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Psoriatic skin-sensitive degradable mesoporous zinc phosphate microsphere as a photosensitizer in photodynamic therapy for anti-psoriasis 银屑病皮肤敏感的可降解介孔磷酸锌微球作为光动力治疗银屑病的光敏剂。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.107000
Nan Jin , Liqiong Huang , Xin Chen , Zhuhang Liu , Ruotong Chen , Mengting Gao , Tianhui Liu , Jianmin Chen
Blue light will be a promising alternative for photodynamic therapy in psoriasis, but the photosensitizer in vivo remains unexplored. Mesoporous zinc phosphate microparticle (MZP) was synthesized successfully in this study, as evidenced by XPS, XRD, and nitrogen adsorption experiments. Its psoriatic skin-sensitive property was corroborated by SEM and the higher cumulative release rate of that impregnated with curcumin (Cur) and glycyrrhizic acid (GA), namely Cur-GA-MZP, at pH 5.4, which mimic the acidic environment of the inflammatory psoriatic skin. Moreover, by detecting the decrease of absorbance of 1,3-Diphenylisobenzofuran (DPBF) which had been mixed with MZP irradiated by blue light, MZP is confirmed to reinforce ROS along with irradiation time at pH 5.4, rather than that at pH 7.2. This phenomenon led to a strengthened anti-inflammatory effect of MZP on xylene-induced auricle inflammation, as well as on imiquimod-induced psoriatic-like plaques exists only under blue light irradiation, with the alleviated macroscopic and microscopic appearance, decreased IL-17A levels of skin lesion area as well as spleen index. The mechanism is likely attributed to the NFƙB pathway as well as the MAPK pathway detected by western blot. In sum, MZP, which could dissociate at psoriatic skin condition, will be a promising photosensitizer with the prerequisite of blue light as an effective photodynamic therapy for the management of psoriasis.
蓝光将成为银屑病光动力治疗的一种有前途的替代方法,但体内的光敏剂仍未被探索。通过XPS、XRD和氮气吸附实验,成功合成了介孔磷酸锌微粒(MZP)。扫描电镜证实了其银屑病皮肤敏感特性,并且在pH 5.4下,姜黄素(Cur)和甘草酸(GA) (Cur -GA- mzp)浸渍的累积释放率较高,模拟炎症性银屑病皮肤的酸性环境。此外,通过检测与蓝光照射MZP混合的1,3-二苯基异苯并呋喃(DPBF)的吸光度下降,证实了MZP在pH为5.4时随照射时间的增加而增强ROS,而在pH为7.2时则相反。这一现象导致MZP对二甲苯致耳穴炎症的抗炎作用增强,对仅在蓝光照射下才存在的吡喹莫德致银屑病样斑块的抗炎作用增强,其宏观和微观外观均有所缓解,皮肤病变区域IL-17A水平和脾脏指数均有所降低。其机制可能与NFƙB通路以及western blot检测到的MAPK通路有关。综上所述,MZP可以在银屑病皮肤状态下解离,是一种有前景的光敏剂,以蓝光为前提,作为治疗银屑病的有效光动力疗法。
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引用次数: 0
Antitumor activity of selenopsammaplin A analog (SPA-10091-HCl) via histone methyltransferase DOT1L degradation and apoptosis induction in castration-resistant prostate cancer cells 硒sammaplin A类似物(SPA-10091-HCl)通过组蛋白甲基转移酶DOT1L降解和诱导凋亡在去势抵抗前列腺癌细胞中的抗肿瘤活性
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106991
Jaeho Han , Sehun Yang , Woong Sub Byun , Sung Chul Jang , Eun Seo Bae , Hyeung-geun Park , Sang Kook Lee
Castrate-resistant prostate cancer (CRPC) is one of the most difficult cancers in men and is characterized by a poor prognosis and a high risk of metastasis. The overexpression of the disruptor of telomeric silencing 1-like (DOT1L), which is a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), has been related to poor outcomes in patients with CRPC. Therefore, targeting DOT1L is considered a potential therapeutic approach to overcome the significant medical challenges of CRPC. In our previous study, we designed selenopsammaplin A (SPA) analogs as non-nucleoside DOT1L inhibitors to suppress human breast cancer cell proliferation and metastasis. However, the antitumor activity and the precise underlying mechanism of SPA analogs in PC cells remain unclear. Herein, we administered SPA-10091-HCl, a DOT1L-targeting degrader, to effectively hinder the growth and DOT1L-mediated H3K79 methylation in CRPC (PC3 and DU145) cells. Mechanistically, SPA-10091-HCl selectively degrades DOT1L protein through the nuclear ubiquitin-proteasome pathway, thereby suppressing H3K79 methylation in CRPC cells. SPA-10091-HCl inhibits CRPC cell proliferation, migration, and invasion, with the E-cadherin expression upregulation and N-cadherin and vimentin expression downregulation. Additionally, prolonged SPA-10091-HCl treatment induced apoptosis by regulating apoptosis-associated protein expressions, including Poly (ADP-ribose) polymerase (PARP), caspase-3, caspase-9, and Bcl-2. Moreover, SPA-10091-HCl effectively inhibited tumor growth in the PC3 cells-implanted xenograft mouse model without any overt toxicity. These results indicate SPA-10091-HCl as a potential candidate for further development as a chemotherapeutic agent against CRPC.
