Frontiers in drug delivery最新文献_第4页

Design of respirable sprayed microparticles of encapsulated bacteriophages 胶囊化噬菌体可吸入喷雾微粒的设计

Frontiers in drug delivery

Pub Date : 2023-06-14 DOI: 10.3389/fddev.2023.1209534

A. Baldelli, Mingtao Liang

Antibiotic resistance is exponentially increasing, and the number of deaths caused by bacterial infections is expected to surge. When dealing with the respiratory system, inefficient antibiotics heighten the chance of death from bacterial infection. However, the alternatives to antibiotics are limited. Bacteriophages are a valid option since they can target a specific type of bacterium. Bacteriophages are highly specific and can avoid any side effects when delivered. However, their poor stability makes their use inefficient. Encapsulation is commonly used to protect any bioactive compound for different types of delivery. In the case of respiratory delivery, particle engineering is used to generate stable dry powders to target the nasal or lung areas. This review article provides a guideline for engineering a process of nasal dry powders of encapsulated bacteriophages.

抗生素耐药性呈指数级增长，细菌感染导致的死亡人数预计将激增。在治疗呼吸系统时，低效的抗生素会增加因细菌感染而死亡的几率。然而，抗生素的替代品是有限的。噬菌体是一种有效的选择，因为它们可以针对特定类型的细菌。噬菌体具有高度特异性，在输送时可以避免任何副作用。然而，它们稳定性差，使用效率低。封装通常用于保护任何生物活性化合物用于不同类型的递送。在呼吸输送的情况下，粒子工程用于产生稳定的干粉，以靶向鼻腔或肺部区域。这篇综述文章为设计包埋噬菌体的鼻腔干粉工艺提供了指导。

引用次数: 1

On a model-based approach to improve intranasal spray targeting for respiratory viral infections 改进呼吸道病毒感染鼻内喷雾靶向性的基于模型的方法

Frontiers in drug delivery

Pub Date : 2023-05-30 DOI: 10.3389/fddev.2023.1164671

Mohammad Mehedi Hasan Akash, Y. Lao, P. A. Balivada, P. Ato, Nogaye K. Ka, A. Mituniewicz, Z. Silfen, J. Suman, A. Chakravarty, D. Joseph-McCarthy, Saikat Basu

The nasopharynx, at the back of the nose, constitutes the dominant initial viral infection trigger zone along the upper respiratory tract. However, as per the standard recommended usage protocol (“Current Use”, or CU) for intranasal sprays, the nozzle should enter the nose almost vertically, resulting in sub-optimal nasopharyngeal drug deposition. Through the Large Eddy Simulation technique, this study has replicated airflow under standard breathing conditions with 15 and 30 L/min inhalation rates, passing through medical scan-based anatomically accurate human airway cavities. The small-scale airflow fluctuations were resolved through use of a sub-grid scale Kinetic Energy Transport Model. Intranasally sprayed droplet trajectories for different spray axis placement and orientation conditions were subsequently tracked via Lagrangian-based inert discrete phase simulations against the ambient inhaled airflow field. Finally, this study verified the computational projections for the upper airway drug deposition trends against representative physical experiments on sprayed delivery performed in a 3D-printed anatomic replica. The model-based exercise has revealed a new “Improved Use” (or, IU) spray usage protocol for viral infections. It entails pointing the spray bottle at a shallower angle (with an almost horizontal placement at the nostril), aiming slightly toward the cheeks. From the conically injected spray droplet simulations, we have summarily derived the following inferences: (a) droplets sized between 7–17 μm are relatively more efficient at directly reaching the nasopharynx via inhaled transport; and (b) with realistic droplet size distributions, as found in current over-the-counter spray products, the targeted drug delivery through the IU protocol outperforms CU by a remarkable 2 orders-of-magnitude.

