Pub Date : 2025-02-19DOI: 10.1016/j.jconrel.2025.02.018
Anshuman Dasgupta , Jan-Niklas May , Geir Klinkenberg , Helena C. Besse , Eva Miriam Buhl , Diana Moeckel , Rahaf Mihyar , Quim Peña , Armin Azadkhah Shalmani , Christopher Hark , Anne Rix , Susanne Koletnik , Josbert Metselaar , Yang Shi , Wim E. Hennink , Gert Storm , Dannis van Vuurden , Chrit Moonen , Mario Ries , Ruth Schmid , Twan Lammers
Brain tumors are difficult to target and treat. The blood-brain barrier (BBB) limits drug delivery to pathological sites, and standard mono-chemotherapy typically results in suboptimal efficacy and development of drug resistance. We here set out to load a synergistic drug combination in polymeric micelles, and combined them with ultrasound- and microbubble-mediated BBB opening in glioma models in mice. Via high-throughput screening of various chemotherapy combinations in different glioma cell lines, valrubicin and panobinostat were identified as a synergic drug combination and co-loaded in mPEG-b-p(HPMAm-Bz)-based polymeric micelles. Intravenous administration of double-drug micelles showed good tolerability and resulted in significant tumor growth inhibition in mice with subcutaneous GL261 gliomas. In orthotopically inoculated patient-derived HSJD-DIPG-007 diffuse intrinsic pontine gliomas, notoriously known to have an intact BBB and poor drug responsiveness, we provide initial experimental evidence showing that multidrug micelles plus sonopermeation can help to improve treatment efficacy. Our work exemplifies that synergistic drug combinations can be efficiently co-loaded in polymeric micelles, and that advanced nanosonochemotherapy combination regimens hold promise for the treatment of hard-to-treat brain tumors.
{"title":"Multidrug micelles and sonopermeation for chemotherapy co-delivery to brain tumors","authors":"Anshuman Dasgupta , Jan-Niklas May , Geir Klinkenberg , Helena C. Besse , Eva Miriam Buhl , Diana Moeckel , Rahaf Mihyar , Quim Peña , Armin Azadkhah Shalmani , Christopher Hark , Anne Rix , Susanne Koletnik , Josbert Metselaar , Yang Shi , Wim E. Hennink , Gert Storm , Dannis van Vuurden , Chrit Moonen , Mario Ries , Ruth Schmid , Twan Lammers","doi":"10.1016/j.jconrel.2025.02.018","DOIUrl":"10.1016/j.jconrel.2025.02.018","url":null,"abstract":"<div><div>Brain tumors are difficult to target and treat. The blood-brain barrier (BBB) limits drug delivery to pathological sites, and standard mono-chemotherapy typically results in suboptimal efficacy and development of drug resistance. We here set out to load a synergistic drug combination in polymeric micelles, and combined them with ultrasound- and microbubble-mediated BBB opening in glioma models in mice. Via high-throughput screening of various chemotherapy combinations in different glioma cell lines, valrubicin and panobinostat were identified as a synergic drug combination and <em>co</em>-loaded in mPEG-<em>b</em>-p(HPMAm-Bz)-based polymeric micelles. Intravenous administration of double-drug micelles showed good tolerability and resulted in significant tumor growth inhibition in mice with subcutaneous GL261 gliomas. In orthotopically inoculated patient-derived HSJD-DIPG-007 diffuse intrinsic pontine gliomas, notoriously known to have an intact BBB and poor drug responsiveness, we provide initial experimental evidence showing that multidrug micelles plus sonopermeation can help to improve treatment efficacy. Our work exemplifies that synergistic drug combinations can be efficiently <em>co</em>-loaded in polymeric micelles, and that advanced nanosonochemotherapy combination regimens hold promise for the treatment of hard-to-treat brain tumors.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 818-828"},"PeriodicalIF":10.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143433180","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 : 2025-02-19DOI: 10.1016/j.jconrel.2025.02.036
Xier Pan , Peng Xian , Yushu Li , Xiao Zhao , Jiaxin Zhang , Yangjie Song , Yunrong Nan , Shuting Ni , Kaili Hu
