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Spermine-Based Poly(β-amino ester)s for siRNA Delivery against Mutated KRAS in Lung Cancer 基于精胺的聚(β-氨基酯)s用于siRNA递送对抗肺癌中突变的KRAS
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-14 DOI: 10.1021/acs.molpharmaceut.3c00206
Yao Jin, Friederike Adams, Lorenz Isert, Domizia Baldassi and Olivia M. Merkel*, 

Polyethylenimine (PEI) is a highly efficient cationic polymer for nucleic acid delivery, and although it is commonly used in preclinical studies, its clinical application is limited because of concerns regarding its cytotoxicity. Poly(β-amino ester)s are a new group of biodegradable and biocompatible cationic polymers that can be used for siRNA delivery. In this study, we synthesized Boc-protected and deprotected poly(β-amino ester)s, P(BSpBAE) and P(SpBAE), respectively, based on spermine and 1,4-butanediol diacrylate to deliver siRNA. The polymers were synthesized by Michael addition in a step-growth polymerization and characterized via 1H NMR spectroscopy and size-exclusion chromatography (SEC). The polymers can encapsulate siRNA as determined by SYBR gold assays. Both polymers and polyplexes were biocompatible in vitro. Furthermore, the cellular uptake of P(BSpBAE) and P(SpBAE) polyplexes was more efficient than for branched PEI (25 kDa) polyplexes at the same N/P ratios. P(BSpBAE) polyplexes achieved 60% eGFP knockdown in vitro, which indicates that the Boc-protection can improve the siRNA delivery and gene silencing efficiency of PBAEs. P(BSpBAE) polyplexes and P(SpBAE) polyplexes showed different cellular uptake mechanisms, and P(BSpBAE) polyplexes demonstrated decreased endosomal entrapment, which could explain why P(BSpBAE) polyplexes more efficiently mediated gene silencing than P(SpBAE) polyplexes. Furthermore, transfection of an siRNA against mutated KRAS in KRAS-mutated lung cancer cells led to around 35% (P(BspBAE)) to 45% (P(SpBAE)) inhibition of KRAS expression and around 33% (P(SpBAE)) to 55% (P(BspBAE)) decreased motility in a migration assay. These results suggest that the newly developed spermine-based poly(β-amino ester)s are promising materials for therapeutic siRNA delivery.

聚乙烯亚胺(PEI)是一种高效的核酸传递阳离子聚合物,虽然常用于临床前研究,但由于担心其细胞毒性,其临床应用受到限制。聚(β-氨基酯)是一类新的可生物降解和生物相容性阳离子聚合物,可用于siRNA的递送。在本研究中,我们以精胺和1,4-丁二醇二丙烯酸酯为基础,分别合成了boc保护和去保护的聚(β-氨基酯)s, P(BSpBAE)和P(SpBAE)来传递siRNA。采用Michael加成法在阶梯生长聚合中合成了聚合物,并通过1H NMR波谱和排粒径层析(SEC)对其进行了表征。经SYBR金测定,该聚合物可以包封siRNA。聚合物和多聚物在体外均具有生物相容性。此外,在相同N/P比下,细胞对P(BSpBAE)和P(SpBAE)多聚体的摄取比分支PEI (25 kDa)多聚体更有效。P(BSpBAE)多聚体在体外实现了60%的eGFP敲除,这表明boc保护可以提高PBAEs的siRNA传递和基因沉默效率。P(BSpBAE)多聚体和P(SpBAE)多聚体表现出不同的细胞摄取机制,P(BSpBAE)多聚体表现出减少的内体包裹,这可以解释为什么P(BSpBAE)多聚体比P(SpBAE)多聚体更有效地介导基因沉默。此外,在KRAS突变的肺癌细胞中转染针对突变KRAS的siRNA,导致KRAS表达抑制约35% (P(SpBAE))至45% (P(SpBAE)),并在迁移实验中降低约33% (P(SpBAE))至55% (P(BspBAE))的运动性。这些结果表明,新开发的基于精胺的聚(β-氨基酯)是一种有前景的治疗性siRNA递送材料。
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引用次数: 0
Research Progress in Oxygen Carrier Design and Application 氧载体设计与应用研究进展
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-14 DOI: 10.1021/acs.molpharmaceut.3c00289
Qingsong Ye, Deyuan Zheng, Kaiyuan Chen and Jinhui Wu*, 