去势抵抗性前列腺癌(CRPC)是男性最困难的癌症之一,其特点是预后差,转移风险高。端粒沉默1样干扰物(DOT1L)的过表达与CRPC患者的不良预后有关,DOT1L是组蛋白H3在赖氨酸残基79 (H3K79)上的特异性甲基转移酶。因此,靶向DOT1L被认为是克服CRPC重大医学挑战的潜在治疗方法。在我们之前的研究中,我们设计了selenopsammaplin A (SPA)类似物作为非核苷类DOT1L抑制剂来抑制人乳腺癌细胞的增殖和转移。然而,SPA类似物在PC细胞中的抗肿瘤活性和确切的潜在机制尚不清楚。在本研究中,我们给药SPA-10091-HCl,一种dot1l靶向降解剂,可以有效地抑制CRPC (PC3和DU145)细胞的生长和dot1l介导的H3K79甲基化。在机制上,SPA-10091-HCl通过核泛素-蛋白酶体途径选择性降解DOT1L蛋白,从而抑制CRPC细胞中的H3K79甲基化。SPA-10091-HCl抑制CRPC细胞的增殖、迁移和侵袭,表达上调E-cadherin,下调N-cadherin和vimentin表达。此外,长时间的SPA-10091-HCl处理通过调节凋亡相关蛋白的表达诱导凋亡,包括聚(adp -核糖)聚合酶(PARP)、caspase-3、caspase-9和Bcl-2。此外,SPA-10091-HCl可有效抑制PC3细胞移植小鼠模型的肿瘤生长,且无明显毒性。这些结果表明,SPA-10091-HCl作为抗CRPC的化疗药物有进一步开发的潜力。
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引用次数: 0
Developing a method for the study of perfusion effects in topical product pharmacokinetics 一种研究外用产品药代动力学灌注效应的方法。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106975
Saara K. Luna , M. Alice Maciel Tabosa , Ting Chean Khoo , Conor L. Evans
Topical drug products are delivered to skin structures to treat numerous skin diseases. Due to the complexities of the skin environment and barrier, topical drug pharmacokinetics are difficult to determine, especially in vivo, as most pharmacokinetic assessment methods can only be performed ex vivo. Notably, in vivo conditions include perfusion via dermal capillaries, which influences topical drug uptake by acting as a clearance route and a “sink” driving permeation through the skin. In this study, we develop a method to examine the effects of perfusion on topical drug uptake in vivo using stimulated Raman scattering (SRS) microscopy, a chemically-specific imaging modality ideal for visualizing topical drug permeation over time. In this pilot study, we imaged the in vivo and ex vivo uptake of tazarotene in 70/30 v/v Transcutol:EtOH in paired mouse ear skin, comparing the effects of perfusion on tazarotene concentration (linearly proportional to SRS signal intensity) over time and pharmacokinetic parameters (Tmax, Cmax, AUC) in lipid-rich and lipid-poor regions in the stratum corneum and sebaceous glands. Obvious variations in SRS signal-time trends and statistically significant differences in stratum corneum pharmacokinetic parameters comparing uptake in lipid-rich and lipid-poor regions in vivo and ex vivo indicated slowed tazarotene flux through ex vivo skin in the absence of perfusion. The observed permeation differences in lipid-rich and lipid-poor regions in perfused and non-perfused skin reflects increased tazarotene permeation rate and removal in the presence of perfusion (in vivo) and decreased permeation rate and lack of elimination route in the absence of perfusion (ex vivo). Our method is demonstrated to be effective in assessing in vivo perfusion effects on topical drug uptake, promoting a better understanding of the influence of perfusion on topical drug delivery.
局部药物产品被输送到皮肤结构,以治疗许多皮肤疾病。由于皮肤环境和屏障的复杂性,局部药物的药代动力学很难确定,特别是在体内,因为大多数药代动力学评估方法只能在体外进行。值得注意的是,体内条件包括通过真皮毛细血管的灌注,它通过作为清除途径和驱动皮肤渗透的“水槽”来影响局部药物摄取。在这项研究中,我们开发了一种方法来检查灌注对体内局部药物摄取的影响,使用受激拉曼散射(SRS)显微镜,这是一种化学特异性成像方式,非常适合观察局部药物随时间的渗透。在这项初步研究中,我们对配对小鼠耳皮肤在70/30 v/v的Transcutol:EtOH下他扎罗汀的体内和体外摄取进行了成像,比较灌注对他扎罗汀浓度(与SRS信号强度成线性关系)随时间的影响,以及角质层和皮脂腺富脂区和贫脂区药代动力学参数(Tmax、Cmax、AUC)的影响。SRS信号时间趋势的明显变化以及角质层药代动力学参数在体内和体外比较富脂区和贫脂区摄取的统计学差异表明,在没有灌注的情况下,他zarotene通过体外皮肤的通量减慢。灌注和非灌注皮肤富脂区和贫脂区渗透差异反映了灌注时他扎罗汀的渗透速率和去除增加(体内),无灌注时他扎罗汀的渗透速率降低和消除途径缺乏(体外)。我们的方法被证明是有效的评估体内灌注对局部药物摄取的影响,促进更好地理解灌注对局部药物递送的影响。
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引用次数: 0
Pyrrolidine SS13 induces oxidative stress and autophagy-mediated cell death in colorectal cancer cells 吡咯烷SS13诱导结直肠癌细胞氧化应激和自噬介导的细胞死亡。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106982
Natalia Nosalova , Monika Majirska , Alexandra Keselakova , Miroslava Martinkova , Dominika Fabianova , Andrej Mirossay , Martina Bago Pilatova , Martin Kello

Introduction

Pyrrolidines, nitrogenous organic compounds, are among the most intensively studied agents because of their antibacterial, antiviral, neurological, and promising antitumor effects. Moreover, many medicinal drugs contain pyrrolidine moiety such as sunitinib (anticancer drug), telaprevir and ombitasvir (antiviral drugs) or ramipril (antihypertensive drug).

Rationale of the Study

Based on the pro-apoptotic effect of pyrrolidine SS13, this study focuses on the pro-oxidative properties of the tested pyrrolidine SS13 on colorectal cancer cells to deepen the understanding of its mechanisms of action.

Research hypothesis

We hypothesize that SS13 induces oxidative stress and autophagy activation in HCT116 and Caco-2 cell lines, thus contributing to antiproliferative effects.

Methods

Flow cytometry, western blot, fluorescence microscopy and qRT-PCR were used to evaluate the effect of pyrrolidine SS13.