Inflammatory bowel disease (IBD) is closely linked to the dysregulation of intestinal homeostasis, accompanied by intestinal epithelial barrier destruction, dysbiosis of gut microbiota, subsequent inflammatory factor infiltration, and excessive oxidative stress. Conventional therapeutics focus on suppressing inflammation and often suffer from metabolic instability as well as limited targeting, thereby leading to suboptimal remission rates and severe side effects. Here, we designed bacterial outer membrane vesicle (OMV, from Stenotrophomonas maltophilia)-fused and borneol-modified liposomes (BO/OMV-lipo@LU) for targeted delivery of luteolin to recover intestinal homeostasis by alleviating inflammation and modulating dysregulated intestinal epithelial barrier, redox balance, and gut microbiota in IBD. In a Caco-2/HT29-MTX monolayer model, the OMV and borneol-bifunctionalized liposomes enhanced the uptake efficiency of unfunctionalized liposomes with a 2-fold increase. Owing to the chemotaxis-driven colon-targeting ability of OMVs and the ability of borneol to promote intestinal epithelial uptake, the hybrid liposomes successfully targeted the inflamed colon. In a colitis mouse model, BO/OMV-lipo@LU exhibited enhanced efficacy following oral administration. The BO/OMV-lipo@LU treatment increased the colon length and body weights of mice suffering colitis by 40 % and 15 %, respectively, with values comparable to the healthy control group. Notably, BO/OMV-lipo@LU alleviated proinflammatory markers, modulated redox balance, and restored the intestinal epithelial barrier. In addition, the formulation increased the abundance of beneficial microbiota while decreasing the abundance of harmful microbiota. These results demonstrated that this biomimetic nanoplatform could be exploited as a safe and effective gut-targeted delivery system in IBD treatment.
{"title":"Chemotaxis-driven hybrid liposomes recover intestinal homeostasis for targeted colitis therapy","authors":"Xier Pan , Peng Xian , Yushu Li , Xiao Zhao , Jiaxin Zhang , Yangjie Song , Yunrong Nan , Shuting Ni , Kaili Hu","doi":"10.1016/j.jconrel.2025.02.036","DOIUrl":"10.1016/j.jconrel.2025.02.036","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is closely linked to the dysregulation of intestinal homeostasis, accompanied by intestinal epithelial barrier destruction, dysbiosis of gut microbiota, subsequent inflammatory factor infiltration, and excessive oxidative stress. Conventional therapeutics focus on suppressing inflammation and often suffer from metabolic instability as well as limited targeting, thereby leading to suboptimal remission rates and severe side effects. Here, we designed bacterial outer membrane vesicle (OMV, from <em>Stenotrophomonas maltophilia</em>)-fused and borneol-modified liposomes (BO/OMV-lipo@LU) for targeted delivery of luteolin to recover intestinal homeostasis by alleviating inflammation and modulating dysregulated intestinal epithelial barrier, redox balance, and gut microbiota in IBD. In a Caco-2/HT29-MTX monolayer model, the OMV and borneol-bifunctionalized liposomes enhanced the uptake efficiency of unfunctionalized liposomes with a 2-fold increase. Owing to the chemotaxis-driven colon-targeting ability of OMVs and the ability of borneol to promote intestinal epithelial uptake, the hybrid liposomes successfully targeted the inflamed colon. In a colitis mouse model, BO/OMV-lipo@LU exhibited enhanced efficacy following oral administration. The BO/OMV-lipo@LU treatment increased the colon length and body weights of mice suffering colitis by 40 % and 15 %, respectively, with values comparable to the healthy control group. Notably, BO/OMV-lipo@LU alleviated proinflammatory markers, modulated redox balance, and restored the intestinal epithelial barrier. In addition, the formulation increased the abundance of beneficial microbiota while decreasing the abundance of harmful microbiota. These results demonstrated that this biomimetic nanoplatform could be exploited as a safe and effective gut-targeted delivery system in IBD treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 829-845"},"PeriodicalIF":10.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436686","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 : 2025-02-19DOI: 10.1016/j.jconrel.2025.02.024
Anqi Wei , Tianhao Ding , Guanghui Li , Feng Pan , Kaisong Tian , Ziwei Sun , Mengyuan Liu , Yinyu Ma , Zhiwei Guo , Yifei Yu , Changyou Zhan , Zui Zhang , Ye Zhu , Xiaoli Wei
The development of new antibiotics has lagged behind the rapid evolution of bacterial resistance, prompting the exploration of alternative antimicrobial strategies. Host-directed therapy (HDT) has emerged as a promising approach by harnessing innate immune system's natural defense mechanisms, which reduces reliance on antibiotics, and mitigates the development of resistance. Building on the important role of platelets in host immunity, activated platelet membrane vesicles (PLTv) are developed here as a host-directed therapy for broad-spectrum antibacterial infection management, leveraging several key mechanisms of action. PLTv neutralizes bacterial toxins, thereby reducing cytotoxicity. The presence of platelet receptors on PLTv enables them to act as decoys, binding