Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.07.021
Hongyan Zhang , Yujie Li , Jingyi Huang , Limei Shen , Yang Xiong
Over the past decade, research has increasingly identified unique dysregulations in lipid metabolism within the tumor microenvironment (TME). Lipids, diverse biomolecules, not only constitute biological membranes but also function as signaling molecules and energy sources. Enhanced synthesis or uptake of lipids in the TME significantly promotes tumorigenesis and proliferation. Moreover, lipids secreted into the TME influence tumor-resident immune cells (TRICs), thereby aiding tumor survival against chemotherapy and immunotherapy. This review aims to highlight recent advancements in understanding lipid metabolism in both tumor cells and TRICs, with a particular emphasis on exogenous lipid uptake and endogenous lipid de novo synthesis. Targeting lipid metabolism for intervention in anticancer therapies offers a promising therapeutic avenue for cancer treatment. Nano-drug delivery systems (NDDSs) have emerged as a means to maximize anti-tumor effects by rewiring tumor metabolism. This review provides a comprehensive overview of recent literature on the development of NDDSs targeting tumor lipid metabolism, particularly in the context of tumor immunotherapy. It covers four key aspects: reprogramming lipid uptake, reprogramming lipolysis, reshaping fatty acid oxidation (FAO), and reshuffling lipid composition on the cell membrane. The review concludes with a discussion of future prospects and challenges in this burgeoning field of research.
{"title":"Precise targeting of lipid metabolism in the era of immuno-oncology and the latest advances in nano-based drug delivery systems for cancer therapy","authors":"Hongyan Zhang , Yujie Li , Jingyi Huang , Limei Shen , Yang Xiong","doi":"10.1016/j.apsb.2024.07.021","DOIUrl":"10.1016/j.apsb.2024.07.021","url":null,"abstract":"<div><div>Over the past decade, research has increasingly identified unique dysregulations in lipid metabolism within the tumor microenvironment (TME). Lipids, diverse biomolecules, not only constitute biological membranes but also function as signaling molecules and energy sources. Enhanced synthesis or uptake of lipids in the TME significantly promotes tumorigenesis and proliferation. Moreover, lipids secreted into the TME influence tumor-resident immune cells (TRICs), thereby aiding tumor survival against chemotherapy and immunotherapy. This review aims to highlight recent advancements in understanding lipid metabolism in both tumor cells and TRICs, with a particular emphasis on exogenous lipid uptake and endogenous lipid <em>de novo</em> synthesis. Targeting lipid metabolism for intervention in anticancer therapies offers a promising therapeutic avenue for cancer treatment. Nano-drug delivery systems (NDDSs) have emerged as a means to maximize anti-tumor effects by rewiring tumor metabolism. This review provides a comprehensive overview of recent literature on the development of NDDSs targeting tumor lipid metabolism, particularly in the context of tumor immunotherapy. It covers four key aspects: reprogramming lipid uptake, reprogramming lipolysis, reshaping fatty acid oxidation (FAO), and reshuffling lipid composition on the cell membrane. The review concludes with a discussion of future prospects and challenges in this burgeoning field of research.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4717-4737"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141839184","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.09.012
Zhenwei Su , Hamza Boucetta , Jiahui Shao , Jinling Huang , Ran Wang , Aining Shen , Wei He , Zhi Ping Xu , Lingxiao Zhang
Aluminum adjuvants (Alum), approved by the US Food and Drug Administration, have been extensively used in vaccines containing recombinant antigens, subunits of pathogens, or toxins for almost a century. While Alums typically elicit strong humoral immune responses, their ability to induce cellular and mucosal immunity is limited. As an alternative, layered double hydroxide (LDH), a widely used antacid, has emerged as a novel class of potent nano-aluminum adjuvants (NanoAlum), demonstrating advantageous physicochemical properties, biocompatibility and adjuvanticity in both humoral and cellular immune responses. In this review, we summarize and compare the advantages and disadvantages of Alum and NanoAlum in these properties and their performance as adjuvants. Moreover, we propose the key features for ideal adjuvants and demonstrate that LDH NanoAlum is a promising candidate by summarizing its current progress in immunotherapeutic cancer treatments. Finally, we conclude the review by offering our integrated perspectives about the remaining challenges and future directions for NanoAlum's application in preclinical/clinical settings.
