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Anti-GPC3 antibody and cell-penetrating peptide CPP44 dual-ligand modified liposomes for targeted delivery of arsenic trioxide in the treatment of hepatocellular carcinoma.
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-15 DOI: 10.1080/1061186X.2025.2461104
Congcong Lin, Jiamin Sun, Yun Yang, Xinyao Pan, Yifan Sun, Bin Sun, Chunli Gan

Arsenic trioxide (ATO), the active ingredient in Chinese arsenic, effectively inhibits hepatocellular carcinoma (HCC) cell growth, but its clinical application is limited by the lack of a targeted delivery system. Phosphatidylinositol proteoglycan 3 (GPC3) is specifically expressed in HCC, and CPP44 is a cell-penetrating peptide that targets HCC cells. Here, we developed a liposome incorporating ATO with dual surface modifications of anti-GPC3 antibody and CPP44. The system was firstly enriched and localised at the liver tumour site through passive targeting by EPR and active targeting by specific binding of anti-GPC3 antibody to GPC3 protein. CPP44 then facilitated ATO penetration into HCC cells. Specifically, we first employed computational modelling to demonstrate that the covalently-coupled antibody maintained its binding ability to the GPC3 antigen. Subsequent experimental assays revealed that Dl-ATO-Lp exhibited higher cell uptake rate and stronger tumour cell killing effect. In an HCC mouse model, Dl-ATO-Lp achieved effective tumour targeting, with a tumour inhibition rate of 63.43%. This dual-ligand liposome system enhances the targeted delivery and therapeutic efficacy of ATO, offering a promising direction for solid tumour therapy and advancing the clinical application of ATO.

{"title":"Anti-GPC3 antibody and cell-penetrating peptide CPP44 dual-ligand modified liposomes for targeted delivery of arsenic trioxide in the treatment of hepatocellular carcinoma.","authors":"Congcong Lin, Jiamin Sun, Yun Yang, Xinyao Pan, Yifan Sun, Bin Sun, Chunli Gan","doi":"10.1080/1061186X.2025.2461104","DOIUrl":"10.1080/1061186X.2025.2461104","url":null,"abstract":"<p><p>Arsenic trioxide (ATO), the active ingredient in Chinese arsenic, effectively inhibits hepatocellular carcinoma (HCC) cell growth, but its clinical application is limited by the lack of a targeted delivery system. Phosphatidylinositol proteoglycan 3 (GPC3) is specifically expressed in HCC, and CPP44 is a cell-penetrating peptide that targets HCC cells. Here, we developed a liposome incorporating ATO with dual surface modifications of anti-GPC3 antibody and CPP44. The system was firstly enriched and localised at the liver tumour site through passive targeting by EPR and active targeting by specific binding of anti-GPC3 antibody to GPC3 protein. CPP44 then facilitated ATO penetration into HCC cells. Specifically, we first employed computational modelling to demonstrate that the covalently-coupled antibody maintained its binding ability to the GPC3 antigen. Subsequent experimental assays revealed that Dl-ATO-Lp exhibited higher cell uptake rate and stronger tumour cell killing effect. In an HCC mouse model, Dl-ATO-Lp achieved effective tumour targeting, with a tumour inhibition rate of 63.43%. This dual-ligand liposome system enhances the targeted delivery and therapeutic efficacy of ATO, offering a promising direction for solid tumour therapy and advancing the clinical application of ATO.</p>","PeriodicalId":15573,"journal":{"name":"Journal of Drug Targeting","volume":" ","pages":"1-10"},"PeriodicalIF":4.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Molecular and therapeutic insight into ER stress signalling in NSCLC.
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-14 DOI: 10.1080/1061186X.2025.2461105
Aastha Jadhav, Arjun Menon, Kush Gupta, Neeru Singh

Endoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analysed the contribution of the three major ER stress pathways-IRE1, ATF6, and PERK-in lung cancer pathogenesis via modulation of tumour microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.