bacteria through receptor interactions and facilitating their phagocytosis by neutrophils and macrophages. Additionally, PLTv bound to bacteria promote the formation of neutrophil extracellular traps (NETs), enhancing the immune system's ability to trap and kill bacteria. In mouse models of pulmonary infections caused by the Methicillin-resistant Staphylococcus aureus, P. aeruginosa, and A. baumannii, administration of PLTv significantly reduces bacterial counts in the lungs and protects against mortality. Taken together, the present work highlights PLTv as a promising host-directed therapy for combating broad-spectrum pulmonary drug-resistant bacterial infections, leveraging their ability to neutralize toxins, act as decoys, promote phagocytosis, and facilitate NETs formation.
{"title":"Activated platelet membrane vesicles for broad-spectrum bacterial pulmonary infections management","authors":"Anqi Wei , Tianhao Ding , Guanghui Li , Feng Pan , Kaisong Tian , Ziwei Sun , Mengyuan Liu , Yinyu Ma , Zhiwei Guo , Yifei Yu , Changyou Zhan , Zui Zhang , Ye Zhu , Xiaoli Wei","doi":"10.1016/j.jconrel.2025.02.024","DOIUrl":"10.1016/j.jconrel.2025.02.024","url":null,"abstract":"<div><div>The development of new antibiotics has lagged behind the rapid evolution of bacterial resistance, prompting the exploration of alternative antimicrobial strategies. Host-directed therapy (HDT) has emerged as a promising approach by harnessing innate immune system's natural defense mechanisms, which reduces reliance on antibiotics, and mitigates the development of resistance. Building on the important role of platelets in host immunity, activated platelet membrane vesicles (PLTv) are developed here as a host-directed therapy for broad-spectrum antibacterial infection management, leveraging several key mechanisms of action. PLTv neutralizes bacterial toxins, thereby reducing cytotoxicity. The presence of platelet receptors on PLTv enables them to act as decoys, binding bacteria through receptor interactions and facilitating their phagocytosis by neutrophils and macrophages. Additionally, PLTv bound to bacteria promote the formation of neutrophil extracellular traps (NETs), enhancing the immune system's ability to trap and kill bacteria. In mouse models of pulmonary infections caused by the Methicillin-resistant <em>Staphylococcus aureus</em>, <em>P. aeruginosa</em>, and <em>A. baumannii</em>, administration of PLTv significantly reduces bacterial counts in the lungs and protects against mortality. Taken together, the present work highlights PLTv as a promising host-directed therapy for combating broad-spectrum pulmonary drug-resistant bacterial infections, leveraging their ability to neutralize toxins, act as decoys, promote phagocytosis, and facilitate NETs formation.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 846-859"},"PeriodicalIF":10.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414353","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 : 2025-02-19DOI: 10.1016/j.jconrel.2025.02.027
Hongjuan Zhao , Mengya Niu , Yuxin Guo , Qing Li , Yinke Wang , Qianqian Jiang , Qingling Song , Yi Zhang , Lei Wang
Abnormal metabolism of melanoma cells on lipids reveals that breaking their lipid addiction provides a starvation strategy to enhance immunotherapy effects and reduce resistance. Herein, we propose an extracellular matrix-inspired scaffold fabricated by multiple cross-linking of collagen and elastin encapsulated with fatty acid transporter proteins (FATP) inhibitor lipofermata (Lipo) to close the “valve” of lipid transported into both melanoma cells and pro-tumor neutrophils. Meanwhile, model TGF-β inhibitor loaded in scaffold synergized with Lipo to polarize postoperative locally enriched neutrophils towards cytotoxic N1 phenotypes after blocking their energy supply and modulate postsurgical immunosuppressive tumor microenvironment. These N1 neutrophils induced tumor pyroptosis through a reactive oxygen species (ROS)-dependent pathway under melanoma cells suffered starvation, and the intracellular contents released from dead melanoma cells stimulated macrophages into producing proinflammatory cytokines, which recruited a secondary wave of neutrophils to the tumor site. Benefiting from the N1 neutrophil induced tumor pyroptosis feedback loop in situ, adaptive and memory antitumor immunity is activated for suppressing aggressive melanoma recurrence and metastasis. Altogether, this lipid starvation strategy synergized with neutrophil activation for amplification of tumor-specific immunotherapy provides a new paradigm for pyroptosis-mediated postsurgical melanoma therapy.