Conclusion and future directions

Pyrrolidine SS13 induced oxidative stress through the accumulation of reactive oxygen and nitrogen species in both cell lines and the modulation of both superoxide dismutase isoenzymes (SOD1, SOD2). Oxidative stress was also associated with the activation of DNA damage response system and modulation of stress/survival pathways. We demonstrated for the first time that pyrrolidine SS13 is involved in the induction of autophagy accompanied by increased levels of autophagic markers (p-AMPK, p-ULK, LC3I/II and ATG7) and a significant decrease in p62 protein levels in both cell lines. Finally, chloroquine, an inhibitor of autophagy, enhanced cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating that SS13 contributes to autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy participate in the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells. Further research using primary cell cultures obtained from different animal tissues as well as performing in vivo experiments is needed to understand these processes in detail and to investigate the potential therapeutic application of new pyrrolidine derivatives.
吡咯烷是一种含氮有机化合物,因其具有抗菌、抗病毒、神经学和抗肿瘤作用而成为研究最深入的药物之一。此外,许多药物含有吡咯烷类,如舒尼替尼(抗癌药物)、特拉匹韦和奥姆比他韦(抗病毒药物)或雷米普利(降压药)。研究基础:本研究基于吡咯烷素SS13的促凋亡作用,重点研究所测试的吡咯烷素SS13对结直肠癌细胞的促氧化特性,加深对其作用机制的了解。研究假设:我们假设SS13诱导HCT116和Caco-2细胞系的氧化应激和自噬激活,从而促进抗增殖作用。方法:采用流式细胞术、western blot、荧光显微镜、qRT-PCR等方法评价吡咯烷素SS13的作用。结论及未来研究方向:吡咯烷酮SS13通过在两种细胞系中积累活性氧和活性氮以及调节两种超氧化物歧化酶同工酶(SOD1, SOD2)诱导氧化应激。氧化应激还与DNA损伤反应系统的激活和应激/生存途径的调节有关。我们首次证明,吡啶SS13参与诱导自噬,并伴随自噬标志物(p-AMPK、p-ULK、LC3I/II和ATG7)水平的升高,以及两种细胞系中p62蛋白水平的显著降低。最后,自噬抑制剂氯喹在HCT116和Caco-2细胞中提高了细胞存活率,抑制了SS13的细胞毒作用,表明SS13参与了自噬介导的细胞死亡。综上所述,我们的研究结果表明氧化应激和自噬参与了吡咯烷素SS13对结直肠癌细胞的抗增殖作用。需要进一步研究从不同动物组织中获得的原代细胞培养物以及进行体内实验,以详细了解这些过程,并研究新的吡咯烷衍生物的潜在治疗应用。
{"title":"Pyrrolidine SS13 induces oxidative stress and autophagy-mediated cell death in colorectal cancer cells","authors":"Natalia Nosalova ,&nbsp;Monika Majirska ,&nbsp;Alexandra Keselakova ,&nbsp;Miroslava Martinkova ,&nbsp;Dominika Fabianova ,&nbsp;Andrej Mirossay ,&nbsp;Martina Bago Pilatova ,&nbsp;Martin Kello","doi":"10.1016/j.ejps.2024.106982","DOIUrl":"10.1016/j.ejps.2024.106982","url":null,"abstract":"<div><h3>Introduction</h3><div>Pyrrolidines, nitrogenous organic compounds, are among the most intensively studied agents because of their antibacterial, antiviral, neurological, and promising antitumor effects. Moreover, many medicinal drugs contain pyrrolidine moiety such as sunitinib (anticancer drug), telaprevir and ombitasvir (antiviral drugs) or ramipril (antihypertensive drug).</div></div><div><h3>Rationale of the Study</h3><div>Based on the pro-apoptotic effect of pyrrolidine SS13, this study focuses on the pro-oxidative properties of the tested pyrrolidine SS13 on colorectal cancer cells to deepen the understanding of its mechanisms of action.</div></div><div><h3>Research hypothesis</h3><div>We hypothesize that SS13 induces oxidative stress and autophagy activation in HCT116 and Caco-2 cell lines, thus contributing to antiproliferative effects.</div></div><div><h3>Methods</h3><div>Flow cytometry, western blot, fluorescence microscopy and qRT-PCR were used to evaluate the effect of pyrrolidine SS13.</div></div><div><h3>Conclusion and future directions</h3><div>Pyrrolidine SS13 induced oxidative stress through the accumulation of reactive oxygen and nitrogen species in both cell lines and the modulation of both superoxide dismutase isoenzymes (SOD1, SOD2). Oxidative stress was also associated with the activation of DNA damage response system and modulation of stress/survival pathways. We demonstrated for the first time that pyrrolidine SS13 is involved in the induction of autophagy accompanied by increased levels of autophagic markers (p-AMPK, p-ULK, LC3I/II and ATG7) and a significant decrease in p62 protein levels in both cell lines. Finally, chloroquine, an inhibitor of autophagy, enhanced cell survival and suppressed the cytotoxic effect of SS13 in HCT116 and Caco-2 cells, indicating that SS13 contributes to autophagy-mediated cell death. Taken together, our results suggest that oxidative stress and autophagy participate in the antiproliferative effect of pyrrolidine SS13 on colorectal cancer cells. Further research using primary cell cultures obtained from different animal tissues as well as performing <em>in vivo</em> experiments is needed to understand these processes in detail and to investigate the potential therapeutic application of new pyrrolidine derivatives.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106982"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants 探索 Soluplus® 与离子表面活性剂结合后的增溶效果。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106957
Justus Johann Lange , Lukas Enzner , Martin Kuentz , Patrick J. O’Dwyer , Wiebke Saal , Brendan T. Griffin , Nicole Wyttenbach
Preclinical testing of new drug candidates frequently necessitates high-dose solution formulations to support robust testing in rodent models. This study aimed to expand the range of high solubilisation capacity formulations by exploring the solubilisation effects of the polymeric surfactant Soluplus® in combination with ionic surfactants. The interactions between Soluplus® and three ionic surfactants, sodium dodecyl sulphate, dioctyl sodium succinate, and sodium oleate, with a primary focus on solubility enhancement were investigated over a range of ionic surfactant concentrations. The solubilisation profiles for seven model drugs were obtained, and the vehicles were characterised by their visual characteristics, dynamic light scattering, and viscosity measurements. The solubilisation profiles were non-linear, indicating the formation of different colloidal species with individual solubilisation strengths depending on surfactant type and concentration, demonstrating substantial solubility enhancement. For certain drugs more than additive solubilisation, facilitated by synergistic interactions between Soluplus® and the ionic surfactants, was obtained. Overall, the solubility increase provided by the excipient combinations resulted in non-linear and drug specific solubilisation profiles. The non-linearities observed were reflected in visual observations of the vehicles appearance, DLS and viscosity measurements, which collectively indicated a change in polymer aggregation with increasing concentration of anionic surfactant. This investigation highlights that already low quantities of ionic surfactants introduced to Soluplus® may substantially enhance solubility, which offers a promising approach for further exploration in preclinical drug development where more conventional solubilising formulation strategies may fall short.