{"title":"Molecular and therapeutic insight into ER stress signalling in NSCLC.","authors":"Aastha Jadhav, Arjun Menon, Kush Gupta, Neeru Singh","doi":"10.1080/1061186X.2025.2461105","DOIUrl":"10.1080/1061186X.2025.2461105","url":null,"abstract":"<p><p>Endoplasmic Reticulum (ER) stress is intricately involved in cancer development, progression and response to chemotherapy. ER stress related genes might play an important role in predicting the prognosis in lung adenocarcinoma patients and may be manipulated to improve the treatment outcome and overall survival rate. In this review, we analysed the contribution of the three major ER stress pathways-IRE1, ATF6, and PERK-in lung cancer pathogenesis <i>via</i> modulation of tumour microenvironment (TME) and processes as metastasis, angiogenesis, apoptosis and N-glycosylation. Furthermore, we discuss the regulatory role of microRNAs in fine-tuning ER stress pathways in Non-Small Cell Lung Cancer (NSCLC). Our review also highlights various promising strategies to overcome chemoresistance by targeting ER stress pathways, offering new therapeutic opportunities.</p>","PeriodicalId":15573,"journal":{"name":"Journal of Drug Targeting","volume":" ","pages":"1-10"},"PeriodicalIF":4.3,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Pseudo-ternary phase diagram based PEGylated nano-dispersion of linezolid to promote wound regeneration: an in vitro and in vivo evaluation.
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-12 DOI: 10.1080/1061186X.2025.2461093
Bani Kumar Jana, Ishita Singha, Nusalu Puro, Rinku Baishya, Rajat Subhra Dutta, Mohini Singh, Bhaskar Mazumder

Open wounds are prone to bacterial infiltration mostly resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), which affects healing of open wounds. Topical linezolid nano-dispersion using essential oils as nanoemulgel can increase solubility of drug and bypass side-effects like GI-irritation of oral administration. Pseudo-ternary phase diagram was built to optimise nanoemulsion. Surfactant/co-surfactant mixture (3:1), deionised water and Oilmix (4:1) with drug were vortexed and then ultrasonicated. 1% carbopol gel of optimised nanoemulsion was prepared and characterised, exposed to antimicrobial study, cytocompatibility study using HEK293 cell-line, and in vivo wound healing study using rat excision model. Histological study was performed to confirm growth of stratum corneum. Optimised formulation has particle size (244.6 ± 178.66 nm), polydispersity index (25%), entrapment efficiency (92.3 ± 3.38%) and in vitro drug release (87.58 ± 4.16%) best fitted in Korsmeyer-Peppas kinetics model. Nanoemulgel F6 (0.2%w/w) was found with viscosity of 5345 ± 6 cP constituting a very excellent antimicrobial effect against MRSA. HEK293 cells had shown good cytocompatibility with formulation. The wound contraction rate was 99.66 ± 0.57% at day 15 on daily application of nanoemulgel and stratum corneum was almost fully regenerated. The developed nanoemulgel has potential antimicrobial efficacy and can promote wound healing.