Ischemia or hypoxia can lead to pathological changes in the metabolism and function of tissues and then lead to various diseases. Timely and effective blood resuscitation or improvement of hypoxia is very important for the treatment of diseases. However, there is a need to develop stable, nontoxic, and immunologically inert oxygen carriers due to limitations such as blood shortages, different blood types, and the risk of transmitting infections. With the development of various technologies, oxygen carriers based on hemoglobin and perfluorocarbon have been widely studied in recent years. This paper reviews the development and application of hemoglobin and perfluorocarbon oxygen carriers. The design of oxygen carriers was analyzed, and their application as blood substitutes or oxygen carriers in various hypoxic diseases was discussed. Finally, the characteristics and future research of ideal oxygen carriers were prospected to provide reference for follow-up research.

缺血或缺氧可引起组织代谢和功能的病理改变,从而导致各种疾病。及时有效的血液复苏或改善缺氧对疾病的治疗至关重要。然而,由于血液短缺、不同血型和传播感染的风险等限制,需要开发稳定、无毒和免疫惰性的氧载体。近年来,随着各种技术的发展,以血红蛋白和全氟碳为基础的氧载体得到了广泛的研究。本文综述了血红蛋白和全氟碳氧载体的发展与应用。分析了氧载体的设计,探讨了其作为血液代用品或氧载体在各种缺氧疾病中的应用。最后对理想氧载体的特点及未来研究方向进行了展望,为后续研究提供参考。
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引用次数: 0
Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease 外泌体作为心血管疾病诊断标志物和靶向载体的研究进展
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-11 DOI: 10.1021/acs.molpharmaceut.3c00268
Ni Li, Tianyuan Zhang, Linwen Zhu, Lebo Sun, Guofeng Shao* and Jianqing Gao*, 

Cardiovascular diseases (CVDs) are the leading cause of human death worldwide. Exosomes act as endogenous biological vectors; they possess advantages of low immunogenicity and low safety risks, also providing tissue selectivity, including the inherent targeting the to heart. Therefore, exosomes not only have been applied as biomarkers for diagnosis and therapeutic outcome confirmation but also showed potential as drug carriers for cardiovascular targeting delivery. This review aims to summarize the progress and challenges of exosomes as novel biomarkers, especially many novel exosomal noncoding RNAs (ncRNAs), and also provides an overview of the improved targeting functions of exosomes by unique engineered approaches, the latest developed administration methods, and the therapeutic effects of exosomes used as the biocarriers of medications for cardiovascular disease treatment. Also, the possible therapeutic mechanisms and the potentials for transferring exosomes to the clinic for CVD treatment are discussed. The advances, in vivo and in vitro applications, modifications, mechanisms, and challenges summarized in this review will provide a general understanding of this promising strategy for CVD treatment.

心血管疾病(cvd)是全世界人类死亡的主要原因。外泌体作为内源性生物载体;它们具有低免疫原性和低安全风险的优点,也具有组织选择性,包括固有的靶向心脏。因此,外泌体不仅被用作诊断和治疗结果确认的生物标志物,而且还显示出作为心血管靶向递送药物载体的潜力。本文综述了外泌体作为新型生物标志物的研究进展和面临的挑战,特别是许多新型的外泌体非编码rna (ncRNAs),并概述了外泌体通过独特的工程方法改进的靶向功能、最新开发的给药方法以及外泌体作为心血管疾病药物生物载体的治疗效果。此外,还讨论了可能的治疗机制和将外泌体转移到临床用于心血管疾病治疗的潜力。本文综述的进展、体内和体外应用、修饰、机制和挑战将使人们对这种有前景的CVD治疗策略有一个大致的了解。
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引用次数: 0
Complex Coacervates as a Promising Vehicle for mRNA Delivery: A Comprehensive Review of Recent Advances and Challenges 复杂凝聚体作为mRNA传递的有前途的载体:近期进展和挑战的综合综述
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-10 DOI: 10.1021/acs.molpharmaceut.3c00439
Chloe Forenzo,  and , Jessica Larsen*, 

