Asian Journal of Pharmaceutical Sciences最新文献_第7页

IL-2-loaded liposomes modified with sorafenib derivative exert a synergistic anti-melanoma effect via improving tumor immune microenvironment and enhancing antiangiogenic activity sorafenib衍生物修饰的il -2负载脂质体通过改善肿瘤免疫微环境和增强抗血管生成活性发挥协同抗黑色素瘤作用

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-10 DOI: 10.1016/j.ajps.2025.101020

Xuan Huang , Kudelaidi Kuerban , Jajun Fan , Danjie Pan , Huaning Chen , Jiayang Liu , Songna Wang , Dianwen Ju , Yi Zhun Zhu , Jiyong Liu , Li Ye

Immunotherapy with interleukin-2 (IL-2) in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise. To address these challenges, IL-2-So-Lipo, a novel liposomal formulation combining IL-2 with sorafenib derivative, was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth. Sorafenib derivatives could target at melanoma-specific receptors, further enhancing liposomal specificity at the tumor site. Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies, as well as their combination. In a B16F10 melanoma model, IL-2-So-Lipo was found to significantly inhibit tumor progression (tumor volume of 108.01 ± 62.99 mm³) compared to the control group (tumor volume of 1,397.13 ± 75.55 mm³), improving the therapeutic efficacy. This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes. Additionally, liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency, promoting tumor cell apoptosis and suppressing angiogenesis. Mechanistically, IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype. Furthermore, IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway, exerting a significant role in mediating tumor resistance to sorafenib. These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers. Moreover, the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy, offering a synergistic approach to improve therapeutic outcomes for solid tumors.

白细胞介素-2 （IL-2）在治疗癌症中的免疫疗法受到一些限制，如全身副作用和对低免疫细胞浸润的肿瘤的疗效降低，尽管它很有希望。为了解决这些挑战，IL-2- so - lipo是一种新型的脂质体制剂，将IL-2与索拉非尼衍生物结合，作为一种抗血管生成药物，抑制新血管的生长，而新血管在肿瘤生长中起着至关重要的作用。索拉非尼衍生物可以靶向黑色素瘤特异性受体，进一步增强肿瘤部位脂质体的特异性。我们的研究结果表明，与IL-2或索拉非尼单药及其联合治疗相比，制备的IL-2- so - lipo的抗肿瘤活性显著增强。在B16F10黑色素瘤模型中，IL-2-So-Lipo明显抑制肿瘤进展（肿瘤体积为108.01±62.99 mm3），而对照组（肿瘤体积为1379.13±75.55 mm3），提高了治疗效果。这种增强的功效归因于靶向递送IL-2，促进细胞毒性T淋巴细胞的浸润和活化。此外，索拉非尼衍生物脂质体包封可提高其递送效率，促进肿瘤细胞凋亡，抑制血管生成。在机制上，IL-2-So-Lipo可以通过促进巨噬细胞向M1表型极化，诱导向抗肿瘤免疫反应的转变来杀死肿瘤。此外，IL-2-So-Lipo下调MAPK信号通路中的几个关键蛋白，在介导肿瘤对索拉非尼的耐药中发挥重要作用。这些发现强调了IL-2-So-Lipo作为提高癌症免疫治疗和靶向治疗疗效的有希望的策略的潜力。此外，IL-2和索拉非尼在脂质体递送系统中的联合使用克服了传统IL-2治疗的局限性，为改善实体瘤的治疗结果提供了一种协同方法。

{"title":"IL-2-loaded liposomes modified with sorafenib derivative exert a synergistic anti-melanoma effect via improving tumor immune microenvironment and enhancing antiangiogenic activity","authors":"Xuan Huang , Kudelaidi Kuerban , Jajun Fan , Danjie Pan , Huaning Chen , Jiayang Liu , Songna Wang , Dianwen Ju , Yi Zhun Zhu , Jiyong Liu , Li Ye","doi":"10.1016/j.ajps.2025.101020","DOIUrl":"10.1016/j.ajps.2025.101020","url":null,"abstract":"<div><div>Immunotherapy with interleukin-2 (IL-2) in treating cancers is subject to several limitations such as systemic side effects and reduced efficacy against tumors with low immune cell infiltration despite its promise. To address these challenges, IL-2-So-Lipo, a novel liposomal formulation combining IL-2 with sorafenib derivative, was developed as an anti-angiogenic drug that inhibits the growth of new blood vessels which play crucial roles in tumor growth. Sorafenib derivatives could target at melanoma-specific receptors, further enhancing liposomal specificity at the tumor site. Our results demonstrated that the prepared IL-2-So-Lipo significantly enhanced anti-tumor activity compared to IL-2 or sorafenib monotherapies, as well as their combination. In a B16F10 melanoma model, IL-2-So-Lipo was found to significantly inhibit tumor progression (tumor volume of 108.01 ± 62.99 mm<sup>3</sup>) compared to the control group (tumor volume of 1,397.13 ± 75.55 mm<sup>3</sup>), improving the therapeutic efficacy. This enhanced efficacy is attributed to the targeted delivery of IL-2 which promoted the infiltration and activation of cytotoxic T lymphocytes. Additionally, liposomal encapsulation of sorafenib derivatives enhanced its delivery efficiency, promoting tumor cell apoptosis and suppressing angiogenesis. Mechanistically, IL-2-So-Lipo could kill tumors by inducing a shift towards an anti-tumor immune response via facilitating the polarization of macrophages towards the M1 phenotype. Furthermore, IL-2-So-Lipo downregulated several key proteins in the MAPK signaling pathway, exerting a significant role in mediating tumor resistance to sorafenib. These findings underscore the potential of IL-2-So-Lipo as a promising strategy to improve the therapeutic efficacy of immunotherapy and targeted therapy in cancers. Moreover, the combination of IL-2 and sorafenib in a liposomal delivery system overcame the limitations of conventional IL-2 therapy, offering a synergistic approach to improve therapeutic outcomes for solid tumors.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 2","pages":"Article 101020"},"PeriodicalIF":10.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route 通过模拟寡肽运输途径增强SLN的淋巴运输