{"title":"Pseudo-ternary phase diagram based PEGylated nano-dispersion of linezolid to promote wound regeneration: an <i>in vitro</i> and <i>in vivo</i> evaluation.","authors":"Bani Kumar Jana, Ishita Singha, Nusalu Puro, Rinku Baishya, Rajat Subhra Dutta, Mohini Singh, Bhaskar Mazumder","doi":"10.1080/1061186X.2025.2461093","DOIUrl":"10.1080/1061186X.2025.2461093","url":null,"abstract":"<p><p>Open wounds are prone to bacterial infiltration mostly resistant strains like methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), which affects healing of open wounds. Topical linezolid nano-dispersion using essential oils as nanoemulgel can increase solubility of drug and bypass side-effects like GI-irritation of oral administration. Pseudo-ternary phase diagram was built to optimise nanoemulsion. Surfactant/co-surfactant mixture (3:1), deionised water and Oil<sub>mix</sub> (4:1) with drug were vortexed and then ultrasonicated. 1% carbopol gel of optimised nanoemulsion was prepared and characterised, exposed to antimicrobial study, cytocompatibility study using HEK293 cell-line, and <i>in vivo</i> wound healing study using rat excision model. Histological study was performed to confirm growth of stratum corneum. Optimised formulation has particle size (244.6 ± 178.66 nm), polydispersity index (25%), entrapment efficiency (92.3 ± 3.38%) and <i>in vitro</i> drug release (87.58 ± 4.16%) best fitted in Korsmeyer-Peppas kinetics model. Nanoemulgel F6 (0.2%w/w) was found with viscosity of 5345 ± 6 cP constituting a very excellent antimicrobial effect against MRSA. HEK293 cells had shown good cytocompatibility with formulation. The wound contraction rate was 99.66 ± 0.57% at day 15 on daily application of nanoemulgel and stratum corneum was almost fully regenerated. The developed nanoemulgel has potential antimicrobial efficacy and can promote wound healing.</p>","PeriodicalId":15573,"journal":{"name":"Journal of Drug Targeting","volume":" ","pages":"1-15"},"PeriodicalIF":4.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
The role of green synthesis metal and metal oxide nanoparticles in oral cancer therapy: a review.
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-08 DOI: 10.1080/1061186X.2025.2461091
Songlin Zhou, Yutao Qin, Anwen Lei, Hai Liu, Yi Sun, Jue Zhang, Chao Deng, Yu Chen

There are 275,000 new cases of oral cancer (OC) per year, making it the sixth most common cancer in the world. Severe adverse effects, including loss of function, deformity, and systemic toxicity, are familiar with traditional therapies such as radiation, chemotherapy, and surgery; due to their unique properties, nanoparticles (NPs) have emerged as a superior alternative over chemo/radiotherapy and surgery due to their targeting capability, bioavailability, compatibility, and high solubility. Due to their unique properties, metallic NPs have garnered significant attention in OC control. In addition to the fact that metal NPs may be harmful to human cells, the reactive chemicals used to make them pose the same risk, which limits their use in medicine. Green synthesis (GS) is a novel strategy that uses biological materials like yeast, bacteria, fungi, and plant extracts. Compared to more traditional chemical synthesis processes, these are more environmentally benign and manageable for living organisms. This article summarises the GS of NPs made of metals and metal oxides and their anticancer effects on OC. The method's potential benefits and drawbacks in advancing metallic NPs' GS and shaping OC therapy's future were also discussed.

{"title":"The role of green synthesis metal and metal oxide nanoparticles in oral cancer therapy: a review.","authors":"Songlin Zhou, Yutao Qin, Anwen Lei, Hai Liu, Yi Sun, Jue Zhang, Chao Deng, Yu Chen","doi":"10.1080/1061186X.2025.2461091","DOIUrl":"10.1080/1061186X.2025.2461091","url":null,"abstract":"<p><p>There are 275,000 new cases of oral cancer (OC) per year, making it the sixth most common cancer in the world. Severe adverse effects, including loss of function, deformity, and systemic toxicity, are familiar with traditional therapies such as radiation, chemotherapy, and surgery; due to their unique properties, nanoparticles (NPs) have emerged as a superior alternative over chemo/radiotherapy and surgery due to their targeting capability, bioavailability, compatibility, and high solubility. Due to their unique properties, metallic NPs have garnered significant attention in OC control. In addition to the fact that metal NPs may be harmful to human cells, the reactive chemicals used to make them pose the same risk, which limits their use in medicine. Green synthesis (GS) is a novel strategy that uses biological materials like yeast, bacteria, fungi, and plant extracts. Compared to more traditional chemical synthesis processes, these are more environmentally benign and manageable for living organisms. This article summarises the GS of NPs made of metals and metal oxides and their anticancer effects on OC. The method's potential benefits and drawbacks in advancing metallic NPs' GS and shaping OC therapy's future were also discussed.</p>","PeriodicalId":15573,"journal":{"name":"Journal of Drug Targeting","volume":" ","pages":"1-24"},"PeriodicalIF":4.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
Strategies and challenges of cytosolic delivery of proteins.
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-04 DOI: 10.1080/1061186X.2025.2458616
Yuanyuan Li, Baojie Du, Lichao Yu, Hong Luo, Haibo Rong, Xiangdong Gao, Jun Yin

