Journal of Controlled Release最新文献_第6页

Fluorinated dendrimer-mediated miR-30a delivery regulates the inflammation of macrophages and mitigates the symptoms of rheumatoid arthritis 氟化树枝状聚合物介导的 miR-30a 递送可调节巨噬细胞的炎症并减轻类风湿性关节炎的症状

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-09 DOI: 10.1016/j.jconrel.2024.11.009

Jiakai Xing , Jiaxin Jia , Hugang Zhang , Haobo Han , Quanshun Li

Abnormal expression of microRNAs (miRNAs) plays a significant role in the pathogenesis of rheumatoid arthritis (RA), and thus miRNA-based therapy has emerged as a promising approach for the RA treatment. Herein, miR-30a was successfully screened and identified to be an essential mediator for the inflammation of RA. MiR-30a could directly target the Snai1 gene and further regulate the Cad11 expression to inhibit the NF-κB and MAPK signaling pathways, contributing to the anti-inflammatory effect. To enhance the therapeutic outcome of miR-30a, fluorinated polyamidoamine dendrimer (FP) was developed as the carrier to achieve the miR-30a delivery in the mice of collagen-induced arthritis. The carrier FP and miR-30a formed stable nanocomplexes and effectively mediated the transfection of miR-30a to execute the anti-inflammatory response in lipopolysaccharide-stimulated macrophages. Further, the intravenous administration of FP/miR-30a showed obvious accumulation in the inflamed joints and inhibited the inflammatory response via the Snai1/Cad11 axis, thereby contributing to the anti-arthritic efficacy. In addition, the FP/miR-30a nanocomplexes displayed favorable biocompatibility, as they did not cause the damage of organs following the systemic administration. Taken together, our study demonstrated that miR-30a is an effective anti-inflammatory oligonucleotide and the fluorinated dendrimer-mediated miR-30a delivery possesses the potential to be a promising approach for the treatment of RA and other autoimmune diseases.

微RNA（miRNA）的异常表达在类风湿性关节炎（RA）的发病机制中起着重要作用，因此基于miRNA的疗法已成为治疗RA的一种有前途的方法。本文成功地筛选出了miR-30a，并确定它是类风湿性关节炎炎症的重要介质。MiR-30a可直接靶向Snai1基因，并进一步调控Cad11的表达，从而抑制NF-κB和MAPK信号通路，起到抗炎作用。为了提高 miR-30a 的治疗效果，研究人员开发了含氟聚酰胺树枝状聚合物（FP）作为载体，以实现 miR-30a 在胶原诱导的关节炎小鼠体内的传递。载体FP和miR-30a形成了稳定的纳米复合物，有效地介导了miR-30a的转染，从而在脂多糖刺激的巨噬细胞中发挥抗炎作用。此外，静脉注射FP/miR-30a后，其在发炎关节中明显蓄积，并通过Snai1/Cad11轴抑制炎症反应，从而起到抗关节炎的作用。此外，FP/miR-30a 纳米复合物具有良好的生物相容性，全身给药后不会对器官造成损伤。综上所述，我们的研究表明，miR-30a是一种有效的抗炎寡核苷酸，氟化树枝状聚合物介导的miR-30a递送有望成为治疗RA和其他自身免疫性疾病的一种有效方法。

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引用次数: 0

Engineering of phosphatidylserine-targeting ROS-responsive polymeric prodrug for the repair of ischemia-reperfusion-induced acute kidney injury 设计磷脂酰丝氨酸靶向 ROS 响应聚合原药，用于修复缺血再灌注诱发的急性肾损伤。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-09 DOI: 10.1016/j.jconrel.2024.10.063