Messenger RNA (mRNA)-based therapies have gained significant attention, following the successful deployment of mRNA-based COVID-19 vaccines. Compared with traditional methods of genetic modification, mRNA-based therapies offer several advantages, including a lower risk of genetic mutations, temporary and controlled therapeutic gene expression, and a shorter production time, which facilitates rapid responses to emerging health challenges. Moreover, mRNA-based therapies have shown immense potential in treating a wide range of diseases including cancers, immune diseases, and neurological disorders. However, the current limitations of non-viral vectors for efficient and safe delivery of mRNA therapies, such as low encapsulation efficiency, potential toxicity, and limited stability, necessitate the exploration of novel strategies to overcome these challenges and fully realize the potential of mRNA-based therapeutics. Coacervate-based delivery systems have recently emerged as promising strategies for enhancing mRNA delivery. Coacervates, which are formed by the aggregation of two or more macromolecules, have shown great potential in delivering a wide range of therapeutics due to their ability to form a separated macromolecular-rich fluid phase in an aqueous environment. This phase separation enables the entrapment and protection of therapeutic agents from degradation as well as efficient cellular uptake and controlled release. Additionally, the natural affinity of coacervates for mRNA molecules presents an excellent opportunity for enhancing mRNA delivery to targeted cells and tissues, making coacervate-based delivery systems an attractive option for mRNA-based therapies. This review highlights the limitations of current strategies for mRNA delivery and the advantages of coacervate-based delivery systems to enable mRNA therapeutics. Coacervates protect mRNA from enzymatic degradation and enhance cellular uptake, leading to sustained and controlled gene expression. Despite their promising properties, the specific use of coacervates as mRNA delivery vehicles remains underexplored. This review aims to provide a comprehensive overview of coacervate-mediated delivery of mRNA, exploring the properties and applications of different coacervating agents as well as the challenges and optimization strategies involved in mRNA encapsulation, release, stability, and translation via coacervate-mediated delivery. Through a comprehensive analysis of recent advancements and recommended future directions, our review sheds light on the promising role of coacervate-mediated delivery for RNA therapeutics, highlighting its potential to enable groundbreaking applications in drug delivery and gene therapy.

在基于信使RNA的COVID-19疫苗成功部署之后,基于信使RNA (mRNA)的疗法获得了极大的关注。与传统的基因修饰方法相比,基于mrna的疗法具有若干优势,包括较低的基因突变风险、暂时和受控的治疗性基因表达以及较短的生产时间,这有助于对新出现的健康挑战作出快速反应。此外,基于mrna的疗法在治疗包括癌症、免疫疾病和神经系统疾病在内的广泛疾病方面显示出巨大的潜力。然而,目前非病毒载体有效和安全递送mRNA治疗的局限性,如低封装效率、潜在毒性和有限的稳定性,需要探索新的策略来克服这些挑战,充分发挥基于mRNA治疗的潜力。基于凝聚体的递送系统最近成为增强mRNA递送的有前途的策略。凝聚体是由两个或多个大分子聚集形成的,由于它们能够在水环境中形成分离的富含大分子的流体相,因此在提供广泛的治疗方面显示出巨大的潜力。这种相分离使治疗剂的包裹和保护免受降解,以及有效的细胞摄取和控制释放。此外,凝聚体对mRNA分子的天然亲和力为增强mRNA向靶细胞和组织的递送提供了极好的机会,使基于凝聚体的递送系统成为基于mRNA的治疗的一个有吸引力的选择。这篇综述强调了目前mRNA递送策略的局限性,以及基于凝聚体的递送系统在mRNA治疗方面的优势。凝聚体保护mRNA免受酶降解并增强细胞摄取,从而导致持续和受控的基因表达。尽管凝聚体具有很好的特性,但其作为mRNA递送载体的具体用途仍未得到充分探索。本文旨在全面概述凝聚体介导的mRNA传递,探讨不同凝聚剂的特性和应用,以及通过凝聚体介导的mRNA包封、释放、稳定性和翻译所涉及的挑战和优化策略。通过对最近进展的综合分析和建议的未来方向,我们的综述揭示了凝聚体介导的RNA治疗的有希望的作用,强调了它在药物传递和基因治疗方面的突破性应用潜力。
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引用次数: 0
Lysozyme–Sucrose Interactions in the Solid State: Glass Transition, Denaturation, and the Effect of Residual Water 溶菌酶-蔗糖在固体状态下的相互作用:玻璃化转变、变性和残余水的影响
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-09 DOI: 10.1021/acs.molpharmaceut.3c00403
Ekaterina Bogdanova, Sebastian Lages, Tuan Phan-Xuan, Md. Arif Kamal, Ann Terry, Anna Millqvist Fureby and Vitaly Kocherbitov*, 