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-10 DOI: 10.1016/j.ajps.2025.101019

Fuya Jia , Xiaoxing Fan , Licheng Wu , Yating Wang , Jisen Zhang , Zhou Zhou , Lian Li , Jingyuan Wen , Yuan Huang

Solid lipid nanoparticles (SLN) could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport. Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment. They are mainly transported by oligopeptide transporter-1 (PepT-1) which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption. Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway. This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation. Herein, two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1 (GLP-1) analogue exenatide as model drugs. These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6 mice and type II diabetic KKAy mice. Compared with un-modified SLN, dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake. Interestingly, after internalization, more SLN could access the systemic circulation via lymphatic transport pathway, highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.

固体脂质纳米颗粒（SLN）可通过淋巴运输提高载蛋白和多肽药物的口服生物利用度。天然寡肽调节几乎所有的生命过程，并作为营养的氮源。它们主要通过寡肽转运体-1 （PepT-1）运输，主要在肠道内表达，具有高容量、低能耗的特点。我们的初步研究发现，通过刺激寡肽吸收途径可以改善SLN的跨膜转运。这意味着将SLN的优势与寡肽转运体介导的转运结合起来的潜力。本实验以胰岛素和胰高血糖素样肽-1 （GLP-1）类似物艾塞那肽为模型药物，设计了两种二肽修饰的SLN。这些药物负载SLN在I型糖尿病小鼠C57BL/6和II型糖尿病小鼠KKAy中均表现出增强的口服生物利用度和降糖作用。与未修饰的SLN相比，二肽修饰的SLN可以通过pept -1介导的内吞作用被肠上皮细胞内化，并且摄取更高。有趣的是，内化后，更多的SLN可以通过淋巴运输途径进入体循环，这突出了将寡肽吸收途径与SLN结合用于口服给药的潜力。

{"title":"Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route","authors":"Fuya Jia , Xiaoxing Fan , Licheng Wu , Yating Wang , Jisen Zhang , Zhou Zhou , Lian Li , Jingyuan Wen , Yuan Huang","doi":"10.1016/j.ajps.2025.101019","DOIUrl":"10.1016/j.ajps.2025.101019","url":null,"abstract":"<div><div>Solid lipid nanoparticles (SLN) could enhance the oral bioavailability of loaded protein and peptide drugs through lymphatic transport. Natural oligopeptides regulate nearly all vital processes and serve as a nitrogen source for nourishment. They are mainly transported by oligopeptide transporter-1 (PepT-1) which are primarily expressed in the intestine with the characteristics of high-capacity and low energy consumption. Our preliminary research discovered the transmembrane transport of SLN could be improved by stimulating the oligopeptide absorption pathway. This implied the potential of combining the advantages of SLN with oligopeptide transporter mediated transportation. Herein, two kinds of dipeptide modified SLN were designed with insulin and glucagon like peptide-1 (GLP-1) analogue exenatide as model drugs. These drugs loaded SLN showed enhanced oral bioavailability and hypoglycemic effect in both type I diabetic C57BL/6 mice and type II diabetic KKAy mice. Compared with un-modified SLN, dipeptide-modified SLN could be internalized by intestinal epithelial cells via PepT-1-mediated endocytosis with higher uptake. Interestingly, after internalization, more SLN could access the systemic circulation via lymphatic transport pathway, highlighting the potential to combine the oligopeptide-absorption route with SLN for oral drug delivery.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 3","pages":"Article 101019"},"PeriodicalIF":10.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144106382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tumor-specific liquid metal nitric oxide nanogenerator for enhanced breast cancer therapy 肿瘤特异性液态金属一氧化氮纳米发生器增强乳腺癌治疗

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-10 DOI: 10.1016/j.ajps.2025.101018

Chen Su , Jianhan Lin , Cong Li , Xinyu Wang , Donghui Pan , Lizhen Wang , Yuping Xu , Chongyang Chen , Kangfan Ji , Jinqiang Wang , Daozhen Chen , Min Yang , Zhen Gu , Junjie Yan

Nitric oxide (NO) modulates several cancer-related physiological processes and has advanced the development of green methods for cancer treatment and integrated platforms for combination or synergistic therapies. Although a nanoengineering strategy has been proposed to overcome deficiencies of NO gas or small NO donor molecules, such as short half-life, lipophilicity, non-selectivity, and poor stability, it remains challenging to prepare NO nanomedicines with simple composition, multiple functions and enhanced therapeutic efficacy. Herein, we build a liquid metal nanodroplet (LMND)-based NO nanogenerator (LMND@HSG) that is stabilized by a bioreducible guanylated hyperbranched poly(amido amine) (HSG) ligand. Mechanically, the tumor microenvironment specifically triggers a cascade process of glutathione elimination, reactive oxygen species (ROS) generation, and NO release. According to actual demand, the ROS and NO concentrations could be readily controlled by tuning the LMND and HSG feed amounts. Along with the intrinsic anticancer property of LMND (ROS-mediated apoptosis and anti-angiogenesis), LMND@HSG administration could further enhance tumor growth suppression compared with LMND and HSG alone. From this study, leveraging LMND for NO gas therapy provides more possibilities for the prospect of LMND-based anticancer nanomedicines.