{"title":"Next-generation aluminum adjuvants: Immunomodulatory layered double hydroxide NanoAlum reengineered from first-line drugs","authors":"Zhenwei Su , Hamza Boucetta , Jiahui Shao , Jinling Huang , Ran Wang , Aining Shen , Wei He , Zhi Ping Xu , Lingxiao Zhang","doi":"10.1016/j.apsb.2024.09.012","DOIUrl":"10.1016/j.apsb.2024.09.012","url":null,"abstract":"<div><div>Aluminum adjuvants (Alum), approved by the US Food and Drug Administration, have been extensively used in vaccines containing recombinant antigens, subunits of pathogens, or toxins for almost a century. While Alums typically elicit strong humoral immune responses, their ability to induce cellular and mucosal immunity is limited. As an alternative, layered double hydroxide (LDH), a widely used antacid, has emerged as a novel class of potent nano-aluminum adjuvants (NanoAlum), demonstrating advantageous physicochemical properties, biocompatibility and adjuvanticity in both humoral and cellular immune responses. In this review, we summarize and compare the advantages and disadvantages of Alum and NanoAlum in these properties and their performance as adjuvants. Moreover, we propose the key features for ideal adjuvants and demonstrate that LDH NanoAlum is a promising candidate by summarizing its current progress in immunotherapeutic cancer treatments. Finally, we conclude the review by offering our integrated perspectives about the remaining challenges and future directions for NanoAlum's application in preclinical/clinical settings.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4665-4682"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707011","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.08.020
Yuqi Yang , Nan Liu , Likun Gong
The APOBEC3 (A3) family plays a pivotal role in the immune system by performing DNA/RNA single-strand deamination. Cancers mostly arise from the accumulation of chronic mutations in somatic cells, and recent research has highlighted the A3 family as a major contributor to tumor-associated mutations, with A3A being a key driver gene leading to cancer-related mutations. A3A helps to defend the host against virus-induced tumors by editing the genome of cancer-associated viruses that invade the host. However, when it is abnormally expressed, it leads to persistent, chronic mutations in the genome, thereby fueling tumorigenesis. Notably, A3A is prominently expressed in innate immune cells, particularly macrophages, thereby affecting the functional state of tumor-infiltrating immune cells and tumor growth. Furthermore, the expression of A3A in tumor cells may directly affect their proliferation and migration. A growing body of research has unveiled that A3A is closely related to various cancers, which signifies the potential significance of A3A in cancer therapy. This paper mainly classifies and summarizes the evidence of the relationship between A3A and tumorigenesis based on the potential mechanisms, aiming to provide valuable references for further research on the functions of A3A and its development in the area of cancer therapy.
{"title":"An overview of the functions and mechanisms of APOBEC3A in tumorigenesis","authors":"Yuqi Yang , Nan Liu , Likun Gong","doi":"10.1016/j.apsb.2024.08.020","DOIUrl":"10.1016/j.apsb.2024.08.020","url":null,"abstract":"<div><div>The APOBEC3 (A3) family plays a pivotal role in the immune system by performing DNA/RNA single-strand deamination. Cancers mostly arise from the accumulation of chronic mutations in somatic cells, and recent research has highlighted the A3 family as a major contributor to tumor-associated mutations, with A3A being a key driver gene leading to cancer-related mutations. A3A helps to defend the host against virus-induced tumors by editing the genome of cancer-associated viruses that invade the host. However, when it is abnormally expressed, it leads to persistent, chronic mutations in the genome, thereby fueling tumorigenesis. Notably, A3A is prominently expressed in innate immune cells, particularly macrophages, thereby affecting the functional state of tumor-infiltrating immune cells and tumor growth. Furthermore, the expression of A3A in tumor cells may directly affect their proliferation and migration. A growing body of research has unveiled that A3A is closely related to various cancers, which signifies the potential significance of A3A in cancer therapy. This paper mainly classifies and summarizes the evidence of the relationship between A3A and tumorigenesis based on the potential mechanisms, aiming to provide valuable references for further research on the functions of A3A and its development in the area of cancer therapy.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4637-4648"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187071","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.08.021
Shufang Na , Yanjie Fan , HongLei Chen , Ling Li , Guolin Li , Furong Zhang , Rongyan Wang , Yafei Yang , Zixia Shen , Zhuang Peng , Yafei Wu , Yong Zhu , Zheqiong Yang , Guicheng Dong , Qifa Ye , Jiang Yue
Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPARα is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPARα signaling on cell death pathways is unknown. Here, we show that Pparα deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal Pparα deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPARα levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPARα up-regulates necroptosis signals in the intestinal organoids triggered by TNF-α and LPS stimuli via TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal Pparα deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPARα is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation via the gut–liver axis.