Jin-Hui Wang , Hai-Bo Mao , Jing-Bo Hu , Shunhua Cheng , Hao Su

Ischemia-reperfusion-induced acute kidney injury (IR-AKI) commonly occurs in situations such as hemorrhagic shock, kidney transplantation, and cardiovascular surgery. As one of the significant causes of AKI, IR-AKI is characterized by its high incidence and mortality rates. Currently, effective inflammation control is the key for the treatment of IR-AKI. In this study, we developed an ROS-responsive polymeric prodrugs (Zn-D/DTH) which could target the externalized PS of apoptotic cells, and then responsively released HDM (anti-inflammatory peptides) in the presence of intracellular ROS. Zn-D/DTH effectively ameliorated renal function and mitigated pathological alterations such as the loss of the brush border, tubular dilation, and accumulation of cellular debris within the tubular lumens. Furthermore, Zn-D/DTH greatly reduced the generation of pro-inflammatory factors like IL-6, COX-2, and iNOS in renal tissues, suggesting its protective role largely stems from suppression of the inflammatory response. Additional mechanism exploration revealed that Zn-D/DTH markedly decreased the expression levels of TLR4 and MyD88, as well as the phosphorylation of NF-κB in the damaged kidneys. This, in turn, reduced the number of apoptotic tubular cells and the activity of Caspase 9 and Caspase 3 caused by ischemia-reperfusion. Additionally, Zn-D/DTH treatment showed improvement in the long-term renal damage and fibrosis induced by ischemia-reperfusion. The experimental outcomes indicated that Zn-D/DTH attenuated renal ischemia-reperfusion injury and delayed the transition from acute kidney injury to chronic kidney disease by downregulating the TLR4/MyD88/NF-κB signaling pathway and reducing the expression of apoptotic caspases, thereby inhibiting inflammation and reducing cell apoptosis.

缺血再灌注诱发的急性肾损伤（IR-AKI）通常发生在失血性休克、肾移植和心血管手术等情况下。作为急性肾损伤的重要原因之一，IR-AKI 的特点是发病率和死亡率高。目前，有效控制炎症是治疗 IR-AKI 的关键。在这项研究中，我们开发了一种 ROS 响应聚合物原药（Zn-D/DTH），它可以靶向凋亡细胞的外化 PS，然后在细胞内 ROS 存在的情况下响应性地释放 HDM（抗炎肽）。Zn-D/DTH 能有效改善肾功能，减轻刷状缘消失、肾小管扩张和肾小管腔内细胞碎片堆积等病理改变。此外，Zn-D/DTH 还大大减少了肾组织中 IL-6、COX-2 和 iNOS 等促炎因子的生成，表明其保护作用主要源于对炎症反应的抑制。其他机制探索显示，Zn-D/DTH 能显著降低受损肾脏中 TLR4 和 MyD88 的表达水平，以及 NF-κB 的磷酸化水平。这反过来又减少了缺血再灌注导致的肾小管细胞凋亡数量以及 Caspase 9 和 Caspase 3 的活性。此外，Zn-D/DTH 治疗对缺血再灌注引起的长期肾损伤和纤维化也有改善作用。实验结果表明，Zn-D/DTH通过下调TLR4/MyD88/NF-κB信号通路和减少凋亡Caspase的表达，从而抑制炎症和减少细胞凋亡，减轻了肾脏缺血再灌注损伤，延缓了急性肾损伤向慢性肾病的转变。

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引用次数: 0

Lipidation-dimerization platform unlocks treatment potential of fibroblast growth factor 21 for non-alcoholic steatohepatitis 脂肪二聚化平台释放成纤维细胞生长因子 21 治疗非酒精性脂肪性肝炎的潜力

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-09 DOI: 10.1016/j.jconrel.2024.11.006

Yapeng Wang , Lei Shen , Chengcheng Wang , Yuanzhen Dong , Haoju Hua , Jun Xu , Ying Zhang , Hao Huang , Zongqing Huang , Fei Zhao , Zhiru Xu , Yunliang Qiu , Jianguang Lu , Dianwen Ju , Jun Feng

Optimizing the druggability of both native and AI-designed bioactive proteins is crucial for realizing their therapeutic potential. A key focus in designing protein-based therapeutics is improving their pharmacokinetic properties. However, a significant challenge is to preserve biological activity while implementing long-acting strategies. Fibroblast growth factor 21 (FGF21), an endogenous hormone with potential as a treatment for non-alcoholic steatohepatitis (NASH), exemplifies this challenge. In this study, we present a novel lipidation-dimerization (LiDi) platform that integrates lipidation with a dimeric form of FGF21 connected by a hydrophilic linker. The lipidation enhances albumin binding, enabling sustained release, while the dimeric structure boosts biological activity. In vivo evaluations of the LiDi FGF21 analogs demonstrated that they offer excellent pharmacokinetic properties and superior efficacy compared to other treatments for NASH. This platform effectively extends the therapeutic half-life of proteins without compromising their activity, substantially broadening the application range of proteins as therapeutics.

