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Bohemian Rhapsody of Future Drug Delivery Systems: Rational Changes Necessary for the Next Revolution. 未来给药系统的波希米亚狂想曲:下一次革命所需的理性变革。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-12 DOI: 10.1021/acs.molpharmaceut.4c00550
Kinam Park, Andrew Otte, Tonglei Li

Controlled drug delivery technology has matured for more than 70 years, starting from a twice-a-day oral formulation to 6 month long-acting injectable formulations. Further technological advances require superior formulations to treat various diseases more efficiently. Developing future formulations with practical innovations for treating existing and new diseases necessitates our continued efforts to overcome at least three main hurdles. They include (i) drug delivery with reduced side effects, (ii) long-term treatment of chronic diseases, and (iii) the overcoming of biological barriers. Such efforts start with the improved ability to accurately test drug delivery efficacy using proper controls. Future development can be aided by artificial intelligence if used properly. The next revolution of drug delivery systems will be augmented if implementation is given equal weight as discovery. Such a process can be accelerated with the systemic revamp of the research funding structure and cultivating a new generation of scientists who can think differently.

从一天两次的口服制剂到 6 个月的长效注射制剂,控释给药技术已经成熟了 70 多年。随着技术的进一步发展,需要有更好的制剂来更有效地治疗各种疾病。要开发出治疗现有疾病和新疾病的具有实用创新性的未来制剂,我们必须继续努力克服至少三个主要障碍。它们包括:(i) 减少副作用的药物输送;(ii) 慢性疾病的长期治疗;(iii) 克服生物障碍。这些努力的起点是提高能力,利用适当的控制手段准确测试给药效果。如果使用得当,人工智能将有助于未来的发展。如果将实施与发现放在同等重要的位置,那么给药系统的下一次革命将得到加强。通过对研究资金结构进行系统性改革,并培养能够换位思考的新一代科学家,可以加速这一进程。
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引用次数: 0
Translocation of Antimicrobial Peptides across Model Membranes: The Role of Peptide Chain Length. 抗菌肽在模型膜上的转运:肽链长度的作用
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-12 DOI: 10.1021/acs.molpharmaceut.4c00450
Amanda E Skog, Nicolò Paracini, Yuri Gerelli, Marie Skepö

Cushioned lipid bilayers are structures consisting of a lipid bilayer supported on a solid substrate with an intervening layer of soft material. They offer possibilities for studying the behavior and interactions of biological membranes more accurately under physiological conditions. In this work, we continue our studies of cushion formation induced by histatin 5 (24Hst5), focusing on the effect of the length of the peptide chain. 24Hst5 is a short, positively charged, intrinsically disordered saliva peptide, and here, both a shorter (14Hst5) and a longer (48Hst5) peptide variant were evaluated. Experimental surface active techniques were combined with coarse-grained Monte Carlo simulations to obtain information about these peptides. Results show that at 10 mM NaCl, both the shorter and the longer peptide variants behave like 24Hst5 and a cushion below the bilayer is formed. At 150 mM NaCl, however, no interaction is observed for 24Hst5. On the contrary, a cushion is formed both in the case of 14Hst5 and 48Hst5, and in the latter, an additional thick, diffuse, and highly hydrated layer of peptide and lipid molecules is formed, on top of the bilayer. Similar trends were observed from the simulations, which allowed us to hypothesize that positively charged patches of the amino acids lysine and arginine in all three peptides are essential for them to interact with and translocate over the bilayer. We therefore hypothesize that electrostatic interactions are important for the interaction between the solid-supported lipid bilayers and the peptide depending on the linear charge density through the primary sequence and the positively charged patches in the sequence. The understanding of how, why, and when the cushion is formed opens up the possibility for this system to be used in the research and development of new drugs and pharmaceuticals.