一氧化氮（NO）调节几种与癌症相关的生理过程，并推动了绿色癌症治疗方法的发展和联合或协同治疗的综合平台。虽然已经提出了一种纳米工程策略来克服NO气体或NO小供体分子半衰期短、亲脂性、非选择性、稳定性差等缺点，但制备成分简单、功能多样、治疗效果增强的NO纳米药物仍然是一个挑战。在此，我们构建了一个基于液态金属纳米液滴（LMND）的NO纳米发生器（LMND@HSG），该发生器由生物可还原的鸟酰化超支化聚氨基胺（HSG）配体稳定。机械地，肿瘤微环境特异性地触发谷胱甘肽消除、活性氧（ROS）生成和NO释放的级联过程。根据实际需要，可以通过调整LMND和HSG的投喂量来控制ROS和NO的浓度。随着LMND固有的抗癌特性（ros介导的细胞凋亡和抗血管生成），与单独使用LMND和HSG相比，LMND@HSG给药可以进一步增强肿瘤生长抑制。从本研究来看，利用LMND进行NO气体治疗为基于LMND的抗癌纳米药物的前景提供了更多的可能性。

{"title":"Tumor-specific liquid metal nitric oxide nanogenerator for enhanced breast cancer therapy","authors":"Chen Su , Jianhan Lin , Cong Li , Xinyu Wang , Donghui Pan , Lizhen Wang , Yuping Xu , Chongyang Chen , Kangfan Ji , Jinqiang Wang , Daozhen Chen , Min Yang , Zhen Gu , Junjie Yan","doi":"10.1016/j.ajps.2025.101018","DOIUrl":"10.1016/j.ajps.2025.101018","url":null,"abstract":"<div><div>Nitric oxide (NO) modulates several cancer-related physiological processes and has advanced the development of green methods for cancer treatment and integrated platforms for combination or synergistic therapies. Although a nanoengineering strategy has been proposed to overcome deficiencies of NO gas or small NO donor molecules, such as short half-life, lipophilicity, non-selectivity, and poor stability, it remains challenging to prepare NO nanomedicines with simple composition, multiple functions and enhanced therapeutic efficacy. Herein, we build a liquid metal nanodroplet (LMND)-based NO nanogenerator (LMND@HSG) that is stabilized by a bioreducible guanylated hyperbranched poly(amido amine) (HSG) ligand. Mechanically, the tumor microenvironment specifically triggers a cascade process of glutathione elimination, reactive oxygen species (ROS) generation, and NO release. According to actual demand, the ROS and NO concentrations could be readily controlled by tuning the LMND and HSG feed amounts. Along with the intrinsic anticancer property of LMND (ROS-mediated apoptosis and anti-angiogenesis), LMND@HSG administration could further enhance tumor growth suppression compared with LMND and HSG alone. From this study, leveraging LMND for NO gas therapy provides more possibilities for the prospect of LMND-based anticancer nanomedicines.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 2","pages":"Article 101018"},"PeriodicalIF":10.7,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Codelivery of apigenin, FdUMP and CD276 antibody synergistic inhibit colorectal cancer by ferroptosis-apoptosis-pyroptosis and CD276 blockade 芹菜素、FdUMP和CD276抗体共递送通过铁凋亡-凋亡-焦亡和CD276阻断协同抑制结直肠癌

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-04 DOI: 10.1016/j.ajps.2025.101016

Weiran Cao , Xue Zhang , Jiaxuan Chen , Lu Sun , Huining He , Fei Yu

Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. In vivo, strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.

线粒体为多种重要运动提供三磷酸腺苷，确保肿瘤细胞增殖。与目前广泛使用的通过诱导DNA复制停止来杀死癌症的方法相比，诱导线粒体损伤导致能量短缺的方法很有前景，因为它可以抑制肿瘤细胞的生物活性，增加细胞内有毒药物的积累，最终使化疗变得敏感，甚至逆转耐药。打破谷胱甘肽（GSH）和活性氧（ROS）含量的平衡分别被证明是破坏线粒体的有效方法。在这里，芹菜素，一种谷胱甘肽外排试剂，和2 ' -脱氧-5-氟吡啶5 ' -单磷酸钠盐（FdUMP），可以诱导毒性ROS通过构建的脂质纳米颗粒（Lip@AF）共同递送。将免疫检查点抑制试剂CD276抗体修饰在Lip@AF表面，具有高反应特异性（标记为αCD276-Lip@AF），增强免疫细胞对肿瘤的识别。结果表明，氧化还原平衡被破坏，线粒体和细胞膜受到严重损伤。此外，还观察到抑制胸腺苷酸合酶功能对DNA/RNA复制的协同抑制作用。最终，通过铁凋亡、细胞凋亡和焦亡等多种机制，显著增强细胞毒性。在体内，αCD276-Lip@AF具有较高的生物安全性，可增强肿瘤生长抑制，为提高化疗敏感性和实现高效化疗免疫治疗提供了新的视角。