鼻咽位于鼻子后部，是沿上呼吸道的主要初始病毒感染触发区。然而，根据鼻内喷雾剂的标准推荐使用方案(“当前使用”或CU)，喷嘴应该几乎垂直进入鼻子，导致鼻咽药物沉积不理想。通过大涡模拟技术，本研究以15和30 L/min的吸入速率复制了标准呼吸条件下的气流，通过基于医学扫描的解剖学精确的人体气道腔。利用亚网格尺度的动能输运模型求解了小尺度气流波动。随后，通过基于拉格朗日的惰性离散相模拟，对吸入气流场进行了不同喷雾轴位置和方向条件下的鼻内喷射液滴轨迹跟踪。最后，本研究通过在3d打印解剖复制品中进行喷射给药的代表性物理实验，验证了上呼吸道药物沉积趋势的计算预测。基于模型的练习揭示了一种新的“改进使用”(或IU)喷雾剂用于病毒感染的使用方案。它需要把喷雾瓶对准一个较浅的角度(几乎是水平的位置在鼻孔上)，稍微对准脸颊。通过对锥形喷射液滴的模拟，我们得出了以下结论:(a)粒径在7 ~ 17 μm之间的液滴通过吸入运输直接到达鼻咽的效率相对较高;(b)与目前非处方喷雾产品中发现的实际液滴大小分布一样，通过IU方案的靶向药物递送比CU高出2个数量级。

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引用次数: 1

Identification of transport systems involved in eflornithine delivery across the blood-brain barrier. 依氟鸟氨酸跨血脑屏障输送系统的鉴定

Frontiers in drug delivery

Pub Date : 2023-05-23 DOI: 10.3389/fddev.2023.1113493

Christopher P Watson, Gayathri Nair Sekhar, Sarah A Thomas

Human African Trypanosomiasis (HAT) is a neglected parasitic disease that continues to persist in sub-Saharan Africa. It is fatal if untreated. The first stage of the disease is associated with the presence of the parasite in the periphery and the second stage with the presence of the parasites in the CNS. The treatment of CNS stage HAT requires the drugs to cross the blood-brain barrier (BBB). Eflornithine is an amino acid analogue that is used to treat second stage HAT gambiense both alone and in combination with nifurtimox. Recent studies have identified that accumulation of eflornithine into the parasites (trypanosomes) involves the amino acid transporter (Trypanosoma brucei AAT6). In this study we tested the hypothesis that eflornithine uses a cationic amino acid transport system to cross the BBB. We particularly focused on system-y⁺ and system-B^0,+. To do this we utilized specialist databases to compare the physicochemical characteristics of relevant molecules and an in vitro model of the BBB to explore the mechanisms of eflornithine delivery into the CNS. Our results confirmed that eflornithine is related to the endogenous amino acid, ornithine. At pH 7.4, eflornithine is predominately (92.39%) a zwitterionic (dipolar) amino acid and ornithine is predominately (99.08%) a cationic (tripolar) amino acid. In addition, the gross charge distribution at pH 7.4 of eflornithine is much smaller (+0.073) than that of ornithine (+0.99). Further results indicated that eflornithine utilized a saturable transport mechanism(s) to cross the hCMEC/D3 cell membranes and that transport was inhibited by the presence of other amino acids including ornithine. Eflornithine transport was also sodium-independent and sensitive to a y⁺-system inhibitor, but not a B^0,+-system inhibitor. Eflornithine transport was also inhibited by pentamidine, suggestive of transport by organic cation transporters (OCT) which are expressed in this cell line. We confirmed expression of the y⁺-system protein, CAT1, and the B^0,+-system protein, ATB^0,+, in the hCMEC/D3 cells. We conclude that eflornithine uses the cationic amino acid transporter, system y⁺, and OCT to cross the BBB. This research highlights the potential of system-y⁺ to deliver drugs, including eflornithine, across the BBB to treat brain diseases.