新药候选物的临床前测试通常需要高剂量溶液配方,以支持啮齿动物模型的稳健测试。本研究旨在通过探索聚合物表面活性剂 Soluplus® 与离子表面活性剂结合的增溶效果,扩大高增溶能力制剂的范围。研究了 Soluplus® 与三种离子表面活性剂(十二烷基硫酸钠、琥珀酸二辛酯钠和油酸钠)之间的相互作用,主要重点是在一定浓度的离子表面活性剂中提高溶解度。获得了七种模型药物的增溶曲线,并通过视觉特征、动态光散射和粘度测量对载体进行了表征。增溶曲线是非线性的,表明根据表面活性剂的类型和浓度形成了不同的胶体物种,其各自的增溶强度也不同,这表明药物的溶解度得到了大幅提高。Soluplus® 与离子表面活性剂之间的协同作用促进了某些药物的增溶。总之,辅料组合带来的溶解度增加导致了非线性和药物特定的溶解曲线。观察到的非线性现象反映在对载体外观的目测、DLS 和粘度测量中,这些结果共同表明,随着阴离子表面活性剂浓度的增加,聚合物的聚集情况也会发生变化。这项研究表明,在 Soluplus® 中加入少量离子表面活性剂就能大大提高溶解度,这为临床前药物开发提供了一种很有前景的方法,因为在临床前药物开发中,传统的增溶配方策略可能会出现不足。
{"title":"Exploration of solubilisation effects facilitated by the combination of Soluplus® with ionic surfactants","authors":"Justus Johann Lange ,&nbsp;Lukas Enzner ,&nbsp;Martin Kuentz ,&nbsp;Patrick J. O’Dwyer ,&nbsp;Wiebke Saal ,&nbsp;Brendan T. Griffin ,&nbsp;Nicole Wyttenbach","doi":"10.1016/j.ejps.2024.106957","DOIUrl":"10.1016/j.ejps.2024.106957","url":null,"abstract":"<div><div>Preclinical testing of new drug candidates frequently necessitates high-dose solution formulations to support robust testing in rodent models. This study aimed to expand the range of high solubilisation capacity formulations by exploring the solubilisation effects of the polymeric surfactant Soluplus® in combination with ionic surfactants. The interactions between Soluplus® and three ionic surfactants, sodium dodecyl sulphate, dioctyl sodium succinate, and sodium oleate, with a primary focus on solubility enhancement were investigated over a range of ionic surfactant concentrations. The solubilisation profiles for seven model drugs were obtained, and the vehicles were characterised by their visual characteristics, dynamic light scattering, and viscosity measurements. The solubilisation profiles were non-linear, indicating the formation of different colloidal species with individual solubilisation strengths depending on surfactant type and concentration, demonstrating substantial solubility enhancement. For certain drugs more than additive solubilisation, facilitated by synergistic interactions between Soluplus® and the ionic surfactants, was obtained. Overall, the solubility increase provided by the excipient combinations resulted in non-linear and drug specific solubilisation profiles. The non-linearities observed were reflected in visual observations of the vehicles appearance, DLS and viscosity measurements, which collectively indicated a change in polymer aggregation with increasing concentration of anionic surfactant. This investigation highlights that already low quantities of ionic surfactants introduced to Soluplus® may substantially enhance solubility, which offers a promising approach for further exploration in preclinical drug development where more conventional solubilising formulation strategies may fall short.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106957"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142647190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dual pH-responsive CRISPR/Cas9 ribonucleoprotein xenopeptide complexes for genome editing 用于基因组编辑的双ph响应CRISPR/Cas9核糖核蛋白外肽复合物。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106983
Xianjin Luo , Janin Germer , Tobias Burghardt , Melina Grau , Yi Lin , Miriam Höhn , Ulrich Lächelt , Ernst Wagner
Clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR associated (Cas) protein has been proved as a powerful tool for the treatment of genetic diseases. The Cas9 protein, when combined with single-guide RNA (sgRNA), forms a Cas9/sgRNA ribonucleoprotein (RNP) capable of targeting and editing the genome. However, the limited availability of effective carriers has restricted the broader application of CRISPR/Cas9 RNP. In this study, we evaluated dual pH-responsive amphiphilic xenopeptides (XPs) for delivering CRISPR/Cas9 RNP. These artificial lipo-XPs contain apolar cationizable lipoamino fatty acid (LAF) and polar cationizable oligoaminoethylene acid units such as succinoyl-tetraethylenepentamine (Stp) in various ratios and U-shaped topologies. The carriers were screened for functional Cas9/sgRNA RNP delivery in four different reporter cell lines, including a Duchenne muscular dystrophy (DMD) exon skipping reporter cell model. Significantly enhanced cellular uptake into HeLa cells, effective endosomal disruption in HeLa gal8-mRuby3 cells, and potent genome editing by several Cas9/sgRNA RNP complexes was observed in four different cell lines in the 5 nM sgRNA range. Comparing Cas9/sgRNA RNP complexes with Cas9 mRNA/sgRNA polyplexes in the DMD reporter cell model demonstrated similar splice site editing and high exon skipping of the two different molecular Cas9 modalities. Based on these studies, analogues of two potent U1 LAF2-Stp and LAF4-Stp2 structures were deployed, tuning the amphiphilicity of the polar Stp group by replacement with the six oligoamino acids dmGtp, chGtp, dGtp, Htp, Stt, or GEIPA. The most potent LAF2-Stp analogues (containing dGtp, chGtp or GEIPA) demonstrated further enhanced gene editing efficiency with EC50 values of 1 nM in the DMD exon skipping reporter cell line. Notably, the EC50 of LAF2-dGtp reached 0.51 nM even upon serum incubation. Another carrier (LAF4-GEIPA2) complexing Cas9/sgRNA RNP and donor DNA, facilitated up to 43 % of homology-directed repair (HDR) in HeLa eGFPd2 cells visualized by the switch from green fluorescent protein (eGFP) to blue fluorescent protein (BFP). This study presents a delivery system tunable for Cas9 RNP complexes or Cas9 RNP/donor DNA polyplexes, offering an effective and easily applicable strategy for gene editing.