{"title":"PPARα affects hepatic lipid homeostasis by perturbing necroptosis signals in the intestinal epithelium","authors":"Shufang Na , Yanjie Fan , HongLei Chen , Ling Li , Guolin Li , Furong Zhang , Rongyan Wang , Yafei Yang , Zixia Shen , Zhuang Peng , Yafei Wu , Yong Zhu , Zheqiong Yang , Guicheng Dong , Qifa Ye , Jiang Yue","doi":"10.1016/j.apsb.2024.08.021","DOIUrl":"10.1016/j.apsb.2024.08.021","url":null,"abstract":"<div><div>Rapid turnover of the intestinal epithelium is a critical strategy to balance the uptake of nutrients and defend against environmental insults, whereas inappropriate death promotes the spread of inflammation. PPAR<em>α</em> is highly expressed in the small intestine and regulates the absorption of dietary lipids. However, as a key mediator of inflammation, the impact of intestinal PPAR<em>α</em> signaling on cell death pathways is unknown. Here, we show that <em>Pparα</em> deficiency of intestinal epithelium up-regulates necroptosis signals, disrupts the gut vascular barrier, and promotes LPS translocation into the liver. Intestinal <em>Pparα</em> deficiency drives age-related hepatic steatosis and aggravates hepatic fibrosis induced by a high-fat plus high-sucrose diet (HFHS). PPAR<em>α</em> levels correlate with TRIM38 and MLKL in the human ileum. Inhibition of PPAR<em>α</em> up-regulates necroptosis signals in the intestinal organoids triggered by TNF-<em>α</em> and LPS stimuli <em>via</em> TRIM38/TRIF and CREB3L3/MLKL pathways. Butyric acid ameliorates hepatic steatosis induced by intestinal <em>Pparα</em> deficiency through the inhibition of necroptosis. Our data suggest that intestinal PPAR<em>α</em> is essential for the maintenance of microenvironmental homeostasis and the spread of inflammation <em>via</em> the gut–liver axis.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4858-4873"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142187072","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.09.002
Jie Li , Guanyi Li , Yiting Mai , Xiao Liu , Dehua Yang , Qingtong Zhou , Ming-Wei Wang
{"title":"Molecular basis of enhanced GLP-1 signaling mediated by GLP-1(9–36) in conjunction with LSN3318839","authors":"Jie Li , Guanyi Li , Yiting Mai , Xiao Liu , Dehua Yang , Qingtong Zhou , Ming-Wei Wang","doi":"10.1016/j.apsb.2024.09.002","DOIUrl":"10.1016/j.apsb.2024.09.002","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5069-5073"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263511","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.08.032
Xi He , Pingyu Wang , Linbo Qing , Xiangrong Song
{"title":"Pioneering integration of combinatorial chemistry and machine learning to accelerate the development of tailored LNPs for mRNA delivery","authors":"Xi He , Pingyu Wang , Linbo Qing , Xiangrong Song","doi":"10.1016/j.apsb.2024.08.032","DOIUrl":"10.1016/j.apsb.2024.08.032","url":null,"abstract":"","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5079-5081"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142263629","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.06.007
Yutian Lei , Yuan Shen , Feng Chen , Rui He , Zhang Zhang , Ying Zhou , Jin-Chen Yu , Jacques Crommen , Zhengjin Jiang , Qiqin Wang
The dynamic tracking of antibody‒drug conjugates (ADCs) in serum is crucial. However, a versatile bioanalytical platform is lacking due to serious matrix interferences, the heterogeneity and complex biotransformation of ADCs, and the recognition deficiencies of traditional affinity technologies. To overcome this, a multiepitope recognition technology (MERT) was developed by simultaneously immobilizing CDR and non-CDR ligands onto MOF@AuNPs. MERT's excellent specificity, ultrahigh ligand density, and potential synergistic recognition ability enable it to target the different key regions of ADCs to overcome the deficiencies of traditional technologies. The binding capacity of MERT for antibodies is ten to hundred times higher than that of the mono-epitope or Fc-specific affinity technologies. Since MERT can efficiently capture target ADCs from serum, a novel bioanalytical platform based on MERT and RPLC‒QTOF-MS has been developed to monitor the dynamic changes of ADCs in serum, including the fast changes of drug-to-antibody ratio from 3.67 to 0.22, the loss of payloads (maytansinol), and the unexpected hydrolysis of the succinimide ring of the linker, which will contribute to clarify the fate of ADCs and provide a theoretical basis for future design. In summary, the MERT-based versatile platform will open a new avenue for in-depth studies of ADCs in biological fluids.