The cytosolic delivery of therapeutic proteins represents a promising strategy for addressing diseases caused by protein dysfunction. Despite significant advances, efficient delivery remains challenging due to barriers such as cell membrane impermeability, endosomal sequestration and protein instability. This review summarises recent progress in protein delivery systems, including physical, chemical and biological approaches, with a particular focus on strategies that enhance endosomal escape and targeting specificity. We further discuss the clinical translatability of these approaches and propose future directions for improving delivery efficiency and safety, ultimately unlocking the therapeutic potential of intracellular proteins.

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引用次数: 0
Comparison of the accumulation manner of a macromolecular drug between two mouse tumour models: study with magnetic resonance imaging and the model macromolecular drug, gadolinium-conjugated dextran. 比较两种小鼠肿瘤模型中大分子药物的蓄积方式:利用磁共振成像和模型大分子药物钆结合葡聚糖进行研究。
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 Epub Date: 2024-10-01 DOI: 10.1080/1061186X.2024.2409886
Keizo Takeshita, Yohei Nakagawa, Eika Yokoyama, Nana Shinohara, Kayoko Miura, Shiho Naka, Masashi Nishida, Keiji Yasukawa, Yuhei Ohta, Jun Fang, Shoko Okazaki

A knowledge of the difference of spatio-temporal behaviour of nanomedicine in different type of tumour models is important to develop well-targeted nanomedicine for tumour. In this study, intratumoral accumulation of the model nanomedicine, gadolinium-conjugated dextran (Gd-Dex), was examined with magnetic resonance imaging in two tumour models; mouse sarcoma S180 and radiation-induced mouse fibrosarcoma RIF-1. From time-course of the distribution images, the plasma-to-tumour interstitial tissue transfer constant (Ktrans) and fractional plasma volume (Vp) were calculated and mapped. Gd-Dex preferentially distributed to the marginal region of S180 tumours immediately after its injection, and then started to accumulate in some parts of the central region. Ktrans and Vp values were large in the marginal region, while only Ktrans was large in some parts of the central region. In contrast, the distribution of Gd-Dex in RIF-1 tumours was fairly homogeneous, and may have resulted from the homogeneous distributions of Ktrans and Vp. The amounts of Gd-Dex that accumulated in entire tumours in both tumour models correlated with the volume of tumours; however, accumulation in large S180 tumours deviated from the correlation in the early phase. The differences in the manner and pharmacokinetics of nanomedicine among tumour models may affect the accumulation of the medicine.