The freeze-drying of proteins, along with excipients, offers a solution for increasing the shelf-life of protein pharmaceuticals. Using differential scanning calorimetry, thermogravimetric analysis, sorption calorimetry, and synchrotron small-angle X-ray scattering (SAXS), we have characterized the properties at low (re)hydration levels of the protein lysozyme, which was freeze-dried together with the excipient sucrose. We observe that the residual moisture content in these samples increases with the addition of lysozyme. This results from an increase in equilibrium water content with lysozyme concentration at constant water activity. Furthermore, we also observed an increase in the glass transition temperature (Tg) of the mixtures with increasing lysozyme concentration. Analysis of the heat capacity step of the mixtures indicates that lysozyme does not participate in the glass transition of the sucrose matrix; as a result, the observed increase in the Tg of the mixtures is the consequence of the confinement of the amorphous sucrose domains in the interstitial space between the lysozyme molecules. Sorption calorimetry experiments demonstrate that the hydration behavior of this formulation is similar to that of the pure amorphous sucrose, while the presence of lysozyme only shifts the sucrose transitions. SAXS analysis of amorphous lysozyme–sucrose mixtures and unfolding of lysozyme in this environment show that prior to unfolding, the size and shape of lysozyme in a solid sucrose matrix are consistent with its native state in an aqueous solution. The results obtained from our study will provide a better understanding of the low hydration behavior of protein–excipient mixtures and support the improved formulation of biologics.

蛋白质和辅料的冷冻干燥为延长蛋白质药物的保质期提供了一种解决方案。利用差示扫描量热法、热重分析、吸附量热法和同步小角度x射线散射(SAXS),我们表征了蛋白溶菌酶在低(再)水化水平下的性质,并将其与赋形剂蔗糖一起冷冻干燥。我们观察到,这些样品中的残余水分含量随着溶菌酶的加入而增加。这是由于在恒定的水活度下溶菌酶浓度增加了平衡含水量。此外,我们还观察到随着溶菌酶浓度的增加,混合物的玻璃化转变温度(Tg)也增加。混合物的热容阶跃分析表明,溶菌酶不参与蔗糖基质的玻璃化转变;因此,观察到的混合物Tg的增加是在溶菌酶分子之间的间隙空间中限制无定形蔗糖结构域的结果。吸附量热实验表明,该配方的水化行为与纯无定形蔗糖相似,而溶菌酶的存在只是改变了蔗糖的转变。无定形溶菌酶-蔗糖混合物的SAXS分析以及在这种环境下溶菌酶的展开表明,在展开之前,溶菌酶在固体蔗糖基质中的大小和形状与其在水溶液中的天然状态一致。从我们的研究中获得的结果将更好地理解蛋白质-赋形剂混合物的低水化行为,并支持生物制剂的改进配方。
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引用次数: 0
Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host–Guest Inclusion Complex with β-Cyclodextrin 通过与β-环糊精形成主客体包合物增强强效肽PACE4抑制剂的药物样特征
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-09 DOI: 10.1021/acs.molpharmaceut.3c00261
Pauline Navals*, Anna Kwiatkowska, Nawel Mekdad, Frédéric Couture, Roxane Desjardins, Robert Day and Yves L. Dory, 

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of “host–guest” complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of βCD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new βCD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.