人类非洲锥虫病（HAT）是一种被忽视的寄生虫病，在撒哈拉以南非洲持续存在。如果不治疗，它是致命的。该疾病的第一阶段与外周寄生虫的存在有关，而第二阶段与CNS中寄生虫的存在相关。中枢神经系统阶段HAT的治疗需要药物穿过血脑屏障（BBB）。依氟尼汀是一种氨基酸类似物，用于单独治疗第二阶段HAT冈比亚，也可与硝呋噻肟联合治疗。最近的研究表明，依氟鸟氨酸在寄生虫（锥虫）中的积累涉及氨基酸转运蛋白（布氏锥虫AAT6）。在这项研究中，我们验证了依氟鸟氨酸使用阳离子氨基酸转运系统穿过血脑屏障的假设。我们特别关注系统y+和系统B0，+。为此，我们利用专业数据库比较了相关分子的物理化学特征和血脑屏障的体外模型，以探索依氟鸟氨酸输送到中枢神经系统的机制。我们的研究结果证实，依氟鸟氨酸与内源性氨基酸鸟氨酸有关。在pH 7.4时，依氟鸟氨酸主要是（92.39%）两性离子（偶极）氨基酸，而鸟氨酸主要（99.08%）阳离子（三极）氨基酸。此外，在pH 7.4时，依氟鸟氨酸的总电荷分布（+0.073）远小于鸟氨酸的（+0.99）。进一步的结果表明，依氟鸟氨酸利用可饱和转运机制穿过hCMEC/D3细胞膜，并且包括鸟氨酸在内的其他氨基酸的存在抑制了转运。依氟尼汀转运也是钠不依赖性的，对y+系统抑制剂敏感，但对B0，+系统抑制剂不敏感。戊脒也抑制了依氟尼汀的转运，提示该细胞系中表达的有机阳离子转运蛋白（OCT）的转运。我们证实了y+系统蛋白CAT1和B0，+系统蛋白ATB0，＋在hCMEC/D3细胞中的表达。我们得出结论，依氟鸟氨酸使用阳离子氨基酸转运蛋白、系统y+和OCT穿过血脑屏障。这项研究强调了y+系统通过血脑屏障输送药物（包括依氟鸟氨酸）治疗脑部疾病的潜力。

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引用次数: 0

Modified dipeptide based nanospheres as a potent adjuvating delivery system for recombinant vaccines 修饰的二肽纳米球作为重组疫苗的有效佐剂递送系统

Frontiers in drug delivery

Pub Date : 2023-04-26 DOI: 10.3389/fddev.2023.1135209

S. Biswas, N. Yadav, A. Somanathan, P. Mukherjee, V. Chauhan

Recombinant protein vaccines offer an advantage without a safety risk in eliciting desired humoral and cell-mediated immune responses against infectious diseases. But one of their disadvantages is their low immunogenicity, thus requiring adjuvants that augment their immunogenicity. It is necessary to explore new technology that could provide a non-toxic, biodegradable, and biocompatible delivery system with adjuvant characteristics and nanotechnology provides an excellent platform for nanomaterial-based vaccine adjuvants. Here, we have synthesized a modified dipeptide, Arg-α, β-dehydrophenyalanine (RΔF) containing ΔF at its C-terminal, and characterized it using reversed-phase high-performance liquid chromatography (RP-HPLC) and mass spectrometry techniques. RΔF upon its self-assembly to spherical nanoparticles (NPs) efficiently condensed a recombinant Plasmodium falciparum surface protein, histidine-tagged MSPFu24 (Fu24H). The morphological characteristics of the nanoparticle formulation was characterized using TEM. RΔF NPs and RΔF-Fu24H complex showed excellent in vitro biocompatibility toward two mammalian cell lines and human red blood cells (RBCs). Furthermore, mice treated with R∆F NPs showed histological and haematological properties similar to the untreated control group which indicated their very high in vivo biocompatibility. Mice treated with RΔF-Fu24H nanoformulation induced a high titers of anti-Fu24H specific antibodies and showed a mixed Th1 and Th2 profile, comparable to the FDA-approved adjuvant Alhydrogel®. The sera from immunized mice inhibited the erythrocyte invasion activity of P. falciparum’s laboratory line 3D7 in vitro which was comparable to that of Alhydrogel®. The present study suggests that the highly biocompatible dipeptide-based nanoparticle formulation can further be developed and used in clinic as a promising antigen delivery platform to elicit immune responses.