缓冲脂质双分子层是由支撑在固体基底上的脂质双分子层和中间的软质材料层组成的结构。它们为更精确地研究生理条件下生物膜的行为和相互作用提供了可能。在这项工作中,我们将继续研究组蛋白 5(24Hst5)诱导的垫层形成,重点关注肽链长度的影响。24Hst5 是一种短的、带正电荷的、内在无序的唾液肽,在此,我们对较短的(14Hst5)和较长的(48Hst5)肽变体进行了评估。实验性表面活性技术与粗粒度蒙特卡洛模拟相结合,获得了这些肽的相关信息。结果表明,在 10 mM NaCl 的条件下,较短和较长的肽变体都表现得像 24Hst5,并在双分子层下方形成一个缓冲。然而,在 150 mM NaCl 的条件下,24Hst5 没有发生相互作用。相反,14Hst5 和 48Hst5 都形成了一个缓冲层,而且后者在双分子层的顶部形成了一个额外的、扩散的、高度水合的肽和脂质分子层。模拟观察到了类似的趋势,因此我们推测,这三种肽中的氨基酸赖氨酸和精氨酸的正电补丁是它们与双分子层相互作用并在双分子层上转移的必要条件。因此我们假设,静电相互作用对于固体支撑的脂质双分子层和多肽之间的相互作用非常重要,这取决于通过主序列的线性电荷密度和序列中的正电荷斑块。了解了缓冲垫形成的方式、原因和时间,就有可能将这一系统用于新药和药物的研究与开发。
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引用次数: 0
PET Imaging of Differentiated Thyroid Cancer with TSHR-Targeted [89Zr]Zr-TR1402. 用 TSHR 靶向 [89Zr]Zr-TR1402 对分化型甲状腺癌进行 PET 成像。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-08 DOI: 10.1021/acs.molpharmaceut.4c00224
Grayson R Gimblet, Hailey A Houson, Jason Whitt, Pratheek Reddy, John Al Copland, Saad S Kenderian, Mariusz W Szkudlinski, Renata Jaskula-Sztul, Suzanne E Lapi

Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [89Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [89Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89Zr (t1/2 = 78.4 h, β+ = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [89Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [89Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (P < 0.0001) and FTC133 (P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (P < 0.0001) and TSHR+ FTC133 (P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [89Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference (P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [89Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.

甲状腺癌是最常见的内分泌癌症,其中分化型甲状腺癌(DTC)占诊断总数的 95%。虽然大多数分化型甲状腺癌患者在确诊后都会接受放射性碘(RAI)治疗,但高达 20% 的分化型甲状腺癌患者会对 RAI 产生难治性(RAI-R)。与接受 RAI 治疗的患者相比,RAI-R 患者的生存率明显降低。本研究探讨了[89Zr]Zr-TR1402作为甲状腺刺激素受体(TSHR)靶向PET放射性药物用于DTC。通过将重组人 TSH(rhTSH)类似物 TR1402 与螯合剂 p-SCN-Bn-去铁胺(DFO)以 3:1 的摩尔比(DFO/TR1402)共轭,并用 89Zr 进行放射性标记,合成了摩尔活性为 25.9 MBq/nmol 的 [89Zr]Zr-TR1402(t1/2 = 78.4 h,β+ = 22.7%)。由于常见的 DTC 衍生细胞系中不存在 TSHR,因此通过稳定的转导方法重新引入了 TSHR,转导的慢病毒含有人类 TSHR 基因的全长编码区。体外评估了稳定转导的 TSHR+ 和野生型 TSHR- DTC 细胞系对 [89Zr]Zr-TR1402 受体介导的摄取。注射后第 1-3 天,在雌雄无胸腺裸鼠体内对 TSHR+ 和 TSHR- 异种移植进行了体内 PET 成像,并在注射后第 3 天进行了体外生物分布。体外摄取 1 nM [89Zr]Zr-TR1402 的 TSHR+ THJ529T(P < 0.0001)和 FTC133(P < 0.01)细胞明显高于 TSHR- THJ529T 和 FTC133 细胞。通过使用 250 nm DFO-TR1402 阻断这种摄取,证明在 TSHR+ THJ529T(P < 0.0001)和 TSHR+ FTC133(P < 0.0001)细胞中这种摄取是特异性的。体内 PET 成像显示,[89Zr]Zr-TR1402 在 TSHR+ 肿瘤中蓄积,第 1 天蓄积量最高。在雄性 FTC133 异种移植模型中,体内外生物分布证实 FTC133+ 肿瘤(1.3 ± 0.1%ID/g)和 FTC133- 肿瘤(0.8 ± 0.1%ID/g)的摄取量存在显著差异(P < 0.001)。在雄性 THJ529T 异种移植模型中,THJ529T+(1.8 ± 0.6%ID/g)和 THJ529T-(0.8 ± 0.4%ID/g)肿瘤之间的摄取量也存在明显差异(P < 0.05)。[89Zr]Zr-TR1402在表达TSHR的DTC细胞系中的体外和体内蓄积支持继续对这种方法进行临床前优化。
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引用次数: 0
Effect of Ibuprofen as an Albumin Binder on Melanoma-Targeting Properties of 177Lu-Labeled Ibuprofen-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides. 布洛芬作为白蛋白粘合剂对 177Lu 标记的布洛芬共轭α-黑色素细胞刺激素肽的黑色素瘤靶向特性的影响
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-07 DOI: 10.1021/acs.molpharmaceut.4c00369
Zheng Qiao, Jingli Xu, Fabio Gallazzi, Darrell R Fisher, Rene Gonzalez, Jennifer Kwak, Yubin Miao

