Pub Date : 2024-09-10DOI: 10.1016/j.apsb.2024.09.006
Dong Liang, Chen Yu, Zhao Ma, Xingye Yang, Zhenzhen Li, Xuhui Dong, Xiaojun Qin, Lupei Du, Minyong Li
{"title":"Author correction to “Identification of anthelmintic parbendazole as a therapeutic molecule for HNSCC through connectivity map-based drug repositioning” [Acta Pharm Sin B 12 (2022) 2429–2442]","authors":"Dong Liang, Chen Yu, Zhao Ma, Xingye Yang, Zhenzhen Li, Xuhui Dong, Xiaojun Qin, Lupei Du, Minyong Li","doi":"10.1016/j.apsb.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.09.006","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263509","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}
Pub Date : 2024-09-04DOI: 10.1016/j.apsb.2024.06.006
Dandan Wan, Ziyi Bai, Yu Zhang, Li Chen, Haiying Que, Tianxia Lan, Weiqi Hong, Jiayu Huang, Cai He, Yuquan Wei, Qiang Pu, Xiawei Wei
Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8 T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip in tumor vaccines. Following immunization with 1V209-Cho-Lip+OVA, we observed a pronounced "depot effect" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip+OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip+OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.
Toll 样受体（TLR）激动剂是一种很有前景的佐剂和免疫治疗剂，有可能通过激活不同的信号通路来增强免疫反应和调节抗原依赖性 T 细胞免疫记忆。然而，它们在临床上的应用却受到不受控制的全身性炎症反应的阻碍。因此，当务之急是为 TLR 受体创造一种既安全又有效的疫苗佐剂。在本研究中，我们设计了淋巴结靶向胆固醇化 TLR7 激动剂阳离子脂质体（1V209-Cho-Lip），以减轻不良副作用。模型抗原 OVA 和胆固醇化 TLR7 激动剂的联合给药有助于通过 TLR 激活促进 DC 成熟，同时确保抗原以最佳方式呈现给 CD8 T 细胞。本研究的主要目的是评估 1V209-Cho-Lip 在肿瘤疫苗中的佐剂效果。在使用 1V209-Cho-Lip+OVA 进行免疫接种后，我们观察到了明显的 "储藏效应 "和向次级淋巴器官的迁移增强。预防性接种 1V209-Cho-Lip+OVA 能显著延缓肿瘤的发展，延长小鼠的存活时间，并建立起防止肿瘤复发的持久免疫力。此外，1V209-Cho-Lip+OVA 作为治疗性肿瘤疫苗，在抑制肿瘤进展方面的疗效已得到证实，与抗-PD-1 结合使用时，可进一步增强抗肿瘤效果。因此，将抗原和淋巴结靶向胆固醇化 TLR7 激动剂联合递送作为癌症疫苗大有可为。
{"title":"Simultaneous enhancement of cellular and humoral immunity by the lymph node-targeted cholesterolized TLR7 agonist liposomes","authors":"Dandan Wan, Ziyi Bai, Yu Zhang, Li Chen, Haiying Que, Tianxia Lan, Weiqi Hong, Jiayu Huang, Cai He, Yuquan Wei, Qiang Pu, Xiawei Wei","doi":"10.1016/j.apsb.2024.06.006","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.06.006","url":null,"abstract":"Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8 T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip in tumor vaccines. Following immunization with 1V209-Cho-Lip+OVA, we observed a pronounced \"depot effect\" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip+OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip+OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263512","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}
The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.
{"title":"Comparison of Jinzhen oral liquid and ambroxol hydrochloride and clenbuterol hydrochloride oral solution in the treatment of acute bronchitis in children: A multicenter, non-inferiority, prospective, randomized controlled trial","authors":"Qinhua Fan, Chongming Wu, Yawei Du, Boyang Wang, Yanming Xie, Zeling Zhang, Wenquan Su, Zizhuo Wang, Changchang Xu, Xueke Li, Ying Ding, Xinjiang An, Jing Chen, Yunying Xiao, Rong Yu, Nan Li, Juan Wang, Yiqun Teng, Hongfen Lv, Nian Yang, Yuling Wen, Xiaoli Huang, Wei Pan, Yufeng Liu, Xueqin Xi, Qianye Zhao, Changshan Liu, Jian Xu, Haitao Zhang, Lie Zhuo, Qiangquan Rong, Yu Xia, Qin Shen, Shao Li, Junhong Wang, Shengxian Wu","doi":"10.1016/j.apsb.2024.09.001","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.09.001","url":null,"abstract":"The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263513","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}
Pub Date : 2024-09-03DOI: 10.1016/j.apsb.2024.06.024
Lai Wang, Haoyuan Yin, Jiao Jiang, Qilin Li, Changxing Gao, Wenrui Li, Bo Zhang, Yue Xin, Hongyang Li, Ming Zhao, Qianjin Lu
Hook F (TWHF) is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus (SLE), with triptolide (TP) as its main active ingredient. However, its side effects also induced by TP, especially hepatotoxicity and reproductive toxicity, largely limit its application in a subset of patients. Monoclonal antibodies (mAbs) developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens, such as CD19, have failed in clinical trials, partly due to their poor efficacy in consuming B cells. Here, we report the development of a rationally designed antibody‒drug conjugate (ADC), CD19 mAb-TP conjugate, to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb. The CD19 mAb-TP conjugate, which was named ADC-TP, selectively depleted B cell subsets both and and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP. Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE, providing a feasible method for improving the current agents used for treating SLE.