重组蛋白疫苗在引发针对传染病的所需体液和细胞介导的免疫反应方面提供了一种没有安全风险的优势。但它们的缺点之一是免疫原性低，因此需要增强免疫原性的佐剂。有必要探索新技术，提供一种具有佐剂特性的无毒、可生物降解和生物相容的递送系统，纳米技术为基于纳米材料的疫苗佐剂提供了一个极好的平台。本文合成了一种C端含有ΔF的修饰二肽Arg-α，β-脱氢苯亚丹宁（RΔF），并用反相高效液相色谱（RP-HPLC）和质谱技术对其进行了表征。RΔF自组装成球形纳米颗粒（NP）后，有效地浓缩了重组恶性疟原虫表面蛋白，组氨酸标记的MSPFu24（Fu24H）。使用TEM对纳米颗粒制剂的形态特征进行了表征。ΔF-NPs和RΔF-Fu24H复合物对两种哺乳动物细胞系和人红细胞（RBCs）表现出良好的体外生物相容性。此外，用R∆F NP处理的小鼠显示出与未处理的对照组相似的组织学和血液学特性，这表明它们具有非常高的体内生物相容性。用RΔF-Fu24H纳米制剂处理的小鼠诱导了高滴度的抗Fu24H特异性抗体，并显示出混合的Th1和Th2特征，与美国食品药品监督管理局批准的佐剂Alhydrogel®相当。来自免疫小鼠的血清在体外抑制恶性疟原虫实验室株系3D7的红细胞侵袭活性，该活性与Alhydrogel®相当。本研究表明，高度生物相容性的基于二肽的纳米颗粒制剂可以进一步开发并在临床上用作引发免疫反应的有前途的抗原递送平台。

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引用次数: 0

Usefulness of direct intratumoral administration of doxorubicin hydrochloride with an electro-osmosis–assisted pump 电渗辅助泵直接瘤内给药盐酸阿霉素的有用性

Frontiers in drug delivery

Pub Date : 2023-04-04 DOI: 10.3389/fddev.2023.1150894

Ayu Ito, S. Itakura, Yuya Hasegawa, Miyu Hashimoto, Akie Okada, Mamoru Hirafuji, H. Nakamura, K. Sugibayashi, H. Todo

Patients receiving chemotherapy by intravenous (i.v.) or oral administration of anticancer drugs often experience side effects. In this study, an electro-osmotic flow (EO) pump was used for the direct administration of an anticancer drug with minimum side effects. Doxorubicin hydrochloride (DXR) was used as an anticancer drug, and its antitumor effect and toxicity were evaluated in comparison with i.v. administration. Balb/c female mice were subcutaneously transplanted with a breast cancer cell line (4T1/Luc) stably expressing luciferase, and 20 μL of DXR solution (1.0 mg/mL) was administered intratumorally (i.t.) at a slow rate (0.6 µL/min) using an EO pump or rapidly using a syringe. For comparison, 100 μL of DXR solution was injected through the tail vein at the same dose and a 5-times higher dose. A tumor growth inhibitory effect without significant weight loss was observed with direct i.t. administration of DXR using an EO pump. On the other hand, no suppressive tumor growth effect was observed with i.v. administration of DXR at the same dose. Although there was no significant difference in the suppression effect on tumor growth between i.t. administration with EO pump and syringe, the peripheral skin concentration of DXR were decreased after slow administration with EO pump compared with that after rapidly administration with a syringe. These results indicated that direct i.t. administration of DXR with lower dosing using an EO pump at slower administration rate may be useful for exhibiting antitumor effects and suppressing systemic side effects. In addition, the blood concentration and the peripheral skin concentration of DXR after administration at lower rate with EO pump were decreased compared with those after the rapidly administration with a syringe.