聚类规则间隔短回文重复(CRISPR)/CRISPR相关(Cas)蛋白已被证明是治疗遗传性疾病的有力工具。Cas9蛋白与单导RNA (sgRNA)结合,形成Cas9/sgRNA核糖核蛋白(RNP),能够靶向和编辑基因组。然而,有效载体的有限可用性限制了CRISPR/Cas9 RNP的广泛应用。在这项研究中,我们评估了双ph响应性两亲性外肽(XPs)递送CRISPR/Cas9 RNP的作用。这些人造脂质xps含有极性阳离子化脂氨基脂肪酸(LAF)和极性阳离子化低氨基乙烯单位,如琥珀酰四乙基戊二胺(Stp),其比例和结构呈u形。这些载体在四种不同的报告细胞系中进行了Cas9/sgRNA RNP递送功能筛选,包括杜氏肌营养不良(DMD)外显子跳跃报告细胞模型。在4种不同的细胞系中,在5 nM sgRNA范围内观察到显著增强HeLa细胞的细胞摄取,有效地破坏HeLa gal8-mRuby3细胞的内体,以及几种Cas9/sgRNA RNP复合物的有效基因组编辑。将DMD报告细胞模型中的Cas9/sgRNA RNP复合物与Cas9 mRNA/sgRNA多plex进行比较,发现两种不同的Cas9分子模式具有相似的剪接位点编辑和高外显子跳变。在这些研究的基础上,研究人员部署了两种有效的U1 LAF2-Stp和LAF4-Stp2结构的类似物,通过替换6个低聚氨基酸dmGtp、chGtp、dGtp、Htp、Stt或GEIPA来调整极性Stp基团的两亲性。最有效的LAF2-Stp类似物(含有dGtp、chGtp或GEIPA)在DMD外显子跳变报告细胞系中显示出进一步增强的基因编辑效率,EC50值为1 nM。值得注意的是,即使在血清孵育后,LAF2-dGtp的EC50也达到了0.51 nM。另一种载体(LAF4-GEIPA2)络合Cas9/sgRNA RNP和供体DNA,在HeLa eGFPd2细胞中促进了高达43%的同源定向修复(HDR),通过绿色荧光蛋白(eGFP)向蓝色荧光蛋白(BFP)的转换可见。本研究提出了一种可调节Cas9 RNP复合物或Cas9 RNP/供体DNA多聚体的递送系统,为基因编辑提供了一种有效且易于应用的策略。
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引用次数: 0
The evaluation of DNA-linked inhibitor antibody and AlphaScreen assays for high-throughput screening of compounds targeting the cap-binding domain in influenza a polymerase 评估 DNA 链接抑制剂抗体和 AlphaScreen 分析法,以高通量筛选针对甲型流感聚合酶帽结合域的化合物。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106990
Kateřina Čermáková , Jiří Gregor , Michal Kráľ , Elena Karlukova , Václav Navrátil , Róbert Reiberger , Carlos Berenguer Albiñana , Vít Bechynský , Pavel Majer , Jan Konvalinka , Aleš Machara , Milan Kožíšek
The PB2 subunit of the influenza virus polymerase complex is essential for viral replication, primarily through a mechanism known as cap-snatching. In this process, PB2 binds to the 5’ cap structure of host pre-mRNAs, enabling the viral polymerase to hijack the host transcriptional machinery. This binding facilitates the cleavage and integration of the capped RNA fragment into viral mRNA, thereby promoting efficient viral replication. Inhibiting the PB2-cap interaction is therefore crucial, as it directly disrupts the viral replication cycle. Consequently, targeting PB2 with specific inhibitors is a promising strategy for antiviral drug development against influenza. However, there are currently no available methods for the high-throughput screening of potential inhibitors. The development of new inhibitor screening methods of potential PB2 binders is the focus of this study.
In this study, we present two novel methods, DIANA and AlphaScreen, for screening influenza PB2 cap-binding inhibitors and evaluate their effectiveness compared to the established differential scanning fluorimetry (DSF) technique. Using a diverse set of substrates and compounds based on the previously described PB2 binder pimodivir, we thoroughly assessed the capabilities of these new methods. Our findings demonstrate that both DIANA and AlphaScreen are highly effective for PB2 inhibitor screening, offering distinct advantages over traditional techniques such as isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). These advantages include improved scalability, reduced sample requirements, and the capacity for label-free detection. Notably, DIANA's ability to determine Ki values from a single-well measurement significantly enhances its practicality and efficiency in inhibitor screening.