{"title":"A lipid starvation strategy-synergized neutrophil activation for postoperative melanoma immunotherapy","authors":"Hongjuan Zhao , Mengya Niu , Yuxin Guo , Qing Li , Yinke Wang , Qianqian Jiang , Qingling Song , Yi Zhang , Lei Wang","doi":"10.1016/j.jconrel.2025.02.027","DOIUrl":"10.1016/j.jconrel.2025.02.027","url":null,"abstract":"<div><div>Abnormal metabolism of melanoma cells on lipids reveals that breaking their lipid addiction provides a starvation strategy to enhance immunotherapy effects and reduce resistance. Herein, we propose an extracellular matrix-inspired scaffold fabricated by multiple cross-linking of collagen and elastin encapsulated with fatty acid transporter proteins (FATP) inhibitor lipofermata (Lipo) to close the “valve” of lipid transported into both melanoma cells and pro-tumor neutrophils. Meanwhile, model TGF-β inhibitor loaded in scaffold synergized with Lipo to polarize postoperative locally enriched neutrophils towards cytotoxic N1 phenotypes after blocking their energy supply and modulate postsurgical immunosuppressive tumor microenvironment. These N1 neutrophils induced tumor pyroptosis through a reactive oxygen species (ROS)-dependent pathway under melanoma cells suffered starvation, and the intracellular contents released from dead melanoma cells stimulated macrophages into producing proinflammatory cytokines, which recruited a secondary wave of neutrophils to the tumor site. Benefiting from the N1 neutrophil induced tumor pyroptosis feedback loop in situ, adaptive and memory antitumor immunity is activated for suppressing aggressive melanoma recurrence and metastasis. Altogether, this lipid starvation strategy synergized with neutrophil activation for amplification of tumor-specific immunotherapy provides a new paradigm for pyroptosis-mediated postsurgical melanoma therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 860-874"},"PeriodicalIF":10.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425369","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}
Heteroduplex oligonucleotide (HDO) is a novel oligonucleotide therapeutic consisting of an antisense oligonucleotide (ASO) and its complementary RNA. A recent report showed that cholesterol-conjugated HDO (Chol-HDO) exhibited antisense activity in various tissues, including the brain; however, little information is available on the pharmacokinetic and plasma protein-binding properties of HDO and Chol-HDO. In the present study, we investigated the tissue distributions of an ASO, HDO, and Chol-HDO in mice and rats after intravenous injection. Tissue distribution was evaluated by measuring the concentration of ASO in tissue samples using liquid chromatography and tandem mass spectroscopy. ASO and HDO disappeared rapidly from the plasma, whereas Chol-HDO showed prolonged retention in the systemic circulation. The amount of ASO in the brain tissue was highest after injection of Chol-HDO, confirming its efficient delivery to the brain. The tissue distribution of oligonucleotides differed less in rats than in mice. Hepatic uptake of ASO and HDO, but not of Chol-HDO, was significantly inhibited by co-administration with the scavenger receptor inhibitor dextran sulfate sodium. The binding to plasma proteins was evaluated. Compared to ASO, HDO showed lower protein binding, but Chol-HDO showed much higher binding, with remarkable differences in binding to high-density and low-density lipoproteins. The binding of Chol-HDO to these proteins was also confirmed in mouse plasma after injection. These results indicate that the binding of Chol-HDO to plasma proteins, especially lipoproteins, is critical for determining tissue distribution and brain delivery after intravenous injection.