了解纳米药物在不同类型肿瘤模型中的时空表现差异,对于开发具有良好靶向性的肿瘤纳米药物非常重要。本研究利用磁共振成像技术检测了模型纳米药物钆结合葡聚糖(Gd-Dex)在两种肿瘤模型(小鼠肉瘤 S180 和辐射诱导的小鼠纤维肉瘤 RIF-1)中的瘤内蓄积情况。根据分布图像的时间进程,计算并绘制了血浆到肿瘤间质组织的转移常数(Ktrans)和血浆体积分数(Vp)。Gd-Dex 在注射后立即优先分布到 S180 肿瘤的边缘区域,然后开始在中心区域的一些部位聚集。边缘区域的 Ktrans 和 Vp 值都很大,而在中心区域的一些地方只有 Ktrans 值较大。相比之下,Gd-Dex 在 RIF-1 肿瘤中的分布相当均匀,这可能是 Ktrans 和 Vp 分布均匀的结果。在两种肿瘤模型中,Gd-Dex在整个肿瘤中的累积量与肿瘤体积相关;但在大型S180肿瘤中的累积量在早期阶段偏离了相关性。不同肿瘤模型在纳米药物作用方式和药代动力学方面的差异可能会影响药物的积累。
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引用次数: 0
Brain targeted polymeric micelles as drug carriers for ischaemic stroke treatment. 脑靶向聚合物胶束作为治疗缺血性中风的药物载体。
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 Epub Date: 2024-10-18 DOI: 10.1080/1061186X.2024.2417190
Zirui Zhao, Huijia Song, Mengge Qi, Yurong Liu, Yanchao Zhang, Shuo Li, Huimin Zhang, Yongjun Sun, Yanping Sun, Zibin Gao

Ischaemic stroke is a central nervous system disease with high morbidity, recurrence and mortality rates. Thrombolytic and neuroprotective therapies are the main therapeutic strategies for ischaemic stroke, however, the poor delivery efficiency of thrombolytic and neuroprotective drugs to the brain limits their clinical application. So far, the development of nanomedicine has brought opportunities for the above challenges, which can not only realise the effective accumulation of drugs in the target site, but also improve the pharmacokinetic behaviour of the drugs. Among the most rapidly developing nanoparticles, micelles gradually emerging as an effective strategy for ischaemic stroke treatment due to their own unique advantages. This review provided an overview of targeted and response-release micelles based on the physicochemical properties of the ischaemic stroke microenvironment, summarised the targeting strategies for delivering micellar formulations to the thrombus, blood-brain barrier, and brain parenchyma, and finally described the potentials and challenges of polymeric micelles in the treatment of ischaemic stroke.

缺血性中风是一种发病率、复发率和死亡率都很高的中枢神经系统疾病。溶栓和神经保护疗法是缺血性脑卒中的主要治疗策略,但溶栓和神经保护药物在脑部的传输效率较低,限制了其临床应用。迄今为止,纳米医学的发展为上述挑战带来了机遇,它不仅能实现药物在靶点的有效蓄积,还能改善药物的药代动力学行为。在发展最迅速的纳米粒子中,胶束因其独特的优势逐渐成为缺血性脑卒中治疗的有效策略。本综述概述了基于缺血性中风微环境理化特性的靶向和反应释放胶束,总结了向血栓、血脑屏障和脑实质输送胶束制剂的靶向策略,最后阐述了聚合物胶束在缺血性中风治疗中的潜力和挑战。
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引用次数: 0
A comprehensive review on recent advancements in drug delivery via selenium nanoparticles. 全面回顾通过硒纳米颗粒给药的最新进展。
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 Epub Date: 2024-10-11 DOI: 10.1080/1061186X.2024.2412142
Muhammad Ahsan Waqar

Nanotechnology has significantly impacted drug discovery and development over the past three decades, offering novel insights and expanded treatment options. Key to this field is nanoparticles, ranging from 1 to 100 nanometres, with unique properties distinct from larger materials. Selenium nanoparticles (SeNPs) are particularly promising due to their low toxicity and selective cytotoxicity against cancer cells. They have shown efficacy in reducing various cancers types and mitigating conditions like diabetic nephropathy and neurological disorders, such as Alzheimer's disease. This review highlights SeNPs' role in enhancing drug delivery systems, improving the absorption of water-soluble compounds, proteins, peptides, vaccines, and other biological therapies. By modifying nanoparticle surfaces with targeting ligands, drug delivery can achieve precise site-specific delivery, increasing effectiveness. SeNPs can be synthesised through physical, chemical, and biological methods, each offering advantages in stability, size, and application potential. Additionally, SeNPs enhance immune responses and reduce oxidative stress, validating their role in biotherapy and nanomedicine. Their ability to target macrophages and regulate polarisation underscores their potential in antimicrobial therapies. Recent advancements, such as mannosylated SeNPs for targeted delivery, exemplify innovative nanotechnology applications in medicine. Overall, SeNPs represent a promising frontier in nanomedicine, offering new avenues for treating and managing various diseases.