钩藤（TWHF）是一种广泛用于治疗系统性红斑狼疮（SLE）的传统中药，其主要活性成分是三苯氧胺（TP）。然而，TP 也会引起副作用，尤其是肝毒性和生殖毒性，这在很大程度上限制了它在部分患者中的应用。为治疗系统性红斑狼疮而开发的单克隆抗体（mAbs）通过靶向 B 细胞表达的抗原（如 CD19）来消耗 B 细胞，但在临床试验中失败了，部分原因是它们消耗 B 细胞的效果不佳。在此，我们报告了一种合理设计的抗体-药物共轭物（ADC）--CD19 mAb-TP共轭物的开发情况，以减轻TWHF的副作用，同时提高CD19 mAb的疗效。CD19 mAb-TP共轭物被命名为ADC-TP，它既能选择性清除B细胞亚群，又能有效缓解小鼠狼疮模型的疾病症状，疗效优于CD19 mAb，而副作用则少于TP。我们的研究提出了一种 CD19 mAb-TP 结合物策略，既能减轻 TWHF 的毒性，又能提高 CD19 mAb 治疗系统性红斑狼疮的疗效，为改进目前治疗系统性红斑狼疮的药物提供了一种可行的方法。
{"title":"A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus","authors":"Lai Wang, Haoyuan Yin, Jiao Jiang, Qilin Li, Changxing Gao, Wenrui Li, Bo Zhang, Yue Xin, Hongyang Li, Ming Zhao, Qianjin Lu","doi":"10.1016/j.apsb.2024.06.024","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.06.024","url":null,"abstract":"Hook F (TWHF) is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus (SLE), with triptolide (TP) as its main active ingredient. However, its side effects also induced by TP, especially hepatotoxicity and reproductive toxicity, largely limit its application in a subset of patients. Monoclonal antibodies (mAbs) developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens, such as CD19, have failed in clinical trials, partly due to their poor efficacy in consuming B cells. Here, we report the development of a rationally designed antibody‒drug conjugate (ADC), CD19 mAb-TP conjugate, to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb. The CD19 mAb-TP conjugate, which was named ADC-TP, selectively depleted B cell subsets both and and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP. Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE, providing a feasible method for improving the current agents used for treating SLE.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263628","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}
Pub Date : 2024-09-02DOI: 10.1016/j.apsb.2024.08.029
Yiwen Zhang, Bingfang Hu, Shaoxing Guan, Pan Li, Yingjie Guo, Pengfei Xu, Yongdong Niu, Yujin Li, Ye Feng, Jiewen Du, Jun Xu, Xiuchen Guan, Jingkai Gu, Haiyan Sun, Min Huang
Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR–FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of Rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.
{"title":"Activation of pregnane X receptor sensitizes alcoholic steatohepatitis by transactivating fatty acid binding protein 4","authors":"Yiwen Zhang, Bingfang Hu, Shaoxing Guan, Pan Li, Yingjie Guo, Pengfei Xu, Yongdong Niu, Yujin Li, Ye Feng, Jiewen Du, Jun Xu, Xiuchen Guan, Jingkai Gu, Haiyan Sun, Min Huang","doi":"10.1016/j.apsb.2024.08.029","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.029","url":null,"abstract":"Alcoholic steatohepatitis (ASH) is a liver disease characterized by steatosis, inflammation, and necrosis of the liver tissue as a result of excessive alcohol consumption. Pregnane X receptor (PXR) is a xenobiotic nuclear receptor best known for its function in the transcriptional regulation of drug metabolism and disposition. Clinical reports suggested that the antibiotic rifampicin, a potent human PXR activator, is a contraindication in alcoholics, but the mechanism was unclear. In this study, we showed that the hepatic expression of fatty acid binding protein 4 (FABP4) was uniquely elevated in ASH patients and a mouse model of ASH. Pharmacological inhibiting FABP4 attenuated ASH in mice. Furthermore, treatment of mice with the mouse PXR agonist pregnenolon-16-carbonitrile (PCN) induced the hepatic and circulating levels of FABP4 and exacerbated ASH in a PXR-dependent manner. Our mechanism study established FABP4 as a transcriptional target of PXR. Treatment with andrographolide, a natural compound and dual inhibitor of PXR and FABP4, alleviated mice from ASH. In summary, our results showed that the PXR–FABP4 gene regulatory axis plays an important role in the progression of ASH, which may have accounted for the contraindication of Rifampicin in patients of alcoholic liver disease. Pharmacological inhibition of PXR and/or FABP4 may have its promise in the clinical management of ASH.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187069","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}
Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both and . Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.