{"title":"Codelivery of apigenin, FdUMP and CD276 antibody synergistic inhibit colorectal cancer by ferroptosis-apoptosis-pyroptosis and CD276 blockade","authors":"Weiran Cao , Xue Zhang , Jiaxuan Chen , Lu Sun , Huining He , Fei Yu","doi":"10.1016/j.ajps.2025.101016","DOIUrl":"10.1016/j.ajps.2025.101016","url":null,"abstract":"<div><div>Mitochondria provides adenosine triphosphate for multiple vital movements to ensure tumor cell proliferation. Compared to the broadly used method of inducing DNA replication arrest to kill cancer, inducing mitochondria damage to cause energy shortage is quite promising as it can inhibit tumor cell bioactivities, increase intracellular accumulation of toxic drugs, eventually sensitize chemotherapy and even reverse drug resistance. Breaking the balance of glutathione (GSH) and reactive oxygen species (ROS) contents have been proven efficient in destroying mitochondria respectively. Herein, apigenin, a GSH efflux reagent, and 2′-deoxy-5-fluorouridine 5′-monophosphate sodium salt (FdUMP) that could induce toxic ROS were co-delivered by constructed lipid nanoparticles, noted as Lip@AF. An immune-checkpoint inhibition reagent CD276 antibody was modified onto the surface of Lip@AF with high reaction specificity (noted as αCD276-Lip@AF) to enhance the recognition of immune cells to tumor. Results showed that the redox balance was destroyed, leading to severe injury to mitochondria and cell membrane. Furthermore, synergistic DNA/RNA replication inhibition caused by inhibiting the function of thymidylate synthase were observed. Eventually, significantly enhanced cytotoxicity was achieved by combining multiple mechanisms including ferroptosis, apoptosis and pyroptosis. <em>In vivo</em>, strengthen tumor growth inhibition was achieved by αCD276-Lip@AF with high biosafety, providing new sights in enhancing chemotherapy sensitiveness and achieving high-performance chemo-immunotherapy.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 2","pages":"Article 101016"},"PeriodicalIF":10.7,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Single-dose oral administration of drug-loaded magnetic 3D-printed microbullets for eradication of Helicobacter pylori 单剂量口服载药磁性3d打印微弹根除幽门螺杆菌

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2025-01-03 DOI: 10.1016/j.ajps.2024.101013

Hua Xie , Dongdong Liu , Jintao Shen , Wenrui Yan , Meng Wei , Yingbao Sun , Yubao Fang , Bochuan Yuan , Pei Deng , Yiguang Jin

Infections of Helicobacter pylori (H. pylori) affect 42.1 % of the Chinese population and 43.1 % of the world population. H. pylori inhabits the mucous sublayer at the pylorus, leading to gastric ulcers, gastritis, and even cancer. Oral antibiotics are usually used to treat H. pylori infections, whereas traditional quadruple therapy has side effects including headaches, nausea, diarrhea, intestinal dysbacteriosis, antibiotic resistance, and repeat infections. Here, a drug-loaded magnetic microbullet was designed to realize long-term retention in the stomach for one-shot treatment for H. pylori infections. It comprises a hollow cylinder wherein eight microneedles homogenously distribute at the top and several round pores located at the bottom. It was three-dimensional (3D)-printed by stereolithography. A clarithromycin (CAM) ground mixture (CGM) was prepared to improve solubility. Enough CGM powders were filled into the cylinder, covered by a small round magnet, and sealed to form a CAM-loaded magnetic microbullet (CMMB). CAM continually released from CMMBs for >24 h. With outside magnetic guidance, an oral CMMB targeted the pylorus site and the microneedles immediately headed into the mucosa followed by long-term local drug release. The in vitro and in vivo safety of CMMBs was confirmed, where their swelling rates were low, and the oral CMMB was finally completely evacuated. An oral CMMB was administered to H. pylori-infected mice and maintained in the stomach for 36 h with magnetic guidance, and the successful eradication of H. pylori was confirmed after single-dose administration. Oral CMMBs are a convenient medication for the eradication of H. pylori.

幽门螺杆菌（h.p ylori）感染影响了42.1% %的中国人口和43.1% %的世界人口。幽门螺旋杆菌寄生于幽门的粘膜下层，可导致胃溃疡、胃炎甚至癌症。口服抗生素通常用于治疗幽门螺杆菌感染，而传统的四联疗法有副作用，包括头痛、恶心、腹泻、肠道菌群失调、抗生素耐药性和重复感染。在这里，一种装载药物的磁性微子弹被设计成在胃中长期保留，用于一次治疗幽门螺杆菌感染。它包括一个中空圆柱体，其中八个微针均匀分布在顶部，几个圆形孔位于底部。它是用立体光刻技术三维打印的。制备了一种克拉霉素（CAM）研磨混合物（CGM），以提高其溶解度。将足够的CGM粉末填充到圆柱体中，用小圆形磁铁覆盖，并密封形成装载cam的磁微弹（CMMB）。CAM从CMMB中持续释放24小时。在外部磁引导下，口服CMMB靶向幽门部位，微针立即进入粘膜，随后长期局部释放药物。证实了CMMB的体外和体内安全性，其肿胀率低，口服CMMB最终完全排出。将CMMB口服给药幽门螺杆菌感染小鼠，并在磁场引导下在胃中维持36 h，单次给药后证实幽门螺杆菌成功根除。口服CMMBs是一种方便的根除幽门螺杆菌的药物。

{"title":"Single-dose oral administration of drug-loaded magnetic 3D-printed microbullets for eradication of Helicobacter pylori","authors":"Hua Xie , Dongdong Liu , Jintao Shen , Wenrui Yan , Meng Wei , Yingbao Sun , Yubao Fang , Bochuan Yuan , Pei Deng , Yiguang Jin","doi":"10.1016/j.ajps.2024.101013","DOIUrl":"10.1016/j.ajps.2024.101013","url":null,"abstract":"<div><div>Infections of <em>Helicobacter pylori</em> (<em>H. pylori</em>) affect 42.1 % of the Chinese population and 43.1 % of the world population. <em>H. pylori</em> inhabits the mucous sublayer at the pylorus, leading to gastric ulcers, gastritis, and even cancer. Oral antibiotics are usually used to treat <em>H. pylori</em> infections, whereas traditional quadruple therapy has side effects including headaches, nausea, diarrhea, intestinal dysbacteriosis, antibiotic resistance, and repeat infections. Here, a drug-loaded magnetic microbullet was designed to realize long-term retention in the stomach for one-shot treatment for <em>H. pylori</em> infections. It comprises a hollow cylinder wherein eight microneedles homogenously distribute at the top and several round pores located at the bottom. It was three-dimensional (3D)-printed by stereolithography. A clarithromycin (CAM) ground mixture (CGM) was prepared to improve solubility. Enough CGM powders were filled into the cylinder, covered by a small round magnet, and sealed to form a CAM-loaded magnetic microbullet (CMMB). CAM continually released from CMMBs for >24 h. With outside magnetic guidance, an oral CMMB targeted the pylorus site and the microneedles immediately headed into the mucosa followed by long-term local drug release. The <em>in vitro</em> and <em>in vivo</em> safety of CMMBs was confirmed, where their swelling rates were low, and the oral CMMB was finally completely evacuated. An oral CMMB was administered to <em>H. pylori</em>-infected mice and maintained in the stomach for 36 h with magnetic guidance, and the successful eradication of <em>H. pylori</em> was confirmed after single-dose administration. Oral CMMBs are a convenient medication for the eradication of <em>H. pylori</em>.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 2","pages":"Article 101013"},"PeriodicalIF":10.7,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143680953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