This research represents a significant step forward in the development of more efficient and scalable screening strategies, helping advance efforts in the discovery of antiviral drugs against influenza.
流感病毒聚合酶复合体的PB2亚基对病毒复制至关重要,主要通过一种被称为cap-snatching的机制进行复制。在这个过程中,PB2结合到宿主前mrna的5´cap结构上,使病毒聚合酶能够劫持宿主的转录机制。这种结合促进了被盖住的RNA片段裂解并整合到病毒mRNA中,从而促进了病毒的高效复制。因此,抑制PB2-cap相互作用至关重要,因为它直接破坏了病毒复制周期。因此,用特异性抑制剂靶向PB2是开发抗流感抗病毒药物的一种很有前途的策略。然而,目前还没有高通量筛选潜在抑制剂的方法。开发新的潜在PB2结合物抑制剂筛选方法是本研究的重点。在这项研究中,我们提出了两种新方法,DIANA和AlphaScreen,用于筛选流感PB2帽结合抑制剂,并与已建立的差示扫描荧光法(DSF)技术比较它们的有效性。使用基于先前描述的PB2结合剂pimodivir的多种底物和化合物,我们彻底评估了这些新方法的能力。我们的研究结果表明,DIANA和AlphaScreen对PB2抑制剂的筛选都非常有效,与等温滴定量热法(ITC)和表面等离子体共振(SPR)等传统技术相比,具有明显的优势。这些优点包括改进的可伸缩性、减少的样本需求以及无标签检测的能力。值得注意的是,DIANA能够从单井测量中确定Ki值,大大提高了其在抑制剂筛选中的实用性和效率。这项研究在开发更有效和可扩展的筛查策略方面迈出了重要一步,有助于推进发现抗流感抗病毒药物的努力。
{"title":"The evaluation of DNA-linked inhibitor antibody and AlphaScreen assays for high-throughput screening of compounds targeting the cap-binding domain in influenza a polymerase","authors":"Kateřina Čermáková ,&nbsp;Jiří Gregor ,&nbsp;Michal Kráľ ,&nbsp;Elena Karlukova ,&nbsp;Václav Navrátil ,&nbsp;Róbert Reiberger ,&nbsp;Carlos Berenguer Albiñana ,&nbsp;Vít Bechynský ,&nbsp;Pavel Majer ,&nbsp;Jan Konvalinka ,&nbsp;Aleš Machara ,&nbsp;Milan Kožíšek","doi":"10.1016/j.ejps.2024.106990","DOIUrl":"10.1016/j.ejps.2024.106990","url":null,"abstract":"<div><div>The PB2 subunit of the influenza virus polymerase complex is essential for viral replication, primarily through a mechanism known as cap-snatching. In this process, PB2 binds to the 5’ cap structure of host pre-mRNAs, enabling the viral polymerase to hijack the host transcriptional machinery. This binding facilitates the cleavage and integration of the capped RNA fragment into viral mRNA, thereby promoting efficient viral replication. Inhibiting the PB2-cap interaction is therefore crucial, as it directly disrupts the viral replication cycle. Consequently, targeting PB2 with specific inhibitors is a promising strategy for antiviral drug development against influenza. However, there are currently no available methods for the high-throughput screening of potential inhibitors. The development of new inhibitor screening methods of potential PB2 binders is the focus of this study.</div><div>In this study, we present two novel methods, DIANA and AlphaScreen, for screening influenza PB2 cap-binding inhibitors and evaluate their effectiveness compared to the established differential scanning fluorimetry (DSF) technique. Using a diverse set of substrates and compounds based on the previously described PB2 binder pimodivir, we thoroughly assessed the capabilities of these new methods. Our findings demonstrate that both DIANA and AlphaScreen are highly effective for PB2 inhibitor screening, offering distinct advantages over traditional techniques such as isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR). These advantages include improved scalability, reduced sample requirements, and the capacity for label-free detection. Notably, DIANA's ability to determine K<sub>i</sub> values from a single-well measurement significantly enhances its practicality and efficiency in inhibitor screening.</div><div>This research represents a significant step forward in the development of more efficient and scalable screening strategies, helping advance efforts in the discovery of antiviral drugs against influenza.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106990"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A journey into siRNA therapeutics development: A focus on Pharmacokinetics and Pharmacodynamics siRNA疗法发展之旅:关注药代动力学和药效学。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106981
Go-Wun Choi, Ju Hee Kim, Dong Wook Kang, Hea-Young Cho
siRNA therapeutics are emerging novel modalities targeting highly specific mRNA via RNA interference mechanism. Its unique pharmacokinetics (PKs) and pharmacodynamics (PDs) are significant challenges for clinical use. Furthermore, naked siRNA is a highly soluble macromolecule with a negative charge, making plasma membrane penetration a significant hurdle. It is also vulnerable to nuclease degradation. Therefore, advanced formulation technologies, such as lipid nanoparticles and N-acetylgalactosamine conjugation, have been developed and are now used in clinical practice to enhance target organ delivery and stability. The innate complex biological mechanisms of siRNA, along with its formulation, are major determinants of the PK/PD characteristics of siRNA products. To systematically and quantitatively understand these characteristics, it is essential to develop and utilize quantitative PK/PD models for siRNA therapeutics. In this review, the effects of formulation on the PKs and PK/PD models of approved siRNA products were presented, highlighting the importance of selecting appropriate biomarkers and understanding formulation, PKs, and PDs for quantitative interpreting the relationship between plasma concentration, organ concentration, biomarkers, and efficacy.