{"title":"AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer","authors":"Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi","doi":"10.1016/j.apsb.2024.08.031","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.031","url":null,"abstract":"Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both and . Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263630","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}
Pub Date : 2024-09-02DOI: 10.1016/j.apsb.2024.08.027
Bing Xie, Yaping Liu, Xiaotong Li, Pei Yang, Wei He
Currently, about 40% of approved drugs and nearly 90% of drug candidates are poorly water-soluble drugs. Low solubility reduces the likelihood that these drugs can be effectively used clinically. Effectively improving the solubility and bioavailability of poorly water-soluble drugs is a critical issue that needs to be urgently addressed in drug development and application. This review briefly introduces the conventional solubilization techniques such as solubilizers, hydrotropes, cosolvents, prodrugs, salt modification, micronization, cyclodextrin inclusion, solid dispersions, and details the crystallization strategies, ionic liquids, and polymer-based, lipid-based, and inorganic-based carriers in improving solubility and bioavailability. Some of the most commonly used approved carrier materials for solubilization techniques are presented, and some approved poorly water-soluble drugs using solubilization techniques are summarized. Furthermore, this review describes in detail the solubilization mechanism of each solubilization technique, reviews the latest research advances and challenges, and evaluates the potential for clinical translation. This review could guide the selection of a solubilization approach, dosage form, and administration route for poorly water-soluble drugs. Moreover, we discuss several promising solubilization techniques attracting increasing attention worldwide.
{"title":"Solubilization techniques used for poorly water-soluble drugs","authors":"Bing Xie, Yaping Liu, Xiaotong Li, Pei Yang, Wei He","doi":"10.1016/j.apsb.2024.08.027","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.027","url":null,"abstract":"Currently, about 40% of approved drugs and nearly 90% of drug candidates are poorly water-soluble drugs. Low solubility reduces the likelihood that these drugs can be effectively used clinically. Effectively improving the solubility and bioavailability of poorly water-soluble drugs is a critical issue that needs to be urgently addressed in drug development and application. This review briefly introduces the conventional solubilization techniques such as solubilizers, hydrotropes, cosolvents, prodrugs, salt modification, micronization, cyclodextrin inclusion, solid dispersions, and details the crystallization strategies, ionic liquids, and polymer-based, lipid-based, and inorganic-based carriers in improving solubility and bioavailability. Some of the most commonly used approved carrier materials for solubilization techniques are presented, and some approved poorly water-soluble drugs using solubilization techniques are summarized. Furthermore, this review describes in detail the solubilization mechanism of each solubilization technique, reviews the latest research advances and challenges, and evaluates the potential for clinical translation. This review could guide the selection of a solubilization approach, dosage form, and administration route for poorly water-soluble drugs. Moreover, we discuss several promising solubilization techniques attracting increasing attention worldwide.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187066","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}
The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of PD-1 and CAR-T therapies. The application of this tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.
{"title":"In situ tumor cell engineering reverses immune escape to enhance immunotherapy effect","authors":"Shujun Liu, Shijun Yuan, Meichen Liu, Jinhu Liu, Shunli Fu, Tong Gao, Shuang Liang, Xinyan Huang, Xinke Zhang, Yongjun Liu, Zipeng Zhang, Na Zhang","doi":"10.1016/j.apsb.2024.08.028","DOIUrl":"https://doi.org/10.1016/j.apsb.2024.08.028","url":null,"abstract":"The underlying cause of low response rates to existing immunotherapies is that tumor cells dominate tumor immune escape through surface antigen deficiency and inducing tumor immunosuppressive microenvironment (TIME). Here, we proposed an tumor cell engineering strategy to disrupt tumor immune escape at the root by restoring tumor cell MHC-I/tumor-specific antigen complex (MHC-I/TSA) expression to promote T-cell recognition and by silencing tumor cell CD55 to increase the ICOSL B-cell proportion and reverse the TIME. A doxorubicin (DOX) and dual-gene plasmid (MAC pDNA, encoding both MHC-I/ASMTNMELM and CD55-shRNA) coloaded drug delivery system (LCPN@ACD) with tumor targeting and charge/size dual–conversion properties was prepared. LCPN@ACD-induced ICD promoted DC maturation and enhanced T-cell activation and infiltration. LCPN@ACD enabled effective expression of MHC-I/TSA on tumor cells, increasing the ability of tumor cell recognition and killing. LCPN@ACD downregulated tumor cell CD55 expression, increased the proportion of ICOSL B cells and CTLs, and reversed the TIME, thus greatly improving the efficacy of PD-1 and CAR-T therapies. The application of this tumor cell engineering strategy eliminated the source of tumor immune escape, providing new ideas for solving the challenges of clinical immunotherapy.","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":null,"pages":null},"PeriodicalIF":14.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263631","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}
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