The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of 177Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSHhex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2}, DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex, DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex, and DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first. Then the biodistribution of 177Lu-labeled peptides was determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to choose the lead peptide for further examination. The full biodistribution and melanoma imaging properties of 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex were further evaluated using B16/F10 melanoma-bearing C57 mice. DOTA-Lys(IBU)-GG-Nle-CycMSHhex, DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex, DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex, and DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex displayed the IC50 values of 1.41 ± 0.37, 1.52 ± 0.08, 0.03 ± 0.01, and 0.58 ± 0.06 nM on B16/F10 melanoma cells, respectively. 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex exhibited the lowest liver and kidney uptake among all four designed 177Lu peptides. Therefore, 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex was further evaluated for its full biodistribution and melanoma imaging properties. The B16/F10 melanoma uptake of 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex was 19.5 ± 3.12, 24.12 ± 3.35, 23.85 ± 2.08, and 10.80 ± 2.89% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Moreover, 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex could clearly visualize the B16/F10 melanoma lesions at 2 h postinjection. The conjugation of IBU with or without a linker to GGNle-CycMSHhex affected the MC1R binding affinities of the designed peptides. The charge of the linker played a key role in the liver and kidney uptake of 177Lu-Asp-IBU, 177Lu-Asn-IBU, and 177Lu-Dab-IBU. 177Lu-Asp-IBU exhibited higher tumor/liver and tumor/kidney uptake ratios than those of 177Lu-Asn-IBU and 177Lu-Dab-IBU, underscoring its potential evaluation for melanoma therapy in the future.