All-stage targeted nanodiscs for glioma treatment by inducing cuproptosis and apoptosis of cancer cells and cancer stem cells 靶向纳米片通过诱导肿瘤细胞和肿瘤干细胞的铜增生和凋亡来治疗胶质瘤

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-12-17 DOI: 10.1016/j.ajps.2024.101010

Yuan Ding , Ruohan Chen , Jianfen Zhou , Yanning Bao , Nana Meng , Xudong Zheng , Shengmin Yang , Jiasheng Lu , Zhixuan Jiang , Yu Liu , Cao Xie , Linwei Lu , Weiyue Lu

There remain several intractable challenges for chemotherapy in glioma treatment, including the blood-brain barrier (BBB), blood-brain tumor barrier (BBTB), and tumor heterogeneity caused by cancer stem cells (CSCs), which are resistant to conventional chemotherapy. Here, we established a nano strategy to kill glioma cells and CSCs, combining carfilzomib and bis(diethyldithiocarbamate)copper. The synergistic drug combination disturbed cell protein metabolism at different stages and induced apoptosis and cuproptosis. The Y-shaped targeting ligand pHA-VAP-modified nanodiscs were designed to help the chemotherapeutic agents cross the BBB/BBTB and finally accumulate in tumor site. This all-stage targeting and all-stage treatment nanomedicine significantly prolonged the survival in glioma-bearing mice and might inspire the rational design of advanced drug delivery platforms.

化疗在胶质瘤治疗中仍然存在一些棘手的挑战，包括血脑屏障（BBB）、血脑肿瘤屏障（BBTB）和肿瘤干细胞（CSCs）引起的肿瘤异质性，这些对传统化疗具有耐药性。在这里，我们建立了一种纳米策略来杀死胶质瘤细胞和CSCs，结合卡非佐米和双（二乙基二硫代氨基甲酸盐）铜。协同用药干扰不同阶段细胞蛋白代谢，诱导细胞凋亡和铜坏死。设计了y形靶向配体pha - vap修饰的纳米圆盘，帮助化疗药物穿过血脑屏障/血脑屏障，最终在肿瘤部位积累。这种全阶段靶向、全阶段治疗的纳米药物显著延长了胶质瘤小鼠的生存期，并可能启发先进给药平台的合理设计。

引用次数: 0

Endosomal disruption by co-encapsulating gentamicin in lipid nanoparticles for efficient siRNA delivery and cancer therapy 通过在脂质纳米颗粒中共包封庆大霉素以实现高效siRNA递送和癌症治疗的内体破坏

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-12-16 DOI: 10.1016/j.ajps.2024.101011

Ning Yang , Qi Sun , Yaoqi Wang , Dong Mei , Xiaoling Wang , Jie Zhang , Danni Liu , Ran Huo , Yang Tian , Yan Su , Shuang Zhang , Chunying Cui

Efficient siRNA delivery is highly desirable for disease treatment. However, the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes. Herein, we report a strategy using small-molecule drugs to enhance siRNA endo‐lysosomal release,addressing this challenge. We encapsulated gentamicin(GM) into the marketed Onpattro® formulation to establish LNP-siRNA/GM nanoparticles that promote siRNA endo‐lysosomal escape through endosomal disruption, mechanistically exhibiting unique functionality and synergistic effects of LNP-siRNA/GM to improve cancer therapy. Besides, GM induced reactive oxygen species (ROS) and phospholipids accumulation in endo‐lysosomes, as well as the physical characteristics of lipid nanoparticles (LNPs) were preserved. We also revealed that GM causes endo‐lysosomal swelling and disrupts the endosomal membrane to enable siRNA release, as confirmed by Galectin 3 recruitment and acridine orange release. This approach achieved ∼81% mRNA-EGFR silencing, which is more than LNP-siEGFR (∼56.23%) by enhancing siRNA endo‐lysosomal escape efficiency. Meanwhile, LNP-siEGFR/GM exhibited significant biological activities in HepG2 cells, driven by the synergistic effects of siEGFR and GM with the VEGF and CXCL12 downregulation of, and ROS and phospholipids upregulation. Furthermore, tumor growth was notably suppressed after intravenous injection of LNP-siEGFR/GM in tumor-bearing nude mice. The combination of EGFR-siRNA and GM could also greatly inhibit angiogenesis, be antiproliferative, and induce tumor cells apoptosis. Therefore, this GM and siRNA co-delivery system would provide an efficient strategy for siRNA endosomal escape, significantly improving knockdown in various LNPs based siRNA delivery systems and efficiently enhancing cancer therapy.