对血清中的抗体药物共轭物（ADC）进行动态跟踪至关重要。然而，由于基质干扰严重、ADC 的异质性和复杂的生物转化以及传统亲和技术的识别缺陷，目前还缺乏一个多功能的生物分析平台。为了克服这一问题，我们开发了一种多位点识别技术（MERT），将 CDR 和非 CDR 配体同时固定在 MOF@AuNPs 上。MERT 具有优异的特异性、超高的配体密度和潜在的协同识别能力，可针对 ADC 的不同关键区域进行识别，克服了传统技术的不足。MERT 与抗体的结合能力是单表位或 Fc 特异性亲和技术的十倍到百倍。由于 MERT 能从血清中有效捕获目标 ADC，因此开发了一种基于 MERT 和 RPLC-QTOF-MS 的新型生物分析平台，用于监测 ADC 在血清中的动态变化，包括药物与抗体比从 3.67 快速变为 0.22、有效载荷（maytansinol）的损失以及连接体琥珀酰亚胺环的意外水解，这将有助于阐明 ADC 的命运，并为未来的设计提供理论依据。总之，基于 MERT 的多功能平台将为深入研究生物液体中的 ADC 开辟一条新途径。
{"title":"Multiepitope recognition technology promotes the in-depth analysis of antibody‒drug conjugates","authors":"Yutian Lei , Yuan Shen , Feng Chen , Rui He , Zhang Zhang , Ying Zhou , Jin-Chen Yu , Jacques Crommen , Zhengjin Jiang , Qiqin Wang","doi":"10.1016/j.apsb.2024.06.007","DOIUrl":"10.1016/j.apsb.2024.06.007","url":null,"abstract":"<div><div>The dynamic tracking of antibody‒drug conjugates (ADCs) in serum is crucial. However, a versatile bioanalytical platform is lacking due to serious matrix interferences, the heterogeneity and complex biotransformation of ADCs, and the recognition deficiencies of traditional affinity technologies. To overcome this, a multiepitope recognition technology (MERT) was developed by simultaneously immobilizing CDR and non-CDR ligands onto MOF@AuNPs. MERT's excellent specificity, ultrahigh ligand density, and potential synergistic recognition ability enable it to target the different key regions of ADCs to overcome the deficiencies of traditional technologies. The binding capacity of MERT for antibodies is ten to hundred times higher than that of the mono-epitope or Fc-specific affinity technologies. Since MERT can efficiently capture target ADCs from serum, a novel bioanalytical platform based on MERT and RPLC‒QTOF-MS has been developed to monitor the dynamic changes of ADCs in serum, including the fast changes of drug-to-antibody ratio from 3.67 to 0.22, the loss of payloads (maytansinol), and the unexpected hydrolysis of the succinimide ring of the linker, which will contribute to clarify the fate of ADCs and provide a theoretical basis for future design. In summary, the MERT-based versatile platform will open a new avenue for in-depth studies of ADCs in biological fluids.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 4962-4976"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141528595","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}
Pub Date : 2024-11-01DOI: 10.1016/j.apsb.2024.08.033
Jinhu Liu , Han Yang , Xiao Sang, Tong Gao, Zipeng Zhang, Shunli Fu, Huizhen Yang, Lili Chang, Xiaoqing Liu, Shuang Liang, Shijun Yuan, Suyun Wei, Yuxin Yang, Xiaoxin Yan, Xinke Zhang, Weiwei Mu, Yongjun Liu, Na Zhang
Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive o-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.