本研究旨在探讨布洛芬(IBU)的引入如何影响177Lu标记的IBU共轭α-黑色素细胞刺激素肽的肿瘤靶向性和生物分布特性。IBU 被用作白蛋白粘合剂,并与 DOTA-Lys 分子共轭(不含或含链接剂),生成 DOTA-Lys(IBU)-GG-Nle-CycMSHhex{1,4,7,10-四氮杂环十二烷-1,4,7、10-四乙酸-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2}、DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex、DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex 和 DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex肽。首先测定了它们与 B16/F10 黑色素瘤细胞中的黑色素皮质素受体 1(MC1R)的结合亲和力。然后测定了177Lu标记肽在B16/F10黑色素瘤C57小鼠注射后2小时的生物分布,以选择进一步研究的先导肽。使用 B16/F10 黑色素瘤 C57 小鼠进一步评估了 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex 的全面生物分布和黑色素瘤成像特性。DOTA-Lys(IBU)-GGNle-CycMSHhex、DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex、DOTA-Lys(Asn-IBU)-GGNle-CycMSHhex 和 DOTA-Lys(Dab-IBU)-GGNle-CycMSHhex的 IC50 值分别为 1.41 ± 0.37、1.52 ± 0.08、0.03 ± 0.01 和 0.58 ± 0.06 nM。在所有四种设计的 177Lu 肽中,177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex 在肝脏和肾脏的吸收率最低。因此,我们进一步评估了 177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex 的全面生物分布和黑色素瘤成像特性。注射后0.5、2、4和24小时,B16/F10黑色素瘤对177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex的摄取率分别为19.5±3.12、24.12±3.35、23.85±2.08和10.80±2.89% ID/g。此外,177Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSHhex在注射后2小时可清晰显示B16/F10黑色素瘤病灶。IBU 与 GGNle-CycMSHhex 连接与否会影响所设计多肽的 MC1R 结合亲和力。连接体的电荷对 177Lu-Asp-IBU、177Lu-Asn-IBU 和 177Lu-Dab-IBU 的肝脏和肾脏吸收起着关键作用。与177Lu-Asn-IBU和177Lu-Dab-IBU相比,177Lu-Asp-IBU表现出更高的肿瘤/肝脏摄取率和肿瘤/肾脏摄取率,这突显了177Lu-Asp-IBU未来用于黑色素瘤治疗的潜力。
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引用次数: 0
Photodynamic Therapy Synergizes CD47 Blockade Strategy for Enhanced Antitumor Therapy. 光动力疗法协同 CD47 阻断策略,增强抗肿瘤治疗。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00254
Zhaoming Fu, Minghui Feng, Jinxian Wu, Bo Liu, Jiajia Fu, Wen Song

The antitumor strategies based on innate immunity activation have become favored by researchers in recent years. In particular, strategies targeting antiphagocytic signaling blockade to enhance phagocytosis have been widely reported. For example, the addition of prophagocytic signals such as calreticulin could make the strategy significantly more effective. In this study, an antitumor strategy that combines photodynamic therapy (PDT) with CD47 blockade has been reported. This approach promotes the maturation of dendritic cells and the presentation of tumor antigens by PDT-mediated tumor immunogenic cell death, as well as the enhancement of cytotoxic T lymphocyte infiltration in tumor areas and the phagocytic activity of phagocytes. Furthermore, the downregulation and blockage of CD47 protein could further promote phagocytic activity, strengthen the innate immune system, and ultimately elevate the antitumor efficacy and inhibit tumor metastasis.

近年来,基于先天免疫激活的抗肿瘤策略受到研究人员的青睐。其中,以阻断抗吞噬细胞信号转导为目标来增强吞噬能力的策略已被广泛报道。例如,添加促吞噬信号(如钙网素)可使该策略的效果显著提高。本研究报告了一种将光动力疗法(PDT)与 CD47 阻断相结合的抗肿瘤策略。这种方法通过 PDT 介导的肿瘤免疫原性细胞死亡,促进树突状细胞的成熟和肿瘤抗原的呈现,并增强肿瘤区域的细胞毒性 T 淋巴细胞浸润和吞噬细胞的吞噬活性。此外,CD47 蛋白的下调和阻断可进一步促进吞噬细胞的活性,增强先天性免疫系统,最终提高抗肿瘤疗效并抑制肿瘤转移。
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引用次数: 0
More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility. 不仅仅是直觉--将生理学驱动的溶解与药物动力学模型相结合,作为了解人体胃动力的工具。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00117
Michał Romański, Marcela Staniszewska, Justyna Dobosz, Daria Myslitska, Jadwiga Paszkowska, Bartosz Kołodziej, Svitlana Romanova, Grzegorz Banach, Grzegorz Garbacz, Inese Sarcevica, Yeamin Huh, Vivek Purohit, Mark McAllister, Suet M Wong, Dorota Danielak

In vivo studies of formulation performance with in vitro and/or in silico simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative PhysioCell apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (n = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other in vitro-in vivo predictions involving immediate-release oral dosage forms.