通过静脉注射（i.v.）或口服抗癌药物接受化疗的患者经常会出现副作用。在本研究中，电渗流（EO）泵用于直接给药副作用最小的抗癌药物。使用盐酸阿霉素（DXR）作为抗癌药物，并与静脉给药进行比较，评价其抗肿瘤作用和毒性。Balb/c雌性小鼠皮下移植稳定表达荧光素酶的癌症细胞系（4T1/Luc），并使用EO泵或使用注射器以慢速（0.6µL/min）在肿瘤内（i.t.）施用20μL DXR溶液（1.0 mg/mL）。相比之下，100μL DXR溶液以相同剂量和5倍高的剂量通过尾静脉注射。使用EO泵直接i.t.给药DXR观察到肿瘤生长抑制作用而没有显著的体重减轻。另一方面，相同剂量的DXR静脉给药未观察到抑制肿瘤生长的作用。尽管EO泵和注射器静脉给药对肿瘤生长的抑制作用没有显著差异，但与注射器快速给药相比，EO泵缓慢给药后DXR的外周皮肤浓度降低。这些结果表明，使用EO泵以较慢的给药速率以较低剂量直接i.t.给药DXR可能有助于表现出抗肿瘤作用和抑制全身副作用。此外，与用注射器快速给药后相比，用EO泵以较低速率给药后的DXR的血液浓度和外周皮肤浓度降低。

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引用次数: 1

CRISPR-mediated optogene expression from a cell-specific endogenous promoter in retinal ON-bipolar cells to restore vision 通过细胞特异性内源性启动子介导的crispr光基因表达在视网膜双极细胞中恢复视力

Frontiers in drug delivery

Pub Date : 2023-03-27 DOI: 10.3389/fddev.2023.934394

A. Maddalena, S. Kleinlogel

Retinitis pigmentosa, an inherited form of retinal degeneration, is characterized by a progressive loss of rods and subsequent degeneration of cones, leading to blindness. However, the remaining neural portion of the retina (bipolar and ganglion cells) remains anatomically and functionally intact for an extended time. A possible treatment to restore the light sensitivity of the retina consists of rendering the remaining retinal cells photosensitive using optogenetic tools like, for example, Opto-mGluR6, a light-sensitive mGluR6 receptor. We have previously demonstrated that AAV vector-mediated expression of Opto-mGluR6 in ON-bipolar cells restores visual function in otherwise blind mice. However, classical gene supplementation therapy still suffers from high off-target expression rates and uncontrollable target gene expression levels that may lead to either cytotoxicity or lack of functional restoration. To address these issues and achieve cell-specific and endogenously controlled Opto-mGluR6 expression, we employed the CRISPR/Cas technology—in particular, homology-independent targeted integration (HITI) and microhomology-dependent targeted integration (MITI)—to knock-in the Opto-mGluR6 gene behind the ON-bipolar cell-specific GRM6 promoter. We compared four Cas systems in vitro and show that SpCas9 for HITI and LbCpf1 for MITI are well suited to promoting knock-in. As AAV2-mediated ON-bipolar cell transduction resulted in inefficiency, we evaluated Exo-AAVs as delivery vehicles and found Exo-AAV1 efficient for targeting ON-bipolar cells. We demonstrate that intravitreal injection of Exo-AAV1 carrying vectors that promote MITI significantly improved visual acuity in otherwise blind rd1 mice. We conclude by confirming and providing a qualitative evaluation of the MITI-mediated knock-in in the correct genomic locus.

色素性视网膜炎是一种遗传性视网膜变性，其特征是视网膜杆的进行性缺失和随后的视锥变性，导致失明。然而，视网膜的剩余神经部分（双极细胞和神经节细胞）在很长一段时间内保持解剖和功能完整。恢复视网膜感光性的一种可能的治疗方法包括使用光遗传学工具，如光敏mGluR6受体Opt-mGlu6，使剩余的视网膜细胞光敏。我们之前已经证明，AAV载体介导的Optom-mGluR6在ON双极细胞中的表达恢复了失明小鼠的视觉功能。然而，经典的基因补充疗法仍然存在高脱靶表达率和不可控的靶基因表达水平，这可能导致细胞毒性或缺乏功能恢复。为了解决这些问题并实现细胞特异性和内源性控制的Optom-mGluR6表达，我们使用CRISPR/Cas技术——特别是同源性非依赖性靶向整合（HITI）和微同源性依赖性靶向整合（MITI）——敲除ON双极细胞特异性GRM6启动子后面的Optom-mGluR6基因。我们在体外比较了四种Cas系统，表明用于HITI的SpCas9和用于MITI的LbCpf1非常适合促进敲入。由于AAV2介导的ON双极细胞转导导致效率低下，我们评估了Exo-AAVs作为递送载体，并发现Exo-AV1对靶向ON双极细胞有效。我们证明，玻璃体内注射携带促进MITI的Exo-AV1载体显著提高了原本失明的rd1小鼠的视力。最后，我们确认并提供了MITI介导的正确基因组基因座敲除的定性评估。