siRNA疗法是通过RNA干扰机制靶向高度特异性mRNA的新兴疗法。其独特的药代动力学(PKs)和药效学(pd)是临床应用的重大挑战。此外,裸siRNA是一种带负电荷的高可溶性大分子,这使得穿透质膜成为一个重大障碍。它也容易受到核酸酶的降解。因此,脂质纳米颗粒和n -乙酰半乳糖胺偶联等先进的配方技术已被开发出来,并已用于临床实践,以增强靶器官的传递和稳定性。siRNA固有的复杂生物学机制及其配方是siRNA产物PK/PD特性的主要决定因素。为了系统和定量地了解这些特征,有必要开发和利用siRNA治疗的定量PK/PD模型。本文综述了制剂对已获批siRNA产品PK/PD模型的影响,强调了选择合适的生物标志物和理解制剂、PK和PD对定量解释血浆浓度、器官浓度、生物标志物和疗效之间关系的重要性。
{"title":"A journey into siRNA therapeutics development: A focus on Pharmacokinetics and Pharmacodynamics","authors":"Go-Wun Choi,&nbsp;Ju Hee Kim,&nbsp;Dong Wook Kang,&nbsp;Hea-Young Cho","doi":"10.1016/j.ejps.2024.106981","DOIUrl":"10.1016/j.ejps.2024.106981","url":null,"abstract":"<div><div>siRNA therapeutics are emerging novel modalities targeting highly specific mRNA via RNA interference mechanism. Its unique pharmacokinetics (PKs) and pharmacodynamics (PDs) are significant challenges for clinical use. Furthermore, naked siRNA is a highly soluble macromolecule with a negative charge, making plasma membrane penetration a significant hurdle. It is also vulnerable to nuclease degradation. Therefore, advanced formulation technologies, such as lipid nanoparticles and N-acetylgalactosamine conjugation, have been developed and are now used in clinical practice to enhance target organ delivery and stability. The innate complex biological mechanisms of siRNA, along with its formulation, are major determinants of the PK/PD characteristics of siRNA products. To systematically and quantitatively understand these characteristics, it is essential to develop and utilize quantitative PK/PD models for siRNA therapeutics. In this review, the effects of formulation on the PKs and PK/PD models of approved siRNA products were presented, highlighting the importance of selecting appropriate biomarkers and understanding formulation, PKs, and PDs for quantitative interpreting the relationship between plasma concentration, organ concentration, biomarkers, and efficacy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106981"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Challenges in the identification and quantification of an unknown impurity in chenodeoxycholic acid drug substance 鹅去氧胆酸原料药中未知杂质鉴定与定量的挑战。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106979
Natalja Bouwhuis , Yasmin Polak , Anneliene M. Schimmel , Yuma A. Bijleveld , Martin A. Giera , Marieke Heijink , Frédéric M. Vaz , Albert H. Bootsma , Laureen A. ten Berg-Lammers , Noortje E.L. Swart , Carla E.M. Hollak , Bart A.W. Jacobs , E. Marleen Kemper
In 2018 the Amsterdam University Medical Centre decided to prepare chenodeoxycholic acid (CDCA) capsules (also known as pharmacy compounding) for patients with the genetic metabolic disease cerebrotendinous xanthomatosis (CTX) when the product with a marketing authorization was commercially unavailable for patients. However, after reanalysis, unknown impurities were identified in the CDCA active pharmaceutical ingredient (API) using thin-layer chromatography from the European Pharmacopoeia (Ph.Eur.) monograph. Therefore, the API did not comply with the Ph.Eur. specifications for related substances and as a result, pharmacy compounding was halted and an investigation was initiated to identify and quantify the unknown impurities. Meanwhile, a second CDCA API was sourced from another manufacturer. However, this API also appeared to contain an unknown impurity. This impurity could be identified as a dimer of CDCA using reversed phase liquid chromatography mass spectrometry. Since the Ph.Eur. at the time did not describe a suitable analytical method for the quantification of this new impurity, a high pressure liquid chromatography with differential refractometer (HPLC-RI) method was developed to quantify the dimer. Subsequently, in 2019, a new draft version of the CDCA Ph.Eur. monograph was published, including the dimer as a new impurity together with a HPLC-RI method for its identification and quantification. The CDCA-dimer is classified as non-toxic and permitted in the CDCA API up to a maximum of 0.5 %. Because the API complied with the updated Ph.Eur. specifications, pharmacy compounding of CDCA capsules could be resumed.
2018年,阿姆斯特丹UMC决定为遗传代谢性疾病脑肌腱黄瘤病(CTX)患者制备鹅去氧胆酸(CDCA)胶囊(也称为复方药物),当时该产品已获得上市许可,无法在商业上用于患者。然而,在重新分析后,使用薄层色谱法从欧洲药典(Ph.Eur.)专著中鉴定出CDCA活性药物成分(API)中的未知杂质。因此API不符合Ph.Eur标准。有关物质的规格。因此,停止了药物配制,并开始调查以确定和量化未知杂质。与此同时,第二个CDCA API来自另一家制造商。然而,该原料药似乎也含有未知杂质。用反相液相色谱-质谱法鉴定该杂质为CDCA二聚体。自从获得博士学位以来。由于当时没有描述一种合适的分析方法来定量这种新杂质,因此开发了高压液相色谱差示折射仪(HPLC-RI)方法来定量二聚体。随后,在2019年,新版本的CDCA Ph.Eur。发表了专著,包括二聚体作为额外的杂质,并使用HPLC-RI方法进行鉴定和定量。CDCA二聚体被归类为无毒,在CDCA API中允许最多0.5%的含量。因为API符合更新后的Ph.Eur。可恢复CDCA胶囊的配药。
{"title":"Challenges in the identification and quantification of an unknown impurity in chenodeoxycholic acid drug substance","authors":"Natalja Bouwhuis ,&nbsp;Yasmin Polak ,&nbsp;Anneliene M. Schimmel ,&nbsp;Yuma A. Bijleveld ,&nbsp;Martin A. Giera ,&nbsp;Marieke Heijink ,&nbsp;Frédéric M. Vaz ,&nbsp;Albert H. Bootsma ,&nbsp;Laureen A. ten Berg-Lammers ,&nbsp;Noortje E.L. Swart ,&nbsp;Carla E.M. Hollak ,&nbsp;Bart A.W. Jacobs ,&nbsp;E. Marleen Kemper","doi":"10.1016/j.ejps.2024.106979","DOIUrl":"10.1016/j.ejps.2024.106979","url":null,"abstract":"<div><div>In 2018 the Amsterdam University Medical Centre decided to prepare chenodeoxycholic acid (CDCA) capsules (also known as pharmacy compounding) for patients with the genetic metabolic disease cerebrotendinous xanthomatosis (CTX) when the product with a marketing authorization was commercially unavailable for patients. However, after