基于巨噬细胞的细胞药物是靶向给药领域的一项突破。然而，如何在保持巨噬细胞活性和发挥其免疫治疗作用的同时，定位和控制药物释放仍然是一个挑战。本文提出了一种局部光触发释放巨噬细胞细胞药物（USIP@M），它可以利用巨噬细胞的肿瘤靶向和免疫治疗作用来逆转肿瘤微环境（TME）的免疫抑制。该研究合成了具有紫外线（UV）响应邻硝基苄基的两亲嵌段共聚物，并将其与索拉非尼（SF）、IMD-0354（IMD）和上转换纳米颗粒（UCNPs）共载，然后被巨噬细胞摄取，利用巨噬细胞的肿瘤滋养特性实现了药物的靶向递送。UCNPs将穿透性强、安全性高的近红外光转化为紫外光，促进嵌段共聚物的光致抗性解聚，促进USIP@M产生外泌体，加速药物外流，保持巨噬细胞的活性。IMD 同时极化了载体巨噬细胞和肿瘤相关巨噬细胞，从而发挥巨噬细胞的抗肿瘤作用，增强 T 细胞免疫，缓解 TME 的免疫抑制状态。与 SF 的化疗作用协同，可有效杀灭肿瘤。总之，本研究基于局部光触发释放策略，构建了一种新型的巨噬细胞细胞药物，它既能局部控制药物释放，又能保留巨噬细胞的活性，发挥其免疫治疗作用，可有效治疗实体瘤。
{"title":"Localized light-triggered release macrophage cytopharmaceuticals containing O-nitrobenzyl group for enhanced solid tumor cell-chemotherapy","authors":"Jinhu Liu , Han Yang , Xiao Sang, Tong Gao, Zipeng Zhang, Shunli Fu, Huizhen Yang, Lili Chang, Xiaoqing Liu, Shuang Liang, Shijun Yuan, Suyun Wei, Yuxin Yang, Xiaoxin Yan, Xinke Zhang, Weiwei Mu, Yongjun Liu, Na Zhang","doi":"10.1016/j.apsb.2024.08.033","DOIUrl":"10.1016/j.apsb.2024.08.033","url":null,"abstract":"<div><div>Cytopharmaceutical based on macrophages is a breakthrough in the field of targeted drug delivery. However, it remains a challenge to localize and control drug release while retaining macrophage activity and exerting its immunotherapeutic effect. Herein, a localized light-triggered release macrophage cytopharmaceutical (USIP@M) was proposed, which could utilize the tumor targeting and immunotherapy effects of macrophages to reverse the immune suppression of tumor microenvironment (TME). Amphiphilic block copolymers with ultraviolet (UV)-responsive <em>o</em>-nitrobenzyl groups were synthesized and co-loaded with sorafenib (SF), IMD-0354 (IMD), and upconverting nanoparticles (UCNPs), which were then taken up by macrophages, and the targeted delivery of drugs was realized by using the tumor tropism of macrophages. UCNPs converted near-infrared light with strong penetrability and high safety into UV light, which promoted the photoresponsive depolymerization of block copolymers and production of exosomes from USIP@M, accelerated drug efflux and maintained the activity of macrophages. IMD simultaneously polarized carrier macrophages and tumor-associated macrophages to exert the antitumor effect of macrophages, enhance T cell immunity, and alleviate the immunosuppressive state of TME. Synergistically with the chemotherapeutic effect of SF, it could effectively kill tumors. In conclusion, based on the localized light-triggered release strategy, this study constructed a novel macrophage cytopharmaceutical that could localize and control drug release while retaining the activity of macrophages and exerting its immunotherapeutic effect, which could effectively treat solid tumors.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 11","pages":"Pages 5053-5068"},"PeriodicalIF":14.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142707029","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}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.06.011
Wei Wang , Shiwei Deng , Jinzhong Lin , Defang Ouyang
The lipid nanoparticle (LNP) has been so far proven as a strongly effective delivery system for mRNA and siRNA. However, the mechanisms of LNP's distribution, metabolism, and elimination are complicated, while the transportation and pharmacokinetics (PK) of LNP are just sparsely investigated and simply described. This study aimed to build a model for the transportation of RNA-LNP in Hela cells, rats, mice, and humans by physiologically based pharmacokinetic (PBPK) and quantum mechanics (QM) models with integrated multi-source data. LNPs with different ionizable lipids, particle sizes, and doses were modeled and compared by recognizing their critical parameters dominating PK. Some interesting results were found by the models. For example, the metabolism of ionizable lipids was first limited by the LNP disassembly rate instead of the hydrolyzation of ionizable lipids; the ability of RNA release from endosomes for three ionizable lipids was quantitively derived and can predict the probability of RNA release. Moreover, the biodegradability of three ionizable lipids was estimated by the QM method and the is generally consistent with the result of PBPK result. In summary, the transportation model of RNA LNP among various species for the first time was successfully constructed. Various in vitro and in vivo pieces of evidence were integrated through QM/PBPK multi-level modeling. The resulting new understandings are related to biodegradability, safety, and RNA release ability which are highly concerned issues of the formulation. This would benefit the design and research of RNA-LNP in the future.