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引用次数: 0

Roles of biomaterials in modulating the innate immune response in ocular therapy 生物材料在眼部治疗中调节先天免疫反应中的作用

Frontiers in drug delivery

Pub Date : 2023-02-15 DOI: 10.3389/fddev.2023.1077253

Mehrnoosh Rafiei, Jin Teng Chung, Y. Chau

The eye is a hard-to-treat organ due to its poor regenerative capacity and susceptibility to inflammation; as a result, it has an immune privilege mechanism. In the case of ocular degenerative disorders, chronic and uncontrolled ocular inflammations can overcome this immune response to initiate and exacerbate tissue degeneration, ultimately leading to blindness. Recent landmark discoveries on the key roles of the ocular innate immune system in regulating acute and chronic inflammations as well as tissue fibrosis and homeostasis have shed light on the value of novel treatment interventions in modulating ocular immune responses at the molecular, cellular, and tissue levels. This strategy can be attained by using therapeutics to target resident phagocytes and antigen-presenting cells, namely, microglia and dendritic cells, as well as infiltrating neutrophils and macrophages. Biomaterials are foreign materials to the host and interact with innate immune cells. To leverage such intrinsic immunomodulatory properties, biomaterials such as implants, injectable depots, and nano/micro particles can be used alone as a treatment or with different payloads as carriers in immune-related ocular disorders. This article discusses how physicochemical properties such as biodegradability, size, shape, and charge affect biomaterials’ interaction with the eye’s innate immune system, therefore influencing outcomes towards pro- or anti-inflammatory responses. Knowledge about the eye’s immunological response is required for designing tolerogenic biomaterials including intraocular lenses, cellular scaffolds, therapeutic molecule depots, or carriers of gene therapies. The discussion presented in this review will shed light on the potential use of biomaterials to direct immune responses toward favorable treatment outcomes.

眼睛是一个难以治疗的器官，因为它的再生能力差，容易发炎；因此，它具有免疫特权机制。在眼部退行性疾病的情况下，慢性和不受控制的眼部炎症可以克服这种免疫反应，引发并加剧组织退化，最终导致失明。最近关于眼部先天免疫系统在调节急性和慢性炎症以及组织纤维化和稳态中的关键作用的里程碑式发现，阐明了新的治疗干预措施在分子、细胞和组织水平上调节眼部免疫反应的价值。这种策略可以通过使用治疗剂靶向常驻吞噬细胞和抗原呈递细胞，即小胶质细胞和树突状细胞，以及浸润的中性粒细胞和巨噬细胞来实现。生物材料是宿主的外来物质，与先天免疫细胞相互作用。为了利用这种内在的免疫调节特性，生物材料，如植入物、注射库和纳米/微米颗粒，可以单独用作治疗，或者与不同的有效载荷一起用作免疫相关眼部疾病的载体。本文讨论了生物降解性、大小、形状和电荷等物理化学性质如何影响生物材料与眼睛先天免疫系统的相互作用，从而影响促炎或抗炎反应的结果。设计耐受性生物材料需要了解眼睛的免疫反应，包括人工晶状体、细胞支架、治疗分子库或基因疗法载体。这篇综述中的讨论将阐明生物材料的潜在用途，将免疫反应导向有利的治疗结果。

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引用次数: 0

Molecular distribution in intradermal injection for transfer and delivery of therapeutics 用于转移和递送治疗药物的皮内注射中的分子分布