高效的siRNA递送对于疾病治疗是非常理想的。然而，传统纳米颗粒的应用受到无法从内溶酶体中逃逸的限制。在此，我们报告了一种使用小分子药物来增强siRNA内溶酶体释放的策略，以解决这一挑战。我们将庆大霉素（GM）封装到已上市的Onpattro®制剂中，建立LNP-siRNA/GM纳米颗粒，通过内体破坏促进siRNA内溶酶体逃逸，在机制上表现出LNP-siRNA/GM的独特功能和协同效应，以改善癌症治疗。此外，转基因诱导的活性氧（ROS）和磷脂在内溶酶体中积累，以及脂质纳米颗粒（LNPs）的物理特性被保留。我们还发现，转基因引起内溶酶体肿胀，破坏内体膜，使siRNA释放，正如半乳糖凝集素3募集和吖啶橙释放所证实的那样。该方法通过提高siRNA内溶酶体逃逸效率，实现了约81%的mRNA-EGFR沉默，高于LNP-siEGFR（约56.23%）。同时，LNP-siEGFR/GM在HepG2细胞中表现出显著的生物活性，这是由于siEGFR和GM与VEGF、CXCL12下调、ROS和磷脂上调协同作用所致。此外，静脉注射LNP-siEGFR/GM后，荷瘤裸鼠的肿瘤生长明显受到抑制。EGFR-siRNA与GM联合使用还能显著抑制血管生成、抑制肿瘤细胞增殖、诱导肿瘤细胞凋亡。因此，这种GM和siRNA共递送系统将为siRNA内体逃逸提供一种有效的策略，显著改善各种基于LNPs的siRNA递送系统的敲低，并有效地增强癌症治疗。

{"title":"Endosomal disruption by co-encapsulating gentamicin in lipid nanoparticles for efficient siRNA delivery and cancer therapy","authors":"Ning Yang , Qi Sun , Yaoqi Wang , Dong Mei , Xiaoling Wang , Jie Zhang , Danni Liu , Ran Huo , Yang Tian , Yan Su , Shuang Zhang , Chunying Cui","doi":"10.1016/j.ajps.2024.101011","DOIUrl":"10.1016/j.ajps.2024.101011","url":null,"abstract":"<div><div>Efficient siRNA delivery is highly desirable for disease treatment. However, the application of conventional nanoparticles is limited by the inability to escape from endo-lysosomes. Herein, we report a strategy using small-molecule drugs to enhance siRNA endo‐lysosomal release,addressing this challenge. We encapsulated gentamicin(GM) into the marketed Onpattro® formulation to establish LNP-siRNA/GM nanoparticles that promote siRNA endo‐lysosomal escape through endosomal disruption, mechanistically exhibiting unique functionality and synergistic effects of LNP-siRNA/GM to improve cancer therapy. Besides, GM induced reactive oxygen species (ROS) and phospholipids accumulation in endo‐lysosomes, as well as the physical characteristics of lipid nanoparticles (LNPs) were preserved. We also revealed that GM causes endo‐lysosomal swelling and disrupts the endosomal membrane to enable siRNA release, as confirmed by Galectin 3 recruitment and acridine orange release. This approach achieved ∼81% mRNA-EGFR silencing, which is more than LNP-siEGFR (∼56.23%) by enhancing siRNA endo‐lysosomal escape efficiency. Meanwhile, LNP-siEGFR/GM exhibited significant biological activities in HepG2 cells, driven by the synergistic effects of siEGFR and GM with the VEGF and CXCL12 downregulation of, and ROS and phospholipids upregulation. Furthermore, tumor growth was notably suppressed after intravenous injection of LNP-siEGFR/GM in tumor-bearing nude mice. The combination of EGFR-siRNA and GM could also greatly inhibit angiogenesis, be antiproliferative, and induce tumor cells apoptosis. Therefore, this GM and siRNA co-delivery system would provide an efficient strategy for siRNA endosomal escape, significantly improving knockdown in various LNPs based siRNA delivery systems and efficiently enhancing cancer therapy.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 3","pages":"Article 101011"},"PeriodicalIF":10.7,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144069899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Porous PLGA microspheres for the inhalation delivery of icariin and miR-23b in the treatment of metastatic lung cancer 多孔PLGA微球用于吸入递送淫羊藿苷和miR-23b治疗转移性肺癌

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-12-11 DOI: 10.1016/j.ajps.2024.101008

Boyu Xiong , Xinxin Shao , Guangxu Fang , Mengmeng Dong , Haobo Han , Quanshun Li

Herein, porous poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared to load icariin and miR-23b for the treatment of metastatic lung cancer. The microspheres exhibited desirable aerodynamic diameter, high drug loading and encapsulation efficiency, as well as a favorable drug release profile, which was beneficial for the deposition and exposure of drugs in the lung tissues. The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase, and meanwhile inhibited the migration and invasion of cancer cells. More importantly, the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the in situ apoptosis of tumor cells and suppress metastasis, using mice bearing melanoma-metastatic lung cancer as a model. Furthermore, inhalation of the microspheres showed favorable biocompatibility, barely causing tissue damage. Overall, porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.