优化原生蛋白质和人工智能设计的生物活性蛋白质的可药用性对于实现其治疗潜力至关重要。设计基于蛋白质的疗法的一个重点是改善其药代动力学特性。然而，如何在实施长效策略的同时保持生物活性是一个重大挑战。成纤维细胞生长因子 21（FGF21）是一种内源性激素，具有治疗非酒精性脂肪性肝炎（NASH）的潜力。在这项研究中，我们提出了一种新型脂化-二聚化（LiDi）平台，它将脂化与由亲水连接体连接的 FGF21 二聚体形式结合在一起。脂化增强了与白蛋白的结合，从而实现了持续释放，而二聚体结构则提高了生物活性。对 LiDi FGF21 类似物的体内评估表明，与其他治疗 NASH 的方法相比，它们具有出色的药代动力学特性和更优越的疗效。该平台有效延长了蛋白质的治疗半衰期，同时不影响其活性，大大拓宽了蛋白质作为治疗药物的应用范围。

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引用次数: 0

Engineered manganese-BODIPY coordinated nanoadjuvants for enhanced NIR-II photo-metalloimmunotherapy 用于增强近红外-II 光金属免疫疗法的工程锰-BODIPY 配位纳米佐剂

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-09 DOI: 10.1016/j.jconrel.2024.11.005

Yushi Zhang , Xuya Yu , Lingpeng Luo , Yigang Xu , Hanjie Zhang , Zhuo Mao , Yuqin Zhang , Cuihong Yang , Lu Wang , Pengcheng Zhang , Sitong Li , Meitong Ou , Ran Luo , Dunwan Zhu , Wen Li , Lin Mei

Immunotherapy, a pivotal and promising approach for tumor treatment, has demonstrated prominent clinical efficacy. However, its effectiveness is often impeded by insufficient antitumor immune responses attributed to the immunosuppressive tumor microenvironment (TME). The combination of immune activation through the stimulator of interferon genes (STING) pathway and phototherapy holds great potential for surmounting this challenge in advanced tumor immunotherapy. Herein, a novel manganese-boosted NIR-II photo-metalloimmunotherapy is proposed to synergistically enhance antitumour efficacy by fabricating Mn²⁺-BODIPY-based coordinated photo-immune nanoadjuvants (BMR), modified with tumor-targeted peptide cRGD. The obtained BMR could effectively deliver Mn²⁺ to tumor sites, and immunogenic cell death (ICD) was evoked by localized photothermal ablation of tumors using NIR-II laser irradiation. Simultaneously, pH-responsive release of Mn²⁺ would trigger the activation of STING pathway to promote the production of type I interferons (I-IFNs), significantly facilitating the maturation of dendritic cells (DCs) and polarization of macrophages to M1 phenotypes. Furthermore, by synergistically initiating systematic and robust antitumour immune responses, the BMR-mediated NIR-II photo-metalloimmunotherapy achieved remarkable therapeutic efficacy against both primary and lung metastasis of B16F10 tumors. Overall, in light of the versatile functionalities and synthetic flexibility of coordinated nanoadjuvants, formulated with photofunctional ligands and diverse metal ions, this work provides new insights into the design of metal coordination nanomedicine for effective antitumor photo-metalloimmunotherapy.

免疫疗法是治疗肿瘤的一种关键且前景广阔的方法，已显示出显著的临床疗效。然而，免疫抑制性肿瘤微环境（TME）导致的抗肿瘤免疫反应不足往往会阻碍免疫疗法的效果。通过干扰素基因刺激器（STING）途径激活免疫反应与光疗相结合，有望克服晚期肿瘤免疫疗法面临的这一挑战。本文提出了一种新型的锰促进近红外-II光金属免疫疗法，通过制备基于Mn2+-BODIPY的协同光免疫纳米佐剂（BMR），并用肿瘤靶向肽cRGD修饰，协同提高抗肿瘤疗效。所获得的 BMR 能有效地将 Mn2+ 递送到肿瘤部位，并利用近红外-II 激光照射肿瘤局部光热消融诱发免疫性细胞死亡（ICD）。同时，Mn2+的pH响应性释放会触发STING通路的激活，促进I型干扰素（I-IFNs）的产生，从而显著促进树突状细胞（DCs）的成熟和巨噬细胞向M1表型的极化。此外，BMR 介导的近红外-II 光金属免疫疗法通过协同启动系统而强大的抗肿瘤免疫反应，对 B16F10 肿瘤的原发和肺转移取得了显著疗效。总之，鉴于配位纳米佐剂具有多功能性和合成灵活性，并由光功能配体和多种金属离子配制而成，这项工作为设计金属配位纳米药物以实现有效的抗肿瘤光-金属免疫疗法提供了新的见解。