过去三十年来,纳米技术对药物发现和开发产生了重大影响,提供了新的见解和更多的治疗选择。这一领域的关键是纳米粒子,其尺寸从 1 纳米到 100 纳米不等,具有不同于大型材料的独特性质。硒纳米粒子(SeNPs)因其低毒性和对癌细胞的选择性细胞毒性而特别具有发展前景。它们在减少各种癌症类型、缓解糖尿病肾病和神经系统疾病(如阿尔茨海默病)等方面显示出功效。本综述重点介绍 SeNPs 在增强给药系统、改善水溶性化合物、蛋白质、肽、疫苗和其他生物疗法的吸收方面的作用。通过用靶向配体修饰纳米粒子表面,药物输送可以实现精确的特定部位输送,从而提高有效性。SeNPs 可以通过物理、化学和生物方法合成,每种方法都具有稳定性、尺寸和应用潜力方面的优势。此外,SeNPs 还能增强免疫反应和减少氧化应激,从而验证其在生物疗法和纳米医学中的作用。它们能够靶向巨噬细胞并调节极化,这突出了它们在抗微生物疗法中的潜力。用于靶向递送的甘露糖基化 SeNPs 等最新进展体现了纳米技术在医学中的创新应用。总之,SeNPs 代表了纳米医学中前景广阔的前沿领域,为治疗和控制各种疾病提供了新的途径。
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引用次数: 0
Humanized recombinant immunotoxin targeting hCG demonstrates therapeutic potential for advanced stage difficult to treat cancers. 靶向 hCG 的人源化重组免疫毒素显示出对晚期难治癌症的治疗潜力
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 Epub Date: 2024-11-05 DOI: 10.1080/1061186X.2024.2416247
Kirti Nain, Kritika Sonar, Sibasis Sahoo, Jagdish C Gupta, Sonam Grover, Arockiasamy Arulandu, G P Talwar

We report the development of an immunotherapeutic molecule, a Humanized immunotoxin, for treating hCG-expressing advanced-stage cancers. PiPP, a high-affinity anti-hCG monoclonal antibody, is used in the immunotoxin for 'homing' hCG-positive cancer cells. The deimmunized (DI) form of α-Sarcin, a fungal-origin toxin that lacks functional T-cell epitopes, is used in the design to ensure minimal immunogenicity of the immunotoxin for repetitive use in humans. A single-chain variable fragment (scFv) of PiPP was constructed by linking the Humanized VH and VL regions of the antibody. The scFv part of the antibody was further linked to the toxin α-Sarcin (DI) at the gene level and expressed as a recombinant protein in E. coli. The immunotoxin was purified from the bacterial cell lysate and analysed for binding and cytotoxicity to hCG-secreting colorectal and pancreatic cancer cells. The results showed that the scFv(PiPP)-Sarcin immunotoxin was able to bind to colorectal and pancreatic cancer cells and killed approximately 85% of the cells. In vivo testing of the immunotoxin produced results similar to those of in vitro testing against colorectal adenocarcinoma-induced tumours. This immunotoxin could be a promising immunotherapeutic agent for treating colorectal, pancreatic and other terminal-stage hCG-expressing cancers.