{"title":"Pharmacokinetics and protein binding of cholesterol-conjugated heteroduplex oligonucleotide","authors":"Yukitake Yoshioka , Syunsuke Yamamoto , Kosuke Kusamori , Miyu Nakayama , Hisashi Fujita , Akihiko Goto , Shinji Iwasaki , Tetsuya Nagata , Shoko Itakura , Hiroyuki Kusuhara , Takanori Yokota , Hideki Hirabayashi , Makiya Nishikawa","doi":"10.1016/j.jconrel.2025.02.025","DOIUrl":"10.1016/j.jconrel.2025.02.025","url":null,"abstract":"<div><div>Heteroduplex oligonucleotide (HDO) is a novel oligonucleotide therapeutic consisting of an antisense oligonucleotide (ASO) and its complementary RNA. A recent report showed that cholesterol-conjugated HDO (Chol-HDO) exhibited antisense activity in various tissues, including the brain; however, little information is available on the pharmacokinetic and plasma protein-binding properties of HDO and Chol-HDO. In the present study, we investigated the tissue distributions of an ASO, HDO, and Chol-HDO in mice and rats after intravenous injection. Tissue distribution was evaluated by measuring the concentration of ASO in tissue samples using liquid chromatography and tandem mass spectroscopy. ASO and HDO disappeared rapidly from the plasma, whereas Chol-HDO showed prolonged retention in the systemic circulation. The amount of ASO in the brain tissue was highest after injection of Chol-HDO, confirming its efficient delivery to the brain. The tissue distribution of oligonucleotides differed less in rats than in mice. Hepatic uptake of ASO and HDO, but not of Chol-HDO, was significantly inhibited by co-administration with the scavenger receptor inhibitor dextran sulfate sodium. The binding to plasma proteins was evaluated. Compared to ASO, HDO showed lower protein binding, but Chol-HDO showed much higher binding, with remarkable differences in binding to high-density and low-density lipoproteins. The binding of Chol-HDO to these proteins was also confirmed in mouse plasma after injection. These results indicate that the binding of Chol-HDO to plasma proteins, especially lipoproteins, is critical for determining tissue distribution and brain delivery after intravenous injection.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 787-799"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414357","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 : 2025-02-18DOI: 10.1016/j.jconrel.2025.02.034
Jie Liu , Zhigui He , Xian Qin , Kun Zhang , Kai Qu , Yuan Zhong , Weihu Yang , Wei Wu
A right-side-out orientated self-assembly of cell membrane-camouflaged theranostic nanoplatform is crucial for ensuring their biological functionality inherited from the source cells. However, the low specificity and fluorescence background interference hampered reliable assessment of lipids content in plaques. In this work, a spontaneous right-side-out coupling-driven ROS-responsive theranostic nanoplatform has been developed to enhance accumulation within atherosclerotic plaques, target lipids imaging in plaques, reduce the interference from background fluorescence and inhibit the progression of atherosclerosis (AS). A ROS-responsive lipid-unlocked fluorescent probe is constructed, followed by loading rapamycin (RAP) for safe and efficient AS therapy. Moreover, the theranostic nanoplatform is functionalized with PS-targeted peptide for binding to phosphatidylserine located on the inner leaflet of the macrophage membrane, harvesting a right-side-out-orientated coating theranostics formulation (M-TPCR) for the reliable imaging of lipids in lipids-sufficient Hela cells, foam cells and atherosclerotic plaques while keeping in fluorescence off in lipid-deficient environments, such as M0 macrophages, M1 macrophages and blood. Most importantly, the FL signals of M-TPCR are positively correlated with lipid content across foam cells, isolated aorta or aortic root sections, confirming its reliability in indicating plaques. Hence, M-TPCR provides a powerful approach for developing the biomimetic cell membrane camouflaged nanotechnology and delivers an impressive potential on the therapeutic efficacy monitoring.