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引用次数: 0

Injectable nanocomposite hydrogel with cascade drug release for treatment of uveal melanoma 用于治疗葡萄膜黑色素瘤的级联药物释放可注射纳米复合水凝胶。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-09 DOI: 10.1016/j.jconrel.2024.11.001

Zhihao Guo , Linyun Xiu , Yumei Li , Jiangcheng Tan , Cailing Wei , Junhui Sui , Shijin Zhang , Ruohua Zhu , Ji-Liang Li

Uveal melanoma (UM) is the most common malignant intraocular tumor with the trait of distant metastases. Currently, the standard clinical therapy results in suboptimal outcomes due to ineffective inhibition of tumor metastasis. Thus, developing novel therapeutic modalities for UM remains a critical priority. Herein, we have developed an injectable nanocomposite hydrogel (HA-DOX/LAP gel) through integrating hyaluronic acid-based drug-loaded nanoparticles into an alginate-dopamine gel, delivering the chemotherapeutic drugs, lapatinib and doxorubicin for combinational treatment of UM. HA-DOX/LAP gel is fabricated in situ by a simple injection of the mixed precursor solution into tumor sites and maintains in vivo for more than 21 days. The entrapped drug-loaded nanoparticles can gradually release from HA-DOX/LAP gel, enhancing tumor targeting and penetration, and synchronously releasing lapatinib and doxorubicin into the acidic intracellular environment to synergistically destroy UM cells. In vivo anti-tumor studies conducted in MuM-2B tumor models demonstrated that HA-DOX/LAP gel significantly impedes tumor growth, diminishes postoperative recurrence, and prolongs overall survivals of UM tumor-bearing mice through only single injection. Remarkably, the escaped drug-loaded nanoparticles effectively reduce the risk of tumor metastases. Our findings provide new insights for the development of multifunctional nanocomposite-incorporating combination therapy against UM by targeting tumor recurrence and metastases.

葡萄膜黑色素瘤（UM）是最常见的眼内恶性肿瘤，具有远处转移的特性。目前，标准的临床疗法由于无法有效抑制肿瘤转移而导致疗效不佳。因此，开发治疗 UM 的新型疗法仍是当务之急。在此，我们开发了一种可注射的纳米复合水凝胶（HA-DOX/LAP 凝胶），它将透明质酸基药物载荷纳米粒子整合到藻酸盐-多巴胺凝胶中，可输送化疗药物拉帕替尼和多柔比星，用于 UM 的联合治疗。只需将混合前体溶液注入肿瘤部位，就能在原位制成 HA-DOX/LAP 凝胶，并在体内维持 21 天以上。夹带药物的纳米颗粒可从 HA-DOX/LAP 凝胶中逐渐释放，增强了肿瘤的靶向性和穿透性，并将拉帕替尼和多柔比星同步释放到酸性细胞内环境中，协同破坏 UM 细胞。在 MuM-2B 肿瘤模型中进行的体内抗肿瘤研究表明，HA-DOX/LAP 凝胶只需注射一次，就能显著抑制肿瘤生长，减少术后复发，并延长 UM 肿瘤小鼠的总体存活时间。值得注意的是，逸出的载药纳米粒子能有效降低肿瘤转移的风险。我们的研究结果为开发针对肿瘤复发和转移的多功能纳米复合材料联合疗法提供了新的思路。

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引用次数: 0

Advancing osteosarcoma 3D modeling in vitro for novel tumor microenvironment-targeted therapies development 推进骨肉瘤三维体外建模，开发新型肿瘤微环境靶向疗法。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-08 DOI: 10.1016/j.jconrel.2024.10.068

Sofia Costa , João Rodrigues , Carolina Vieira , Sofia Dias , Juliana Viegas , Flávia Castro , Bruno Sarmento , Catarina Leite Pereira