由于我们对给药制剂与人体胃肠道之间相互作用的了解存在巨大差距,因此通过体外和/或硅学模拟对制剂性能进行的体内研究往往受到限制。本研究提出了一种研究胃动力对制剂性能影响的新方法,将创新型 PhysioCell 仪器中的生物预测溶出试验与基于生理学的机理药代动力学建模相结合。该方法基于一大批(n = 118)健康志愿者的药代动力学数据,他们在空腹条件下摄入了含有高溶解度和快速吸收药物的胶囊。所开发的溶解试验包括生物相关介质、不同的流体流量以及生理时间和强度的机械应力事件。溶解结果被用作药代动力学模型的输入,从而推断出五种胃动力模式及其在研究人群中的流行程度。由于这些模式对观察到的药代动力学特征有很大影响,因此所提出的方法可能对其他涉及速释口服剂型的体外-体内预测有用。
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引用次数: 0
Hydroxypropyl Cellulose-Based Orally Dissolving Film Loaded with Insoluble Dexamethasone for Treatment of Oral Ulcers. 含不溶性地塞米松的羟丙基纤维素口腔溶解膜用于治疗口腔溃疡
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00391
Xinyu Cao, Bingyu Wu, Jiayi Chen, Zhikuan Liu, Yang Yang, Shanshan Li, Hongyan Zhu, Lixing Xu, Haiqing Huang

Oral ulcers present as recurrent and spontaneous lesions, often causing intolerable burning pain that significantly disrupts patients' daily lives and compromises their quality of life. In addressing this clinical challenge, oral dissolving films (ODFs) have emerged as promising pharmaceutical formulations for oral ulcer management due to their rapid onset of action, ease of administration, and portability. In this study, ODFs containing the insoluble drug dexamethasone (Dex) were formulated for the treatment of oral ulcers in rabbits using a solvent casting method with ethanol as the solvent. To optimize the composition of the ODFs, a Box-Behnken Design (BBD) experiment was employed to investigate the effects of varying concentrations of hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (L-HPC), and plasticizer (glycerol) on key parameters, such as disintegration time, tensile strength, and peel-off efficiency of the films. Subsequently, the film properties of the Dex-loaded ODFs (ODF@Dex) were thoroughly assessed, revealing favorable attributes, including homogeneity, mechanical strength, and solubility. Notably, the use of ethanol as the solvent in the ODF preparation facilitated the homogeneous distribution of insoluble drugs within the film matrix, thereby enhancing their solubility and dissolution rate. Leveraging the potent pharmacological activity of Dex, ODF@Dex was further evaluated for its efficacy in promoting ulcer healing and mitigating the expression of inflammatory factors both in vitro and in vivo. The findings demonstrated that the ODF@Dex exerted significant antiulcer effects by modulating the PI3K/Akt signaling pathway, thus contributing to ulcer resolution. In conclusion, our study underscores the potential of HPC-based ODFs formulated with ethanol as a solvent as a promising platform for delivering insoluble drugs, offering a viable strategy for the clinical management of oral ulcers.