{"title":"Modeling on in vivo disposition and cellular transportation of RNA lipid nanoparticles via quantum mechanics/physiologically-based pharmacokinetic approaches","authors":"Wei Wang , Shiwei Deng , Jinzhong Lin , Defang Ouyang","doi":"10.1016/j.apsb.2024.06.011","DOIUrl":"10.1016/j.apsb.2024.06.011","url":null,"abstract":"<div><div>The lipid nanoparticle (LNP) has been so far proven as a strongly effective delivery system for mRNA and siRNA. However, the mechanisms of LNP's distribution, metabolism, and elimination are complicated, while the transportation and pharmacokinetics (PK) of LNP are just sparsely investigated and simply described. This study aimed to build a model for the transportation of RNA-LNP in Hela cells, rats, mice, and humans by physiologically based pharmacokinetic (PBPK) and quantum mechanics (QM) models with integrated multi-source data. LNPs with different ionizable lipids, particle sizes, and doses were modeled and compared by recognizing their critical parameters dominating PK. Some interesting results were found by the models. For example, the metabolism of ionizable lipids was first limited by the LNP disassembly rate instead of the hydrolyzation of ionizable lipids; the ability of RNA release from endosomes for three ionizable lipids was quantitively derived and can predict the probability of RNA release. Moreover, the biodegradability of three ionizable lipids was estimated by the QM method and the is generally consistent with the result of PBPK result. In summary, the transportation model of RNA LNP among various species for the first time was successfully constructed. Various <em>in vitro</em> and <em>in vivo</em> pieces of evidence were integrated through QM/PBPK multi-level modeling. The resulting new understandings are related to biodegradability, safety, and RNA release ability which are highly concerned issues of the formulation. This would benefit the design and research of RNA-LNP in the future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4591-4607"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141775590","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}
Pub Date : 2024-10-01DOI: 10.1016/j.apsb.2024.05.019
Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products (PNPs). Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient production of PNPs through synthetic biology. In this study, we engineered Saccharomyces cerevisiae to optimize the microenvironment for boosting the activities of P450s, including coexpression with the redox partner genes, enhancing NADPH supply, expanding the endoplasmic reticulum (ER), strengthening heme biosynthesis, and regulating iron uptake. This created a platform for the efficient production 11,20-dihydroxyferruginol, a key intermediate of the bioactive compound tanshinones. The yield was enhanced by 42.1-fold through 24 effective genetic edits. The optimized strain produced up to 67.69 ± 1.33 mg/L 11,20-dihydroxyferruginol in shake flasks. Our work represents a promising advancement toward constructing yeast cell factories containing P450s and paves the way for microbial biosynthesis of tanshinones in the future.
{"title":"Engineering the microenvironment of P450s to enhance the production of diterpenoids in Saccharomyces cerevisiae","authors":"","doi":"10.1016/j.apsb.2024.05.019","DOIUrl":"10.1016/j.apsb.2024.05.019","url":null,"abstract":"<div><div>Cytochrome P450 enzymes play a crucial role as catalysts in the biosynthesis of numerous plant natural products (PNPs). Enhancing the catalytic activity of P450s in host microorganisms is essential for the efficient production of PNPs through synthetic biology. In this study, we engineered <em>Saccharomyces cerevisiae</em> to optimize the microenvironment for boosting the activities of P450s, including coexpression with the redox partner genes, enhancing NADPH supply, expanding the endoplasmic reticulum (ER), strengthening heme biosynthesis, and regulating iron uptake. This created a platform for the efficient production 11,20-dihydroxyferruginol, a key intermediate of the bioactive compound tanshinones. The yield was enhanced by 42.1-fold through 24 effective genetic edits. The optimized strain produced up to 67.69 ± 1.33 mg/L 11,20-dihydroxyferruginol in shake flasks. Our work represents a promising advancement toward constructing yeast cell factories containing P450s and paves the way for microbial biosynthesis of tanshinones in the future.</div></div>","PeriodicalId":6906,"journal":{"name":"Acta Pharmaceutica Sinica. B","volume":"14 10","pages":"Pages 4608-4618"},"PeriodicalIF":14.7,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141141231","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}
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