Osteosarcoma (OS) represents one of the most common primary bone cancers affecting children and young adults. The available treatments have remained unimproved for the past decades, hampered by the poor knowledge of OS etiology/pathophysiology and the lack of innovative, predictive and biologically relevant in vitro models, that can recapitulate the 3D OS tumor microenvironment (TME). Here, we report the development and characterization of an innovative 3D model of OS, composed of OS tumor cells, immune cells (macrophages) and mesenchymal stem cells (MSCs), that formed a multicellular tissue spheroid (MCTS). This fully humanized 3D model was shown to accurately mimic the native histological features of OS, while innately leading to the polarization of macrophages towards an M2-like phenotype, highly aggressive and pro-tumor profile. Upon the exposure to immunomodulatory molecules, the MCTS were shown to be responsive by shifting macrophages polarization, and dramatically altering the TME secretome. In agreement, when treated with immunomodulatory/stimulatory nanoparticles (NPSs), we were able to revert the TME secretome towards an anti-inflammatory profile. This study establishes an advanced 3D OS model capable of shedding light on macrophages and MSCs contributions to disease progression, paving the way for the development of innovative therapeutic approaches targeting the OS TME, while providing a biologically relevant in vitro tool for the efficacy screening of novel OS therapeutic approaches.

骨肉瘤（Osteosarcoma，OS）是儿童和年轻人最常见的原发性骨癌之一。由于对骨肉瘤的病因学/病理生理学知之甚少，以及缺乏可再现三维骨肉瘤肿瘤微环境（TME）的创新性、预测性和生物相关性体外模型，现有的治疗方法在过去几十年中一直没有得到改善。在此，我们报告了由 OS 肿瘤细胞、免疫细胞（巨噬细胞）和间充质干细胞（间充质干细胞）组成的 OS 创新三维模型的开发和特征描述，该模型形成了一个多细胞组织球体（MCTS）。研究表明，这种完全人源化的三维模型能准确模拟 OS 的原生组织学特征，同时导致巨噬细胞向 M2 样表型极化，具有高度侵袭性和促肿瘤特征。在暴露于免疫调节分子后，MCTS 通过改变巨噬细胞的极化和显著改变 TME 分泌组而显示出反应能力。同样，当使用免疫调节/刺激性纳米颗粒（NPSs）治疗时，我们能够将TME分泌组恢复到抗炎状态。这项研究建立了一种先进的三维 OS 模型，能够揭示巨噬细胞和间充质干细胞对疾病进展的影响，为开发针对 OS TME 的创新治疗方法铺平了道路，同时也为新型 OS 治疗方法的疗效筛选提供了一种生物相关的体外工具。

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引用次数: 0

Cerebral biomimetic nano-drug delivery systems: A frontier strategy for immunotherapy 脑生物仿生纳米给药系统：免疫疗法的前沿策略

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-08 DOI: 10.1016/j.jconrel.2024.10.058

Hao Tian , Jiaxin Yao , Qi Ba , Yuanyuan Meng , Yanan Cui , Liangzhu Quan , Wei Gong , Yuli Wang , Yang Yang , Meiyan Yang , Chunsheng Gao

Brain diseases are a significant threat to human health, especially in the elderly, and this problem is growing as the aging population increases. Efficient brain-targeted drug delivery has been the greatest challenge in treating brain disorders due to the unique immune environment of the brain, including the blood-brain barrier (BBB). Recently, cerebral biomimetic nano-drug delivery systems (CBNDSs) have provided a promising strategy for brain targeting by mimicking natural biological materials. Herein, this review explores the latest understanding of the immune microenvironment of the brain, emphasizing the immune mechanisms of the occurrence and progression of brain disease. Several brain targeting systems are summarized, including cell-based, exosome-based, protein-based, and microbe-based CBNDSs, and their immunological mechanisms are highlighted. Moreover, given the rise of immunotherapy, the latest applications of CBNDSs in immunotherapy are also discussed. This review provides a comprehensive understanding of CBNDSs and serves as a guideline for immunotherapy in treating brain diseases. In addition, it provides inspiration for the future of CBNDSs.

脑部疾病是人类健康的重大威胁，尤其是在老年人中，而且随着老龄化人口的增加，这一问题正在日益严重。由于大脑独特的免疫环境，包括血脑屏障（BBB），高效的脑靶向给药一直是治疗脑部疾病的最大挑战。最近，脑生物仿生纳米给药系统（CBNDS）通过模仿天然生物材料，为脑靶向给药提供了一种前景广阔的策略。本综述探讨了对脑部免疫微环境的最新认识，强调了脑部疾病发生和发展的免疫机制。综述了几种脑靶向系统，包括基于细胞的、基于外泌体的、基于蛋白质的和基于微生物的 CBNDS，并重点介绍了它们的免疫学机制。此外，鉴于免疫疗法的兴起，还讨论了 CBNDS 在免疫疗法中的最新应用。这篇综述提供了对 CBNDS 的全面了解，可作为治疗脑部疾病的免疫疗法指南。此外，它还为 CBNDS 的未来发展提供了启示。

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引用次数: 0

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer 多价 DR5 受体集群激动剂与组蛋白去乙酰化酶抑制剂联合治疗结肠癌。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-08 DOI: 10.1016/j.jconrel.2024.10.062

Jiahui Li , Jaden Arnold , Monika Sima , Hasan Al Faruque , Jacob Galang , Sophia Hu-Lieskovan , Jindřich Kopeček , Jiyuan Yang

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering.