口腔溃疡是一种复发性和自发性病变,通常会引起难以忍受的灼痛,严重干扰患者的日常生活,影响其生活质量。为应对这一临床挑战,口腔溶解膜(ODF)因其起效迅速、给药方便、携带方便等特点,已成为治疗口腔溃疡的一种前景广阔的药物制剂。本研究以乙醇为溶剂,采用溶剂浇铸法配制了含有不溶性药物地塞米松(Dex)的口腔溶解膜,用于治疗兔子的口腔溃疡。为了优化 ODF 的组成,采用了箱式贝肯设计(BBD)实验来研究不同浓度的羟丙基纤维素(HPC)、低取代羟丙基纤维素(L-HPC)和增塑剂(甘油)对薄膜崩解时间、拉伸强度和剥离效率等关键参数的影响。随后,我们全面评估了含 Dex 的 ODF(ODF@Dex)薄膜的特性,发现其具有良好的属性,包括均匀性、机械强度和可溶性。值得注意的是,在制备 ODF 时使用乙醇作为溶剂有利于不溶性药物在薄膜基质中均匀分布,从而提高药物的溶解度和溶解速率。利用 Dex 的强大药理活性,我们进一步评估了 ODF@Dex 在体外和体内促进溃疡愈合和减轻炎症因子表达的功效。研究结果表明,ODF@Dex 通过调节 PI3K/Akt 信号通路发挥了显著的抗溃疡作用,从而促进了溃疡的愈合。总之,我们的研究强调了以乙醇为溶剂配制的基于 HPC 的 ODFs 作为递送不溶性药物的平台的潜力,为口腔溃疡的临床治疗提供了一种可行的策略。
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引用次数: 0
Small-Angle X-ray Scattering as a Powerful Tool for Phase and Crystallinity Assessment of Monoclonal Antibody Crystallites in Support of Batch Crystallization. 小角 X 射线散射是评估单克隆抗体结晶的相位和结晶度以支持批量结晶的有力工具。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00418
Patrick Larpent, Lorenzo Codan, Jameson R Bothe, Luca Iuzzolino, Suzette Pabit, Sudipta Gupta, Thierry Fischmann, Yongchao Su, Paul Reichert, Dirk Stueber, Aaron Cote

Crystalline suspensions of monoclonal antibodies (mAbs) have great potential to improve drug substance isolation and purification on a large scale and to be used for drug delivery via high-concentration formulations. Crystalline mAb suspensions are expected to have enhanced chemical and physical properties relative to mAb solutions delivered intravenously, making them attractive candidates for subcutaneous delivery. In contrast to small molecules, the development of protein crystalline suspensions is not a widely used approach in the pharmaceutical industry. This is mainly due to the challenges in finding crystalline hits and the suboptimal physical properties of the resulting crystallites when hits are found. Modern advances in instrumentation and increased knowledge of mAb crystallization have, however, resulted in higher probabilities of discovering crystal forms and improving their particle properties and characterization. In this regard, physical, analytical characterization plays a central role in the initial steps of understanding and later optimizing the crystallization of mAbs and requires careful selection of the appropriate tools. This contribution describes a novel crystal structure of the antibody pembrolizumab and demonstrates the usefulness of small-angle X-ray scattering (SAXS) for characterizing its crystalline suspensions. It illustrates the advantages of SAXS when used to (i) confirm crystallinity and crystal phase of crystallites produced in batch mode; (ii) confirm crystallinity under various conditions and detect variations in crystal phases, enabling fine-tuning of the crystallizations for phase control across multiple batches; (iii) monitor the physical response and stability of the crystallites in suspension with regard to filtration and washing; and (iv) monitor the physical stability of the crystallites upon drying. Overall, this work highlights how SAXS is an essential tool for mAb crystallization characterization.