PACE4酶已被证实是一个有希望的治疗靶点,以扩大前列腺癌(PCa)的治疗范围。近年来,我们开发了一种有效的拟肽抑制剂,即化合物C23 (Ac-(DLeu) lllrvk -4-氨基苄酶酰胺)。像许多多肽一样,C23具有不利的药物样特征,尽管我们做出了努力,但尚未从常规的SAR研究中获益。因此,我们将注意力转向了一种新的配方策略,即使用环糊精(cd)。CDs可以通过形成“宿主-客体”复合物使化合物受益,保护客体免受降解并提高生物存活率。本研究生成了一系列βCD-C23复合物,并对其性质进行了评估,包括体外酶效、细胞增殖试验和血浆稳定性。结果发现了一种新的β cd配制的先导化合物,该化合物除了具有更强的可溶性和更强的效力外,还表现出更好的稳定性。
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引用次数: 0
Advances in Structure Pharmaceutics from Discovery to Evaluation and Design 结构药物研究进展:从发现到评价和设计
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-08 DOI: 10.1021/acs.molpharmaceut.3c00514
Huipeng Xu, Li Wu, Yanling Xue, Ting Yang, Ting Xiong, Caifen Wang, Siyu He, Hongyu Sun, Zeying Cao, Jun Liu, Siwen Wang, Zhe Li, Abid Naeem*, Xianzhen Yin* and Jiwen Zhang*, 

Drug delivery systems (DDSs) play an important role in delivering active pharmaceutical ingredients (APIs) to targeted sites with a predesigned release pattern. The chemical and biological properties of APIs and excipients have been extensively studied for their contribution to DDS quality and effectiveness; however, the structural characteristics of DDSs have not been adequately explored. Structure pharmaceutics involves the study of the structure of DDSs, especially the three-dimensional (3D) structures, and its interaction with the physiological and pathological structure of organisms, possibly influencing their release kinetics and targeting abilities. A systematic overview of the structures of a variety of dosage forms, such as tablets, granules, pellets, microspheres, powders, and nanoparticles, is presented. Moreover, the influence of structures on the release and targeting capability of DDSs has also been discussed, especially the in vitro and in vivo release correlation and the structure-based organ- and tumor-targeting capabilities of particles with different structures. Additionally, an in-depth discussion is provided regarding the application of structural strategies in the DDSs design and evaluation. Furthermore, some of the most frequently used characterization techniques in structure pharmaceutics are briefly described along with their potential future applications.

药物传递系统(dds)在将活性药物成分(api)以预先设计的释放模式递送到目标部位方面发挥着重要作用。原料药和赋形剂的化学和生物学特性已被广泛研究,因为它们对DDS的质量和有效性做出了贡献;然而,对dds的结构特征还没有充分的研究。结构药剂学是研究dds的结构,特别是三维结构及其与生物体生理和病理结构的相互作用,可能影响其释放动力学和靶向能力的学科。系统概述了各种剂型的结构,如片剂、颗粒、微球、粉末和纳米颗粒。此外,还讨论了结构对dds释放和靶向能力的影响,特别是不同结构颗粒的体内体外释放相关性和基于结构的器官和肿瘤靶向能力。此外,本文还对结构策略在dds设计和评价中的应用进行了深入的讨论。此外,简要描述了结构制药中一些最常用的表征技术及其潜在的未来应用。
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引用次数: 0
Voices in Molecular Pharmaceutics: Meet Dr. Niloufar Salehi, an Enthusiastic Developer of Physiologically Based Biopharmaceutical Models 分子药剂学的声音:认识Niloufar Salehi博士,一位基于生理的生物制药模型的热情开发者
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-08 DOI: 10.1021/acs.molpharmaceut.3c00687
Niloufar Salehi*, 
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引用次数: 0
Evaluation of [89Zr]Zr-DFO-2Rs15d Nanobody for Imaging of HER2-Positive Breast Cancer [89Zr]Zr-DFO-2Rs15d纳米体在her2阳性乳腺癌中的成像价值
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-08 DOI: 10.1021/acs.molpharmaceut.3c00360
Maxwell Ducharme, Lucinda Hall, Whitney Eckenroad, Shelbie J. Cingoranelli, Hailey A. Houson, Luke Jaskowski, Chanelle Hunter, Benjamin M. Larimer and Suzanne E. Lapi*, 