To address the limitation, we developed N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WDCLDNRIGRRQCVKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as P_H-cDR5 (high valence), P_M-cDR5 (medium valence) and P_L-cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells P_M-cDR5 exhibited an IC50 of 94 pM, while P_H-cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC₅₀ for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.

死亡受体5（DR5）靶向疗法在介导细胞凋亡的外在途径中发挥着关键作用，因此前景广阔。尽管DR5在各种恶性肿瘤中过度表达，而且肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）也具有潜力，但抗DR5单克隆抗体（mAbs）的临床应用却受到了阻碍，原因可能是缺乏受体集群，导致疗效不理想。为了解决这一局限性，我们开发了基于 N-（2-羟基丙基）甲基丙烯酰胺（HPMA）共聚物的共轭物，其中整合了多份 DR5 靶向肽（环 WDCLDNRIGRRQCVKL；cDR5），以增强受体集群和细胞凋亡。我们制备了三种具有不同数量 cDR5 的共轭物，分别称为 PH-cDR5（高价）、PM-cDR5（中价）和 PL-cDR5（低价）。我们在对 TRAIL 敏感和耐药的癌细胞系中进行的研究表明，HPMA 共聚物-多肽共轭物（P-cDR5）能显著改善 DR5 受体的聚集，并有效诱导细胞凋亡。在对 TRAIL 敏感的结肠癌细胞（COLO205、HCT-116）中，P-cDR5 的疗效与抗 DR5 mAb 屈珠单抗（DRO）相当，但在对 TRAIL 抗性的细胞（HT-29）中，P-cDR5 的疗效优于 DRO，这凸显了有效受体聚类的重要性。在 COLO205 细胞中，PM-cDR5 的 IC50 为 94 pM，而 PH-cDR5 的 IC50 甚至更低，仅为 15 pM（基于 cDR5 的等效浓度），这表明与 TRAIL 的 IC50 0.12 nM 相比，基于多价 HPMA 共聚物的柔性聚合物骨架系统的效力更强。将 P-cDR5 与组蛋白去乙酰化酶抑制剂丙戊酸结合使用，可进一步增强诱导细胞凋亡的功效，同时还能破坏线粒体膜的稳定性，并提高 TRAIL 抗性细胞的敏感性。这些研究结果表明，将多个 cDR5 肽连接到柔性水溶性聚合物载体上不仅克服了以往设计的局限性，还为治疗耐药性癌症提供了一条前景广阔的途径，这表明有必要对这一创新策略进行进一步的临床前探索和验证。

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引用次数: 0

Leveraging machine learning to streamline the development of liposomal drug delivery systems 利用机器学习简化脂质体给药系统的开发。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-08 DOI: 10.1016/j.jconrel.2024.10.065

Remo Eugster , Markus Orsi , Giorgio Buttitta , Nicola Serafini , Mattia Tiboni , Luca Casettari , Jean-Louis Reymond , Simone Aleandri , Paola Luciani

Drug delivery systems efficiently and safely administer therapeutic agents to specific body sites. Liposomes, spherical vesicles made of phospholipid bilayers, have become a powerful tool in this field, especially with the rise of microfluidic manufacturing during the COVID-19 pandemic. Despite its efficiency, microfluidic liposomal production poses challenges, often requiring laborious, optimization on a case-by-case basis. This is due to a lack of comprehensive understanding and robust methodologies, compounded by limited data on microfluidic production with varying lipids. Artificial intelligence offers promise in predicting lipid behaviour during microfluidic production, with the still unexploited potential of streamlining development. Herein we employ machine learning to predict critical quality attributes and process parameters for microfluidic-based liposome production. Validated models predict liposome formation, size, and production parameters, significantly advancing our understanding of lipid behaviour. Extensive model analysis enhanced interpretability and investigated underlying mechanisms, supporting the transition to microfluidic production. Unlocking the potential of machine learning in drug development can accelerate pharmaceutical innovation, making drug delivery systems more adaptable and accessible.