{"title":"Macrophage membrane enveloped on double-locked nanoplatform with right-side-out orientation to improving precise theranostic for atherosclerosis","authors":"Jie Liu , Zhigui He , Xian Qin , Kun Zhang , Kai Qu , Yuan Zhong , Weihu Yang , Wei Wu","doi":"10.1016/j.jconrel.2025.02.034","DOIUrl":"10.1016/j.jconrel.2025.02.034","url":null,"abstract":"<div><div>A right-side-out orientated self-assembly of cell membrane-camouflaged theranostic nanoplatform is crucial for ensuring their biological functionality inherited from the source cells. However, the low specificity and fluorescence background interference hampered reliable assessment of lipids content in plaques. In this work, a spontaneous right-side-out coupling-driven ROS-responsive theranostic nanoplatform has been developed to enhance accumulation within atherosclerotic plaques, target lipids imaging in plaques, reduce the interference from background fluorescence and inhibit the progression of atherosclerosis (AS). A ROS-responsive lipid-unlocked fluorescent probe is constructed, followed by loading rapamycin (RAP) for safe and efficient AS therapy. Moreover, the theranostic nanoplatform is functionalized with PS-targeted peptide for binding to phosphatidylserine located on the inner leaflet of the macrophage membrane, harvesting a right-side-out-orientated coating theranostics formulation (M-TPCR) for the reliable imaging of lipids in lipids-sufficient Hela cells, foam cells and atherosclerotic plaques while keeping in fluorescence off in lipid-deficient environments, such as M0 macrophages, M1 macrophages and blood. Most importantly, the FL signals of M-TPCR are positively correlated with lipid content across foam cells, isolated aorta or aortic root sections, confirming its reliability in indicating plaques. Hence, M-TPCR provides a powerful approach for developing the biomimetic cell membrane camouflaged nanotechnology and delivers an impressive potential on the therapeutic efficacy monitoring.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 800-817"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143436685","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 : 2025-02-18DOI: 10.1016/j.jconrel.2025.02.026
Youjia Zhang , Xiaoguang Ge , Shi Gao , Jibin Song
Gold nanorods (AuNRs) have become promising as radiosensitizers and photoacoustic (PA) imaging agents due to their strong X-ray attenuation ability and adjustable near-infrared (NIR) absorption. However, there remains room to further improve AuNRs for the imaging and treatment of tumors. We developed a biomarker responsive AuNR-based Janus nanoprobe by integrating MnO2 on one end of the AuNRs and specific ligands on the other end. In the tumor microenvironment, highly expressed transglutaminase (TGase), which facilitates the formation of isopeptide linkages between glutamine (Gln) and lysine (Lys), induces the aggregation of AuNRs. This in-situ aggregation amplifies the PA signal, extends the time window for PA imaging and enhances the radiosensitization effect. Meanwhile, the highly expressed glutathione (GSH) in tumors degrades MnO2 which triggers a chemodynamic treatment.