One of the most aggressive forms of breast cancer involves the overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in ~25% of all breast cancers and is associated with increased proliferation, increased rates of metastasis, and poor prognosis. Treatment for HER2-positive breast cancer has vastly improved since the development of the monoclonal antibody trastuzumab (Herceptin) as well as other biological constructs. However, patients still commonly develop resistance, illustrating the need for newer therapies. Nanobodies have become an important focus for potential development as HER2-targeting imaging agents and therapeutics. Nanobodies have many favorable characteristics, including high stability in heat and nonphysiological pH, while maintaining their low-nanomolar affinity for their designed targets. Specifically, the 2Rs15d nanobody has been developed for targeting HER2 and has been evaluated as a diagnostic imaging agent for single-photon emission computed tomography (SPECT) and positron emission tomography (PET). While a construct of 2Rs15d with the positron emitter 68Ga is currently in phase I clinical trials, the only PET images acquired in preclinical or clinical research have been within 3 h postinjection. We evaluated our in-house produced 2Rs15d nanobody, conjugated with the chelator deferoxamine (DFO), and radiolabeled with 89Zr for PET imaging up to 72 h postinjection. [89Zr]Zr-DFO-2Rs15d demonstrated high stability in both phosphate-buffered saline (PBS) and human serum. Cell binding studies showed high binding and specificity for HER2, as well as prominent internalization. Our in vivo PET imaging confirmed high-quality visualization of HER2-positive tumors up to 72 h postinjection, whereas HER2-negative tumors were not visualized. Subsequent biodistribution studies quantitatively supported the significant HER2-positive tumor uptake compared to the negative control. Our studies fill an important gap in understanding the imaging and binding properties of the 2Rs15d nanobody at extended time points. As many therapeutic radioisotopes have single or multiday half-lives, this information will directly benefit the potential of the radiotherapy development of 2Rs15d for HER2-positive breast cancer patients.

最具侵袭性的乳腺癌之一涉及人表皮生长因子受体2 (HER2)的过度表达。HER2在约25%的乳腺癌中过表达,并与增殖增加、转移率增加和预后不良相关。自单克隆抗体曲妥珠单抗(赫赛汀)以及其他生物构建物的开发以来,her2阳性乳腺癌的治疗已经大大改善。然而,患者仍然普遍产生耐药性,说明需要更新的治疗方法。纳米体已成为潜在开发的her2靶向显像剂和治疗药物的重要焦点。纳米体具有许多有利的特性,包括在高温和非生理pH下的高稳定性,同时保持对其设计目标的低纳摩尔亲和力。具体来说,2Rs15d纳米体已被开发用于靶向HER2,并已被评估为单光子发射计算机断层扫描(SPECT)和正电子发射断层扫描(PET)的诊断显像剂。虽然含有正电子发射器68Ga的2Rs15d构建体目前处于I期临床试验阶段,但临床前或临床研究中获得的PET图像仅在注射后3小时内。我们评估了我们内部生产的2Rs15d纳米体,与螯合剂去铁胺(DFO)结合,并用89Zr进行放射性标记,用于注射后72小时的PET成像。[89Zr]Zr-DFO-2Rs15d在磷酸盐缓冲盐水(PBS)和人血清中均表现出较高的稳定性。细胞结合研究显示HER2具有高的结合性和特异性,并具有显著的内化。我们的体内PET成像证实了注射后72小时her2阳性肿瘤的高质量可视化,而her2阴性肿瘤则没有可视化。随后的生物分布研究定量地支持与阴性对照相比,her2阳性肿瘤摄取显著。我们的研究填补了了解2Rs15d纳米体在延长时间点上的成像和结合特性的重要空白。由于许多治疗性放射性同位素具有单天或多日的半衰期,这一信息将直接有利于2Rs15d治疗her2阳性乳腺癌患者的放疗发展潜力。
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引用次数: 1
Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats 吩噻嗪类药物作为动力蛋白II抑制剂对内吞细胞对聚乙二醇化脂质体摄取的剂量依赖性影响及聚乙二醇化脂质体阿霉素在大鼠体内的药动学
IF 4.9 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2023-08-07 DOI: 10.1021/acs.molpharmaceut.3c00102
Christopher N. Subasic, Neville J. Butcher, Fiona Simpson, Rodney F. Minchin and Lisa M. Kaminskas*, 

Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to “bud off”. An important class of dynII inhibitors that are used clinically are phenothiazines, such as prochlorperazine (PCZ). PCZ is an antipsychotic drug but is also currently in clinical trials at higher concentrations as an adjuvant in cancer patients that increases the efficacy of monoclonal antibodies at high intravenous doses. It is unknown, however, whether high-dose dynII inhibitors have the potential to alter the pharmacokinetics of co-administered chemotherapeutic nanomedicines that are largely cleared via the mononuclear phagocyte system. This work therefore sought to investigate the impact of clinically relevant concentrations of phenothiazines, PCZ and thioridazine, on in vitro liposome endocytosis and in vivo liposome pharmacokinetics after PCZ infusion in rats. The uptake of fluorescently labeled PEGylated liposomes into differentiated and undifferentiated THP-1 and RAW246.7 cells, and primary human peripheral white blood cells, was investigated via flow cytometry after co-incubation with dynII inhibitors. The IV pharmacokinetics of PEGylated liposomes were also investigated in rats after a 20 min infusion with PCZ. Phenothiazines and dyngo4a reduced the uptake of PEGylated liposomes by THP-1 and RAW264.7 cells in a concentration-dependent manner in vitro. However, dynII inhibitors did not alter the mean uptake of liposomes by human peripheral white blood cells, but endocytic white cells from some donors exhibited sensitivity to phenothiazine exposure. When a clinically relevant dose of PCZ was co-administered with PEGylated liposomal doxorubicin (Caelyx/Doxil) in rats, the pharmacokinetics and biodistribution of liposomes were unaltered. These data suggest that while clinically relevant doses of dynII inhibitors can inhibit the uptake of liposomes by endocytic cells in vitro, they are unlikely to significantly affect the pharmacokinetics of long-circulating, co-administered liposomes.

动力蛋白II (dynII)在内吞细胞的内化途径中发挥重要作用,使膜内陷“脱芽”。临床上使用的一类重要的dynII抑制剂是吩噻嗪类药物,如prochlorperazine (PCZ)。PCZ是一种抗精神病药物,但目前也在临床试验中以更高的浓度作为癌症患者的辅助剂,在高静脉注射剂量下增加单克隆抗体的疗效。然而,目前尚不清楚,大剂量的dynII抑制剂是否有可能改变共同施用的化疗纳米药物的药代动力学,这些药物主要通过单核吞噬细胞系统清除。因此,本研究旨在研究临床相关浓度的吩噻嗪、PCZ和硫硝嗪对大鼠PCZ输注后体外脂质体内吞和体内脂质体药代动力学的影响。在与dynII抑制剂共孵育后,通过流式细胞术研究荧光标记的聚乙二醇化脂质体在分化和未分化的THP-1和RAW246.7细胞以及原代人外周血细胞中的吸收情况。在大鼠体内注射PCZ 20 min后,研究了聚乙二醇化脂质体的静脉药代动力学。在体外实验中,吩噻嗪类药物和dyngo4a以浓度依赖的方式降低THP-1和RAW264.7细胞对聚乙二醇化脂质体的摄取。然而,dynII抑制剂并没有改变人类外周白细胞对脂质体的平均摄取,但来自一些供体的内吞白细胞对吩噻嗪暴露表现出敏感性。当临床相关剂量的PCZ与聚乙二醇化脂质体阿霉素(Caelyx/Doxil)在大鼠体内共同施用时,脂质体的药代动力学和生物分布未发生改变。这些数据表明,虽然临床相关剂量的dynII抑制剂可以在体外抑制内吞细胞对脂质体的摄取,但它们不太可能显著影响长期循环的共给药脂质体的药代动力学。
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Molecular Pharmaceutics
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