单克隆抗体(mAb)结晶悬浮液在大规模改进药物物质分离和纯化以及通过高浓度制剂给药方面具有巨大潜力。与静脉注射的 mAb 溶液相比,mAb 结晶悬浮液的化学和物理性质有望得到改善,使其成为皮下给药的理想选择。与小分子相比,蛋白质结晶悬浮液的开发在制药业中并不广泛。这主要是由于寻找结晶的难题,以及即使找到了结晶,所得结晶的物理性质也不理想。然而,现代仪器的进步和对 mAb 结晶知识的增加提高了发现晶体的概率,并改善了其颗粒特性和表征。在这方面,物理分析表征在理解和优化 mAb 结晶的初始步骤中起着核心作用,需要谨慎选择合适的工具。这篇论文描述了抗体 pembrolizumab 的新型晶体结构,并展示了小角 X 射线散射 (SAXS) 在表征其晶体悬浮液方面的实用性。它说明了 SAXS 在以下方面的优势:(i) 确认以批量模式生产的晶体的结晶度和晶相;(ii) 确认各种条件下的结晶度并检测晶相的变化,从而对结晶进行微调,以实现多批次的晶相控制;(iii) 监控悬浮液中晶体对过滤和洗涤的物理反应和稳定性;(iv) 监控干燥后晶体的物理稳定性。总之,这项工作凸显了 SAXS 如何成为 mAb 结晶表征的重要工具。
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引用次数: 0
Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R. 开发和验证基于 Z-360 的新型大分子,用于主动靶向 CCK2-R。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-03 DOI: 10.1021/acs.molpharmaceut.4c00124
Elisa Vettorato, Marco Verona, Greta Bellio, Stefania Croci, Riccardo Filadi, Alessandra Bisio, Eugenia Spessot, Alberto Andrighetto, Devid Maniglio, Mattia Asti, Giovanni Marzaro, Francesca Mastrotto

The cholecystokinin type 2 receptor (CCK2-R) represents an ideal target for cancer therapy since it is overexpressed in several tumors and is associated with poor prognosis. Nastorazepide (Z-360), a selective CCK2-R antagonist, has been widely investigated as a CCK2-R ligand for targeted therapy; however, its high hydrophobicity may represent a limit to cell selectivity and optimal in vivo biodistribution. Here, we present three new fluorescent Z-360 derivatives (IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho) in which nastorazepide was linked, through spacers bearing different saccharides (glucose (G), lactose (L), and maltotriose (M)), to sulforhodamine B. A fourth compound (IP-002H-Rho) with no pendant sugar was also synthesized as a control. Through two-dimensional (2D) and three-dimensional (3D) in vitro studies, we evaluated the compound association with and selectivity for CCK2-R-overexpressing cells (A431-CCK2-R+) vs CCK2-R-underexpressing cells (A431 WT). 2D in vitro studies highlighted a progressive increase of IP-002x-Rho association with A431-CCK2-R+ cells according to the linker hydrophilicity, that is, maltotriose > lactose > glucose > hydrogen, with IP-002M-Rho showing a 2.4- and a 1.36-fold higher uptake than IP-002G-Rho and IP-002L-Rho, respectively. Unexpectedly, IP-002H-Rho showed a similar cell association to that of IP-002L-Rho but with no difference between the two tested cell lines. On the contrary, association with A431-CCK2-R+ cells as compared to the A431 WT was found to be 1.08-, 1.14-, and 1.37-fold higher for IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho, respectively, proving IP-002M-Rho to be the best-performing compound, as also confirmed by competition studies. Trafficking studies on A431-CCK2-R+ cells incubated with IP-002M-Rho suggested the coexistence of receptor-mediated endocytosis and simple diffusion. On the contrary, a high and selective uptake of IP-002M-Rho by A431-CCK2-R+ cells only was observed on 3D scaffolds embedded with cells, underlining the importance of 3D models in in vitro preliminary evaluation.