Frontiers in drug delivery

Pub Date : 2023-01-13 DOI: 10.3389/fddev.2023.1095181

E. Lallow, Kishankumar J. Busha, Sarah H. Park, Maria Atzampou, N. C. Jhumur, Yasir Demiryurek, C. Roberts, J. Shan, J. Zahn, D. Shreiber, Young K Park, J. Singer, J. Maslow, Hao Lin

Intradermal (ID) injection is a technique widely used in laboratorial and clinical applications. The boundary of the dome-like bleb formed during injection is assumed to represent the lateral extent of the injected material. This work systematically characterizes cargo molecule distribution (puddle) as a function of injection volume and molecular/particle size in rat skin post ID injection. In general, results indicate that the puddle forms a subdomain laterally contained within the bleb, with an area inversely correlating to the molecular size of the injected material. For 50 μL and 100 µL injections, the average area of the bleb was 40.97 ± 6.30 mm2 and 55.64 ± 8.20 mm2, respectively, regardless of the molecular/particle size. On the other hand, the area of the puddle was dependent on the molecular size and ranged between 45.38 ± 8.29 mm2 and 6.14 ± 4.50 mm2 for 50 µL injections, and 66.64 ± 11.22 mm2 and 11.50 ± 9.67 mm2 for 100 µL injections. The lateral distribution appears to have no time-dependency up to 10 min post injection. The trend in the depth of cargo penetration is also similar, with smaller particles extending deeper into the dermis and subcutaneous fat layers. Because the area of puddle can be significantly less than that of the bleb, establishing base characterization is essential to understand cellular interactions with the injected biological substances.

皮内注射是一种广泛应用于实验室和临床的技术。假设在注射过程中形成的圆顶状气泡的边界代表注射材料的横向范围。这项工作系统地表征了大鼠皮肤注射后的货物分子分布(水坑)作为注射量和分子/颗粒大小的函数。总的来说，结果表明，水坑形成一个横向包含在气泡内的子域，其面积与注入材料的分子大小成反比。注射50 μL和100 μL时，无论分子/颗粒大小如何，气泡的平均面积分别为40.97±6.30 mm2和55.64±8.20 mm2。另一方面，水坑面积与分子大小有关，50µL注射时，水坑面积在45.38±8.29 mm2 ~ 6.14±4.50 mm2之间，100µL注射时，水坑面积在66.64±11.22 mm2 ~ 11.50±9.67 mm2之间。注射后10分钟内的横向分布似乎没有时间依赖性。货物渗透深度的趋势也相似，较小的颗粒深入真皮层和皮下脂肪层。由于水坑的面积可能明显小于气泡的面积，因此建立碱基表征对于了解细胞与注射生物物质的相互作用至关重要。

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引用次数: 1

SorLA in astrocytes regulates blood-brain barrier integrity 星形胶质细胞中的SorLA调节血脑屏障完整性

Frontiers in drug delivery

Pub Date : 2023-01-05 DOI: 10.3389/fddev.2022.1082689

A. Tóth, Adrián Klepe, Dora V. Lipka, C. Goldeman, B. Brodin, M. Nielsen

The brain`s homeostasis depends heavily on the integrity of the blood-brain barrier (BBB). Astrocytes are an essential part of the BBB in modulating and maintaining the barrier properties of the brain endothelial cells (BECs). Despite decades of research, the elements of glial regulation are not fully elucidated. SorLA/SorL1/LR11, a multifunctional receptor, is the most composite member of the Vps10p domain receptor family. In this study, we characterize the expression and function of SorLA in the cells of the BBB. The applied in vitro approaches describe BBB functions in primary cells isolated from wild-type and Sorl1 −/− knock-out rats. Here, we present that Sorl1 gene is highly expressed in wild-type astrocytes but not in BECs and pericytes. Furthermore, we show that SorLA in astrocytes is an important regulator of the BBB’s tightness. The primary rat BBB models where astrocytes lack SorLA protein proved leaky, which correlated well with the decrease in claudin-5 tight junction protein in BECs. Meanwhile, other junctional proteins, i.e., occludin and zonula occludens-1 are unaffected. Collectively, these data suggest that the absence of SorLA in astrocytes affects the tight junctions of BECs, thereby disturbing the BBB. Our results add another layer to understanding astrocyte-endothelial interactions in the healthy and diseased BBB.