reanalysis, unknown impurities were identified in the CDCA active pharmaceutical ingredient (API) using thin-layer chromatography from the European Pharmacopoeia (Ph.Eur.) monograph. Therefore, the API did not comply with the Ph.Eur. specifications for related substances and as a result, pharmacy compounding was halted and an investigation was initiated to identify and quantify the unknown impurities. Meanwhile, a second CDCA API was sourced from another manufacturer. However, this API also appeared to contain an unknown impurity. This impurity could be identified as a dimer of CDCA using reversed phase liquid chromatography mass spectrometry. Since the Ph.Eur. at the time did not describe a suitable analytical method for the quantification of this new impurity, a high pressure liquid chromatography with differential refractometer (HPLC-RI) method was developed to quantify the dimer. Subsequently, in 2019, a new draft version of the CDCA Ph.Eur. monograph was published, including the dimer as a new impurity together with a HPLC-RI method for its identification and quantification. The CDCA-dimer is classified as non-toxic and permitted in the CDCA API up to a maximum of 0.5 %. Because the API complied with the updated Ph.Eur. specifications, pharmacy compounding of CDCA capsules could be resumed.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106979"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142791315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Nanoparticle-enabled In Situ drug potency activation for enhanced tumor-specific therapy 纳米颗粒激活原位药物效力增强肿瘤特异性治疗。
IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 DOI: 10.1016/j.ejps.2024.106989
Yitian Chen , Lishan Liu , Ming Li , Xiaolian Chen , Yaoqi Li , Jing Tao , Yibin Deng
Cancer treatment faces significant challenges including inadequate tumor specificity, drug resistance, and severe side effects, often resulting in unsatisfactory patient outcomes. Nanomedicines offer a transformative platform for tumor-targeted drug delivery and antitumor potency activation, providing an indispensable strategy for overcoming the severe damage to normal tissues caused by the inherent "always-on" cytotoxicity of conventional therapeutic agents. This review focuses on the emerging concept of "nanoparticle-enabled in situ drug potency activation", where inactive or minimally toxic agents are selectively activated within tumors to enhance the therapeutic efficacy and minimize the adverse effects. We systematically analyzed literature from PubMed and Web of Science databases spanning the last two decades, emphasizing experimental evidence supporting this in situ drug potency activation concept. Key strategies including stimuli-responsive prodrug nanoparticles, metal-induced activation, and bioorthogonal reactions are critically evaluated for their potential to overcome limitations in current cancer therapies. The findings highlight the potential of in situ potency activation as a promising alternative to conventional therapeutics, with far-reaching implications for advancing effective and safe cancer treatments.
癌症治疗面临着重大挑战,包括肿瘤特异性不足、耐药和严重的副作用,往往导致患者预后不理想。纳米药物为肿瘤靶向药物传递和抗肿瘤效力激活提供了一个变革性的平台,为克服传统治疗药物固有的“永远在线”细胞毒性对正常组织造成的严重损伤提供了不可或缺的策略。这篇综述的重点是“纳米颗粒原位药物效力激活”这一新兴概念,即在肿瘤内选择性激活无活性或毒性最小的药物,以提高治疗效果并将不良反应降到最低。我们系统地分析了PubMed和Web of Science数据库中过去20年的文献,强调了支持这种原位药物效力激活概念的实验证据。关键策略包括刺激反应前药纳米颗粒、金属诱导活化和生物正交反应,因为它们有潜力克服当前癌症治疗的局限性。这些发现突出了原位效力激活作为传统治疗方法的一种有希望的替代方法的潜力,对推进有效和安全的癌症治疗具有深远的意义。
{"title":"Nanoparticle-enabled In Situ drug potency activation for enhanced tumor-specific therapy","authors":"Yitian Chen ,&nbsp;Lishan Liu ,&nbsp;Ming Li ,&nbsp;Xiaolian Chen ,&nbsp;Yaoqi Li ,&nbsp;Jing Tao ,&nbsp;Yibin Deng","doi":"10.1016/j.ejps.2024.106989","DOIUrl":"10.1016/j.ejps.2024.106989","url":null,"abstract":"<div><div>Cancer treatment faces significant challenges including inadequate tumor specificity, drug resistance, and severe side effects, often resulting in unsatisfactory patient outcomes. Nanomedicines offer a transformative platform for tumor-targeted drug delivery and antitumor potency activation, providing an indispensable strategy for overcoming the severe damage to normal tissues caused by the inherent \"always-on\" cytotoxicity of conventional therapeutic agents. This review focuses on the emerging concept of \"nanoparticle-enabled <em>in situ</em> drug potency activation\", where inactive or minimally toxic agents are selectively activated within tumors to enhance the therapeutic efficacy and minimize the adverse effects. We systematically analyzed literature from PubMed and Web of Science databases spanning the last two decades, emphasizing experimental evidence supporting this <em>in situ</em> drug potency activation concept. Key strategies including stimuli-responsive prodrug nanoparticles, metal-induced activation, and bioorthogonal reactions are critically evaluated for their potential to overcome limitations in current cancer therapies. The findings highlight the potential of <em>in situ</em> potency activation as a promising alternative to conventional therapeutics, with far-reaching implications for advancing effective and safe cancer treatments.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"205 ","pages":"Article 106989"},"PeriodicalIF":4.3,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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European Journal of Pharmaceutical Sciences
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