本文制备多孔聚乳酸-羟基乙酸（PLGA）微球，负载淫羊羊苷和miR-23b，用于治疗转移性肺癌。该微球具有良好的空气动力学直径、较高的载药量和包封效率，以及良好的药物释放特性，有利于药物在肺组织中的沉积和暴露。微球释放液通过诱导细胞凋亡和阻滞细胞周期G1期，表现出良好的抗增殖作用，同时抑制癌细胞的迁移和侵袭。更重要的是，以黑色素瘤-转移性肺癌小鼠为模型，该微球可被有效吸入并在肺组织中积累，从而触发肿瘤细胞的原位凋亡，抑制转移。此外，吸入微球具有良好的生物相容性，几乎不会造成组织损伤。总之，多孔PLGA微球为药物和基因的可吸入共递送提供了一个很有前景的平台，从而在肺癌和其他肺部疾病中获得理想的治疗效果。

{"title":"Porous PLGA microspheres for the inhalation delivery of icariin and miR-23b in the treatment of metastatic lung cancer","authors":"Boyu Xiong , Xinxin Shao , Guangxu Fang , Mengmeng Dong , Haobo Han , Quanshun Li","doi":"10.1016/j.ajps.2024.101008","DOIUrl":"10.1016/j.ajps.2024.101008","url":null,"abstract":"<div><div>Herein, porous poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared to load icariin and miR-23b for the treatment of metastatic lung cancer. The microspheres exhibited desirable aerodynamic diameter, high drug loading and encapsulation efficiency, as well as a favorable drug release profile, which was beneficial for the deposition and exposure of drugs in the lung tissues. The release solution from microspheres exhibited a favorable anti-proliferative effect by inducting cell apoptosis and arresting the cell cycle at G1 phase, and meanwhile inhibited the migration and invasion of cancer cells. More importantly, the microspheres could be effectively inhaled and accumulated in the lung tissues to trigger the <em>in situ</em> apoptosis of tumor cells and suppress metastasis, using mice bearing melanoma-metastatic lung cancer as a model. Furthermore, inhalation of the microspheres showed favorable biocompatibility, barely causing tissue damage. Overall, porous PLGA microspheres provide a promising platform for the inhalable co-delivery of drugs and genes to obtain ideal therapeutic efficacy in lung cancer and other pulmonary diseases.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"20 2","pages":"Article 101008"},"PeriodicalIF":10.7,"publicationDate":"2024-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

CaCO3-encircled hollow CuS nanovehicles to suppress cervical cancer through enhanced calcium overload-triggered mitochondria damage 环绕 CaCO3 的中空 CuS 纳米颗粒通过增强钙超载触发的线粒体损伤抑制宫颈癌

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-11-02 DOI: 10.1016/j.ajps.2024.100989

Pengfei Wang , Xichen Sun , Liuyan Tang , Ningning Li , Qing Wang , Bicheng Gan , Yuezhou Zhang

Cervical cancer stands is a formidable malignancy that poses a significant threat to women's health. Calcium overload, a minimally invasive tumor treatment, aims to accumulate an excessive concentration of Ca²⁺ within mitochondria, triggering apoptosis. Copper sulfide (CuS) represents a photothermal mediator for tumor hyperthermia. However, relying solely on thermotherapy often proves insufficient in controlling tumor growth. Curcumin (CUR), an herbal compound with anti-cancer properties, inhibits the efflux of exogenous Ca²⁺ while promoting its excretion from the endoplasmic reticulum into the cytoplasm. To harness these therapeutic modalities, we have developed a nanoplatform that incorporates hollow CuS nanoparticles (NPs) adorned with multiple CaCO₃ particles and internally loaded with CUR. This nanocomposite exhibits high uptake and easy escape from lysosomes, along with the degradation of surrounding CaCO₃, provoking the generation of abundant exogenous Ca²⁺ in situ, ultimately damaging the mitochondria of diseased cells. Impressively, under laser excitation, the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO₃, synergistically enhancing the antitumor effect through photothermal therapy. Additionally, fluorescence imaging reveals the distribution of these nanovehicles in vivo, indicating their effective accumulation at the tumor site. This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer, achieved through cascade enhancement of calcium overload-based dual therapy.

宫颈癌是一种严重威胁妇女健康的恶性肿瘤。钙超载是一种微创肿瘤治疗方法，旨在使线粒体内积聚过量的 Ca2+，从而引发细胞凋亡。硫化铜（CuS）是肿瘤热疗的光热介质。然而，仅靠热疗往往不足以控制肿瘤生长。姜黄素（CUR）是一种具有抗癌特性的草药化合物，它能抑制外源性 Ca2+ 的外流，同时促进其从内质网排泄到细胞质中。为了利用这些治疗模式，我们开发了一种纳米平台，其中包含中空的 CuS 纳米颗粒（NPs），上面缀有多个 CaCO3 颗粒，内部装有 CUR。这种纳米复合材料具有高吸收率，易于从溶酶体中逸出，同时周围的 CaCO3 也会降解，从而在原位产生大量外源 Ca2+，最终破坏病变细胞的线粒体。令人印象深刻的是，在激光激发下，CuS NPs 表现出光热效应，加速了 CaCO3 的降解，通过光热疗法协同增强了抗肿瘤效果。此外，荧光成像显示了这些纳米颗粒在体内的分布，表明它们在肿瘤部位的有效聚集。这种纳米平台通过级联增强基于钙超载的双重疗法，在小鼠宫颈癌模型中显示出肿瘤靶向和有效治疗的良好效果。

