation,and differentiation potential.The elimination of CSCs is thus the key to cure cancer,and targeting CSCs provides a new method for tumor treatment.Due to the advantages of controlled sustained release,targeting and high biocompatibility,a variety of nanomaterials are used in the diagnosis and treatments targeting CSCs and promote the recognition and removal of tumor cells and CSCs.This article mainly reviews the research progress of nanotechnology in sorting CSCs and nanodrug delivery systems targeting CSCs.Furthermore,we identify the problems and future research directions of nanotechnology in CSC therapy.We hope that this review will provide guidance for the design of nanotechnology as a drug carrier so that it can be used in clinic for cancer therapy as soon as possible.

载亚硝基脲的多功能纳米载体的构建及其评价

氯乙基亚硝基脲(CENUs)是临床上重要的抗肿瘤烷化剂,但因其水溶性差、毒副作用高以及肿瘤细胞内高表达的O^(6)-烷基鸟嘌呤-DNA烷基转移酶介导的肿瘤细胞耐药性,降低了CENUs的抗癌效果。为了克服上述弊端,合成了一种叶酸修饰抗耐药低氧激活纳米递送系统,用于CENUs的靶向递送。终产物及各中间体的结构经1HNMR、13 CNMR、IR及HRMS确证,使用动态光散射(DLS)、紫外-可见分光光度计(UV-Vis)和透射电子显微镜(TEM)等表征纳米载体的理化性质及形貌,并利用高效液相色谱法(HPLC)测定纳米载体的包封率、载药量及其释药行为。此外,经细胞摄取、细胞毒性和划痕实验评价载药纳米载体的靶向性、低氧响应性和肿瘤细胞抑制能力。结果表明,该纳米载体具有合适的粒径、良好的安全性和优良的载药性能,可实现CENUs的靶向递送和低氧响应释放,能够有效抑制肿瘤细胞的增殖。

信使RNA药物修饰及其递送系统研究进展

信使RNA(mRNA)药物在多种疾病的预防和治疗中展现了巨大的应用价值。最大程度提高mRNA的稳定性和翻译效率,保证mRNA免受核酸酶的降解并靶向特定组织和细胞是临床转化的要求。通过修饰核苷酸降低mRNA免疫原性,密码子优化增加mRNA翻译效率,5'帽结构和3'多聚腺苷酸尾结构增加mRNA稳定性,以及添加5'和3'非翻译区功能调控mRNA稳定性和翻译效率。通过纳米粒递送系统保护mRNA不被核酸酶降解,增加mRNA血液循环,并帮助mRNA进入细胞质发挥治疗和预防作用。本文综述了mRNA药物的制剂工程技术进展,讨论了提高mRNA稳定性和翻译效率的方法及设计原理,总结了具有产业转换潜力的mRNA递送系统的设计要求及其临床应用,并展望了mRNA药物未来可能的研究方向,以满足实现个性化精准医疗的需求。

基于纳米药物递送载体的肿瘤免疫调控策略研究进展

肿瘤免疫疗法是利用免疫学原理和方法,激活和增强机体免疫系统并产生免疫应答,达到清除肿瘤细胞的一种治疗模式。许多新型的免疫治疗药物展现出有效的抗肿瘤能力,但复杂的肿瘤免疫逃逸机制使其临床运用仍面临诸多挑战。同时,免疫治疗药物应用人体后,会分布至全身各组织器官,无法实现精准的病灶靶向性,从而引起了一系列的免疫相关不良反应,这也极大阻碍了其临床应用潜力。纳米药物递送载体能够将免疫治疗药物精准递送到靶组织或特定的免疫细胞,增强免疫抗肿瘤效果,同时降低不良反应。本文将以肿瘤免疫调控策略为角度,对近几年纳米药物递送载体在肿瘤免疫治疗研究领域取得的成果进行总结阐述,并对该领域的挑战和发展方向进行展望。