药物输送系统能高效、安全地将治疗药物输送到人体特定部位。脂质体是由磷脂双分子层构成的球形囊泡，已成为这一领域的有力工具，尤其是在 COVID-19 大流行期间，微流控生产技术的兴起更是如此。尽管微流控脂质体生产效率很高，但它也带来了挑战，往往需要逐个进行费力的优化。这是由于缺乏全面的了解和可靠的方法，再加上使用不同脂质进行微流控生产的数据有限。人工智能在预测微流控生产过程中的脂质行为方面大有可为，其简化开发的潜力仍有待开发。在此，我们利用机器学习预测基于微流控生产脂质体的关键质量属性和工艺参数。经过验证的模型可以预测脂质体的形成、大小和生产参数，极大地促进了我们对脂质行为的理解。广泛的模型分析增强了可解释性并研究了潜在机制，为过渡到微流控生产提供了支持。释放机器学习在药物开发中的潜力可以加速制药创新，使药物输送系统更具适应性和可及性。

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引用次数: 0

Reactive oxygen species-responsive polydopamine-PtCuTe nanoparticle-loaded microneedle system for promoting the healing of infected skin wounds 促进感染性皮肤伤口愈合的活性氧反应型多巴胺-铂铜碲纳米粒子微针系统。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release

Pub Date : 2024-11-07 DOI: 10.1016/j.jconrel.2024.11.002

Hongfan Che , Junzhi Xu , Dong Wu , Siliang Chen , Chengkang Liu , Chongbao Zhao , Kun Peng

Nanozymes, known for their high efficiency in scavenging reactive oxygen species (ROS), have received significant attention in promoting the healing of infected wounds. Herein, we reported a novel multifunctional PDA-PtCuTe nanozyme with excellent ROS scavenging, antibacterial, pro-angiogenic, anti-inflammatory, and immune regulatory properties. It was loaded onto microneedles (PTPP-MN) for treating infected wounds. In vitro experiments demonstrated its ability to scavenge ROS and exhibit antioxidant properties. Compared to PT-MN (11.03 ± 3.37 %) and PTP-MN (42.30 ± 2.60 %), the ROS scavenging rate of PTPP-MN reached 63.63 ± 4.42 %. The microneedle exhibits good biocompatibility, stimulating fibroblast migration, endothelial angiogenesis, and M2 macrophage polarization. Additionally, it effectively eliminates ROS and provides antioxidant effects while inhibiting the viability of S. aureus and E. coli. Animal experiments showed that the PTPP-MN group achieved near-complete re-epithelialization by the third day compared to other groups. Histological observations revealed that the PTPP-MN group exhibited enhanced granulation tissue formation, epithelial regeneration, and angiogenesis. After PTPP-MN treatment, the local immune response shifted from a pro-inflammatory state to a pro-regenerative state. Our results indicate that PTPP-MN holds great promise for infected wound healing with reduced scar formation.

纳米酶以其高效清除活性氧（ROS）而闻名，在促进感染伤口愈合方面备受关注。在此，我们报告了一种新型多功能 PDA-PtCuTe 纳米酶，它具有出色的清除 ROS、抗菌、促血管生成、抗炎和免疫调节特性。它被载入微针（PTPP-MN），用于治疗感染伤口。体外实验证明了它清除 ROS 和抗氧化的能力。与 PT-MN（11.03 ± 3.37 %）和 PTP-MN（42.30 ± 2.60 %）相比，PTPP-MN 的 ROS 清除率达到了 63.63 ± 4.42 %。微针具有良好的生物相容性，可刺激成纤维细胞迁移、内皮血管生成和 M2 巨噬细胞极化。此外，它还能有效消除 ROS 并提供抗氧化作用，同时抑制金黄色葡萄球菌和大肠杆菌的活力。动物实验表明，与其他组相比，PTPP-MN 组在第三天就实现了几乎完全的再上皮化。组织学观察显示，PTPP-MN 组的肉芽组织形成、上皮再生和血管生成均有所增强。经 PTPP-MN 处理后，局部免疫反应从促炎症状态转变为促再生状态。我们的研究结果表明，PTPP-MN 在感染伤口愈合和减少疤痕形成方面大有可为。

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引用次数: 0