{"title":"CaCO3-encircled hollow CuS nanovehicles to suppress cervical cancer through enhanced calcium overload-triggered mitochondria damage","authors":"Pengfei Wang , Xichen Sun , Liuyan Tang , Ningning Li , Qing Wang , Bicheng Gan , Yuezhou Zhang","doi":"10.1016/j.ajps.2024.100989","DOIUrl":"10.1016/j.ajps.2024.100989","url":null,"abstract":"<div><div>Cervical cancer stands is a formidable malignancy that poses a significant threat to women's health. Calcium overload, a minimally invasive tumor treatment, aims to accumulate an excessive concentration of Ca<sup>2+</sup> within mitochondria, triggering apoptosis. Copper sulfide (CuS) represents a photothermal mediator for tumor hyperthermia. However, relying solely on thermotherapy often proves insufficient in controlling tumor growth. Curcumin (CUR), an herbal compound with anti-cancer properties, inhibits the efflux of exogenous Ca<sup>2+</sup> while promoting its excretion from the endoplasmic reticulum into the cytoplasm. To harness these therapeutic modalities, we have developed a nanoplatform that incorporates hollow CuS nanoparticles (NPs) adorned with multiple CaCO<sub>3</sub> particles and internally loaded with CUR. This nanocomposite exhibits high uptake and easy escape from lysosomes, along with the degradation of surrounding CaCO<sub>3</sub>, provoking the generation of abundant exogenous Ca<sup>2+</sup> <em>in situ</em>, ultimately damaging the mitochondria of diseased cells. Impressively, under laser excitation, the CuS NPs demonstrate a photothermal effect that accelerates the degradation of CaCO<sub>3</sub>, synergistically enhancing the antitumor effect through photothermal therapy. Additionally, fluorescence imaging reveals the distribution of these nanovehicles <em>in vivo</em>, indicating their effective accumulation at the tumor site. This nanoplatform shows promising outcomes for tumor-targeting and the effective treatment in a murine model of cervical cancer, achieved through cascade enhancement of calcium overload-based dual therapy.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"19 6","pages":"Article 100989"},"PeriodicalIF":10.7,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142705971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors 推动小分子酪氨酸激酶抑制剂纳米制剂发展的生物制药和药代动力学特性

IF 10.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Asian Journal of Pharmaceutical Sciences

Pub Date : 2024-10-26 DOI: 10.1016/j.ajps.2024.100980

Soumyadip Mukherjee , Vedant Joshi , Kolimi Prashanth Reddy, Nidhi Singh, Priyanka Das, Pallab Datta

Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKIs), significant impact has been made in cancer chemotherapeutics. However, some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient variations in plasma concentration-time profiles. Thus, therapeutic drug monitoring, dose adjustments and precision medicine are being contemplated by clinicians. Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release, overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes. In this context, the present review comprehensively tabulates and critically analyzes all the relevant properties (T_1/2, solubility, pK_a, therapeutic index, IC₅₀, metabolism etc.) of the approved smTKIs. A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs, with a focus on strategies to enhance their pharmacokinetic profile, tumor targeting ability, and therapeutic efficacy. Various nanocarrier platforms, have been discussed, highlighting their unique features and potential applications in cancer therapy. Nanoformulations have been shown to improve area under the curve and peak plasma concentration, and reduce dosing frequency for several smTKIs in animal models. It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future. There, the review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.

小分子酪氨酸激酶抑制剂（smTKIs）的发现对癌症化疗产生了重大影响。然而，由于其生物制药和/或药代动力学特性较差，其中一些药物仍然存在脱靶毒性和疗效不理想的问题。几乎所有这些分子的血浆浓度-时间曲线在患者之间和患者内部都有显著差异。因此，临床医生正在考虑进行治疗药物监测、剂量调整和精准医疗。复杂制剂或以纳米制剂为基础的给药系统为提供药物封装或时空释放控制、克服生物制药和药代动力学限制以及改善治疗效果提供了前景广阔的方法。在此背景下，本综述对已批准的 smTKIs 的所有相关特性（T1/2、溶解度、pKa、治疗指数、IC50、代谢等）进行了全面的列表和批判性分析。报告详细评估了smTKIs复方制剂方面的进展，重点介绍了增强其药代动力学特征、肿瘤靶向能力和疗效的策略。文章讨论了各种纳米载体平台，强调了它们在癌症治疗中的独特功能和潜在应用。在动物模型中，纳米制剂已被证明可提高多种 smTKIs 的曲线下面积和血浆峰值浓度，并减少给药次数。可以推断，在不久的将来，人们将在开发 smTKIs 复杂制剂方面做出广泛努力。综述最后提出了开发 smTKIs 的主要建议，以促进其早日转化为临床药物。

{"title":"Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors","authors":"Soumyadip Mukherjee , Vedant Joshi , Kolimi Prashanth Reddy, Nidhi Singh, Priyanka Das, Pallab Datta","doi":"10.1016/j.ajps.2024.100980","DOIUrl":"10.1016/j.ajps.2024.100980","url":null,"abstract":"<div><div>Buoyed by the discovery of small-molecule tyrosine kinase inhibitors (smTKIs), significant impact has been made in cancer chemotherapeutics. However, some of these agents still encounter off-target toxicities and suboptimal efficacies due to their inferior biopharmaceutical and/or pharmacokinetic properties. Almost all of these molecules exhibit significant inter- and intra-patient variations in plasma concentration-time profiles. Thus, therapeutic drug monitoring, dose adjustments and precision medicine are being contemplated by clinicians. Complex formulations or nanoformulation-based drug delivery systems offer promising approaches to provide drug encapsulation or spatiotemporal control over the release, overcoming the biopharmaceutical and pharmacokinetic limitations and improving the therapeutic outcomes. In this context, the present review comprehensively tabulates and critically analyzes all the relevant properties (T<sub>1/2</sub>, solubility, pK<sub>a</sub>, therapeutic index, IC<sub>50</sub>, metabolism etc.) of the approved smTKIs. A detailed appraisal is conducted on the advancements made in complex formulations of smTKIs, with a focus on strategies to enhance their pharmacokinetic profile, tumor targeting ability, and therapeutic efficacy. Various nanocarrier platforms, have been discussed, highlighting their unique features and potential applications in cancer therapy. Nanoformulations have been shown to improve area under the curve and peak plasma concentration, and reduce dosing frequency for several smTKIs in animal models. It is inferred that extensive efforts will be made in developing complex formulations of smTKIs in near future. There, the review concludes with key recommendations for the developing of smTKIs to facilitate early clinical translation.</div></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"19 6","pages":"Article 100980"},"PeriodicalIF":10.7,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142706558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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