我们报告了一种用于治疗表达 hCG 的晚期癌症的免疫治疗分子--人源化免疫毒素的开发情况。PiPP是一种高亲和力的抗hCG单克隆抗体,用于免疫毒素 "归巢 "hCG阳性癌细胞。α-Sarcin是一种缺乏功能性T细胞表位的真菌源毒素,设计中使用了去免疫(DI)形式的α-Sarcin,以确保将免疫毒素的免疫原性降至最低,以便在人体中重复使用。通过连接抗体的人源化 VH 和 VL 区域,构建了 PiPP 的单链可变片段(scFv)。抗体的 scFv 部分在基因水平上进一步与毒素 α-Sarcin (DI) 连接,并在大肠杆菌中表达为重组蛋白。从细菌细胞裂解液中纯化出免疫毒素,并分析其与分泌 hCG 的结直肠癌和胰腺癌细胞的结合力和细胞毒性。结果表明,scFv(PiPP)-Sarcin 免疫毒素能够与结直肠癌和胰腺癌细胞结合,并杀死约 85% 的细胞。免疫毒素的体内测试结果与针对结直肠腺癌诱发肿瘤的体外测试结果相似。这种免疫毒素可能是治疗结直肠癌、胰腺癌和其他表达 hCG 的晚期癌症的一种很有前途的免疫治疗药物。
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引用次数: 0
Development of non-viral targeted RNA delivery vehicles - a key factor in success of therapeutic RNA. 开发非病毒靶向 RNA 运送载体--治疗 RNA 成功的关键因素。
IF 4.3 4区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2025-02-01 Epub Date: 2024-10-17 DOI: 10.1080/1061186X.2024.2416241
Muhammad Waqas Choudry, Rabia Riaz, Muhammad Hassan Raza, Pashma Nawaz, Bilal Ahmad, Neelam Jahan, Shazia Rafique, Samia Afzal, Iram Amin, Muhammad Shahid

Decade-long efforts in medicinal biotechnology have enabled large-scale in-vitro production of optimised therapeutic RNA constructs for stable in-vivo delivery and modify the expression of disease-related genes. The success of lipid nanoparticle-formulated mRNA vaccines against Severe acute respiratory syndrome Coronavirus-2 (SARS-Cov2) has opened a new era of RNA therapeutics and non-viral drug delivery systems. The major limiting factor in the clinical translation of RNA-based drugs is the availability of suitable delivery vehicles that can protect RNA payloads from degradation, offer controlled release, and pose minimal inherent toxicity. Unwanted immune response, payload size constraints, genome integration, and non-specific tissue targeting limit the application of conventional viral drug-delivery vehicles. This review summarises current research on nano-sized drug carriers, including lipid nanoparticles, polymer-based formulations, cationic nanoemulsion, and cell-penetrating peptides, for targeted therapeutic RNA delivery. Further, this paper highlights the biomimetic approaches (i.e. mimicking naturally occurring bio-compositions, molecular designs, and systems), including virus-like particles (VLPs), exosomes, and selective endogenous eNcapsidation (SEND) technology being explored as safer and more efficient alternatives.

经过数十年在医药生物技术领域的努力,已能在体外大规模生产优化的治疗用 RNA 构建物,以便在体内稳定输送并改变疾病相关基因的表达。针对严重急性呼吸系统综合征冠状病毒-2(SARS-Cov2)的脂质纳米粒子配方 mRNA 疫苗的成功开创了 RNA 疗法和非病毒给药系统的新纪元。RNA 药物临床转化的主要限制因素是能否找到合适的给药载体,以保护 RNA 有效载荷不被降解、控制释放并将其固有毒性降至最低。不必要的免疫反应、有效载荷大小限制、基因组整合和非特异性组织靶向等因素限制了传统病毒载药工具的应用。本综述总结了目前有关纳米药物载体的研究,包括用于靶向治疗 RNA 递送的脂质纳米颗粒、聚合物制剂、阳离子纳米乳液和细胞穿透肽。此外,本文还重点介绍了生物仿生方法(即模仿自然存在的生物成分、分子设计和系统),包括病毒样颗粒 (VLP)、外泌体和选择性内源性电子囊化 (SEND) 技术,这些技术正在被探索为更安全、更高效的替代方法。
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引用次数: 0
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Journal of Drug Targeting
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