胆囊收缩素 2 型受体(CCK2-R)是癌症治疗的理想靶点,因为它在多种肿瘤中过度表达,而且与预后不良有关。作为一种用于靶向治疗的 CCK2-R 配体,选择性 CCK2-R 拮抗剂 Nastorazepide (Z-360) 已被广泛研究;然而,它的高疏水性可能会限制其细胞选择性和最佳体内生物分布。在这里,我们展示了三种新的荧光 Z-360 衍生物(IP-002G-Rho、IP-002L-Rho 和 IP-002M-Rho),其中纳斯托拉西肽通过含有不同糖类(葡萄糖 (G)、乳糖 (L) 和麦芽三糖 (M))的间隔物与磺胺多巴胺 B 连接。通过二维(2D)和三维(3D)体外研究,我们评估了化合物与CCK2-R高表达细胞(A431-CCK2-R+)和CCK2-R低表达细胞(A431 WT)的关联性和选择性。二维体外研究显示,IP-002x-Rho与A431-CCK2-R+细胞的结合力随连接体亲水性的不同而逐渐增强,即麦芽三糖>乳糖>葡萄糖>氢,IP-002M-Rho的吸收率分别比IP-002G-Rho和IP-002L-Rho高2.4倍和1.36倍。出乎意料的是,IP-002H-Rho 与 IP-002L-Rho 的细胞关联性相似,但两种测试细胞系之间没有差异。相反,与 A431-CCK2-R+ 细胞相比,IP-002G-Rho、IP-002L-Rho 和 IP-002M-Rho 与 A431 WT 细胞的关联度分别高出 1.08 倍、1.14 倍和 1.37 倍,证明 IP-002M-Rho 是表现最好的化合物,竞争研究也证实了这一点。对与 IP-002M-Rho 一起培养的 A431-CCK2-R+ 细胞进行的迁移研究表明,受体介导的内吞和简单的扩散是并存的。相反,仅在嵌入细胞的三维支架上观察到 A431-CCK2-R+ 细胞对 IP-002M-Rho 的高选择性吸收,这凸显了三维模型在体外初步评估中的重要性。
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引用次数: 0
Advancing mRNA Therapeutics: The Role and Future of Nanoparticle Delivery Systems. 推进 mRNA 治疗:纳米颗粒传输系统的作用和未来。
IF 4.5 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-07-02 DOI: 10.1021/acs.molpharmaceut.4c00276
Jiaxuan Li, Yuning Zhang, Yong-Guang Yang, Tianmeng Sun

The coronavirus (COVID-19) pandemic has underscored the critical role of mRNA-based vaccines as powerful, adaptable, readily manufacturable, and safe methodologies for prophylaxis. mRNA-based treatments are emerging as a hopeful avenue for a plethora of conditions, encompassing infectious diseases, cancer, autoimmune diseases, genetic diseases, and rare disorders. Nonetheless, the in vivo delivery of mRNA faces challenges due to its instability, suboptimal delivery, and potential for triggering undesired immune reactions. In this context, the development of effective drug delivery systems, particularly nanoparticles (NPs), is paramount. Tailored with biophysical and chemical properties and susceptible to surface customization, these NPs have demonstrated enhanced mRNA delivery in vivo and led to the approval of several NPs-based formulations for clinical use. Despite these advancements, the necessity for developing a refined, targeted NP delivery system remains imperative. This review comprehensively surveys the biological, translational, and clinical progress in NPs-mediated mRNA therapeutics for both the prevention and treatment of diverse diseases. By addressing critical factors for enhancing existing methodologies, it aims to inform the future development of precise and efficacious mRNA-based therapeutic interventions.

冠状病毒(COVID-19)大流行凸显了基于 mRNA 的疫苗作为强大、适应性强、可随时制造且安全的预防方法的关键作用。基于 mRNA 的治疗方法正在成为治疗包括传染病、癌症、自身免疫性疾病、遗传性疾病和罕见疾病在内的多种疾病的希望疗法。然而,由于 mRNA 不稳定、传递效果不理想以及可能引发不良免疫反应等原因,mRNA 的体内传递面临着挑战。在这种情况下,开发有效的给药系统,尤其是纳米颗粒(NPs)就显得尤为重要。这些 NPs 具有生物物理和化学特性,可进行表面定制,已证明可增强 mRNA 在体内的递送,并使一些基于 NPs 的制剂获准用于临床。尽管取得了这些进展,但开发精细、有针对性的 NP 递送系统仍是当务之急。本综述全面探讨了 NPs 介导的 mRNA 治疗在预防和治疗各种疾病方面所取得的生物学、转化和临床进展。通过探讨加强现有方法的关键因素,旨在为未来开发精确有效的基于 mRNA 的治疗干预措施提供参考。
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引用次数: 0
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