大脑的内稳态在很大程度上依赖于血脑屏障(BBB)的完整性。星形胶质细胞是血脑屏障调节和维持脑内皮细胞(BECs)屏障特性的重要组成部分。尽管经过数十年的研究，神经胶质调节的要素尚未完全阐明。SorLA/SorL1/LR11是一种多功能受体，是Vps10p结构域受体家族中最复杂的成员。在这项研究中，我们表征了SorLA在血脑屏障细胞中的表达和功能。应用的体外方法描述了从野生型和Sorl1 - / -敲除大鼠分离的原代细胞中的血脑屏障功能。在这里，我们发现Sorl1基因在野生型星形胶质细胞中高表达，而在BECs和周细胞中不表达。此外，我们发现星形胶质细胞中的SorLA是血脑屏障紧密度的重要调节因子。星形胶质细胞缺乏SorLA蛋白的原代大鼠血脑屏障模型存在渗漏，这与BECs中claudin-5紧密连接蛋白的减少密切相关。同时，其他连接蛋白，即occludin和zonula occludens-1不受影响。总的来说，这些数据表明星形胶质细胞中SorLA的缺失会影响BECs的紧密连接，从而干扰血脑屏障。我们的研究结果为理解健康和患病血脑屏障中星形胶质细胞-内皮细胞的相互作用增加了另一个层面。

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引用次数: 1

Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier. 受体介导的双特异性治疗性抗体通过血脑屏障的药物传递。

Frontiers in drug delivery

Pub Date : 2023-01-01 DOI: 10.3389/fddev.2023.1227816

William M Pardridge

Therapeutic antibody drug development is a rapidly growing sector of the pharmaceutical industry. However, antibody drug development for the brain is a technical challenge, and therapeutic antibodies for the central nervous system account for ~3% of all such agents. The principal obstacle to antibody drug development for brain or spinal cord is the lack of transport of large molecule biologics across the blood-brain barrier (BBB). Therapeutic antibodies can be made transportable through the blood-brain barrier by the re-engineering of the therapeutic antibody as a BBB-penetrating bispecific antibody (BSA). One arm of the BSA is the therapeutic antibody and the other arm of the BSA is a transporting antibody. The transporting antibody targets an exofacial epitope on a BBB receptor, and this enables receptor-mediated transcytosis (RMT) of the BSA across the BBB. Following BBB transport, the therapeutic antibody then engages the target receptor in brain. RMT systems at the BBB that are potential conduits to the brain include the insulin receptor (IR), the transferrin receptor (TfR), the insulin-like growth factor receptor (IGFR) and the leptin receptor. Therapeutic antibodies have been re-engineered as BSAs that target the insulin receptor, TfR, or IGFR RMT systems at the BBB for the treatment of Alzheimer's disease and Parkinson's disease.

治疗性抗体药物开发是制药工业中一个快速增长的领域。然而，针对大脑的抗体药物开发是一项技术挑战，针对中枢神经系统的治疗性抗体占所有此类药物的3%左右。脑或脊髓抗体药物开发的主要障碍是缺乏大分子生物制剂通过血脑屏障(BBB)的运输。通过将治疗性抗体重组为穿透血脑屏障的双特异性抗体(BSA)，治疗性抗体可以通过血脑屏障运输。BSA的一个臂是治疗抗体，另一个臂是运输抗体。这种转运抗体靶向血脑屏障受体上的外表面表位，从而实现受体介导的血白蛋白跨血脑屏障的转胞作用(RMT)。在血脑屏障转运之后，治疗性抗体随后与脑中的靶受体结合。血脑屏障上的RMT系统是通往大脑的潜在通道，包括胰岛素受体(IR)、转铁蛋白受体(TfR)、胰岛素样生长因子受体(IGFR)和瘦素受体。治疗性抗体已被重新设计为靶向血脑屏障上的胰岛素受体、TfR或IGFR RMT系统的bsa，用于治疗阿尔茨海默病和帕金森病。

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引用次数: 1