{"title":"Glutathione and transglutaminase responsive janus gold nanorods for photoacoustic imaging-guided radiotherapy and chemodynamic therapy of tumors","authors":"Youjia Zhang , Xiaoguang Ge , Shi Gao , Jibin Song","doi":"10.1016/j.jconrel.2025.02.026","DOIUrl":"10.1016/j.jconrel.2025.02.026","url":null,"abstract":"<div><div>Gold nanorods (AuNRs) have become promising as radiosensitizers and photoacoustic (PA) imaging agents due to their strong X-ray attenuation ability and adjustable near-infrared (NIR) absorption. However, there remains room to further improve AuNRs for the imaging and treatment of tumors. We developed a biomarker responsive AuNR-based Janus nanoprobe by integrating MnO<sub>2</sub> on one end of the AuNRs and specific ligands on the other end. In the tumor microenvironment, highly expressed transglutaminase (TGase), which facilitates the formation of isopeptide linkages between glutamine (Gln) and lysine (Lys), induces the aggregation of AuNRs. This <em>in-situ</em> aggregation amplifies the PA signal, extends the time window for PA imaging and enhances the radiosensitization effect. Meanwhile, the highly expressed glutathione (GSH) in tumors degrades MnO<sub>2</sub> which triggers a chemodynamic treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 751-759"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414355","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 : 2025-02-18DOI: 10.1016/j.jconrel.2025.02.020
Xue Wei , Ming Yang , Haoyang Zou , Songjie Shen , Yuechong Li , Li Chen , Yahui Liu , Di Li , Jianxun Ding
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) selectively arrest malignant cells in the G1 phase of cell cycle by inhibiting CDK4/6-mediated phosphorylation of retinoblastoma protein. However, CDK4/6i therapy is often ineffective against triple-negative breast cancer (TNBC) due to the high lysosomal content in TNBC cells, which sequesters the drugs and prevents them from reaching their nuclear target. To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels composed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-co-L-cystine) (mPEG−P(Glu10-co-Cys25)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells. These nanogels bypassed lysosomal sequestration, thereby enhancing the efficacy of molecularly targeted immunotherapy. Among the nanogels, the formulation with mPEG2000 (NG2000) exhibited the highest efficiency in delivering ABE, resulting in increased cell apoptosis, activation of an anti-cancer immune response, reduction of immunosuppression, and improved therapeutic outcomes against TNBC. Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66%. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.
{"title":"Poly(amino acid) nanoformulation of cyclin-dependent kinase 4 and 6 inhibitor for molecularly targeted immunotherapy in triple-negative breast cancer","authors":"Xue Wei , Ming Yang , Haoyang Zou , Songjie Shen , Yuechong Li , Li Chen , Yahui Liu , Di Li , Jianxun Ding","doi":"10.1016/j.jconrel.2025.02.020","DOIUrl":"10.1016/j.jconrel.2025.02.020","url":null,"abstract":"<div><div>Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) selectively arrest malignant cells in the G1 phase of cell cycle by inhibiting CDK4/6-mediated phosphorylation of retinoblastoma protein. However, CDK4/6i therapy is often ineffective against triple-negative breast cancer (TNBC) due to the high lysosomal content in TNBC cells, which sequesters the drugs and prevents them from reaching their nuclear target. To address this challenge, three pH- and glutathione-responsive poly(amino acid) nanogels c<em>o</em>mposed of methoxy poly(ethylene glycol) of various lengths and poly(L-glutamic acid-<em>co</em>-L-cystine) (mPEG−P(Glu<sub>10</sub>-<em>co</em>-Cys<sup>2</sup><sub>5</sub>)) were developed to efficiently deliver the CDK4/6i abemaciclib (ABE) to TNBC cells. These nanogels bypassed lysosomal sequestration, thereby enhancing the efficacy of molecularly targeted immunotherapy. Among the nanogels, the formulation with mPEG2000 (NG2000) exhibited the highest efficiency in delivering ABE, resulting in increased cell apoptosis, activation of an anti-cancer immune response, reduction of immunosuppression, and improved therapeutic outcomes against TNBC. Furthermore, NG2000/ABE enhanced immune checkpoint therapy for TNBC, achieving a tumor inhibition rate of 89.66%. These findings demonstrate the potential of poly(amino acid) nanoformulations for delivering CDK4/6 inhibitors as molecularly targeted immunotherapy for TNBC in clinical applications.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 760-772"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414359","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 : 2025-02-18DOI: 10.1016/j.jconrel.2025.02.019
Xinxin Xie , Jinxia Zhang , Lihong Sun , Shuyu Xu , Shiti Sha Ma , Haonan Wang , Xiaoda Li , Qiong Xiang , Ligang Cui , Xiaolong Liang
Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. In vitro experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. In vivo animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.
{"title":"Ultrasound-triggered topical oxygen delivery enhances synergistic sonodynamic and antibody therapies against hypoxic gastric cancer","authors":"Xinxin Xie , Jinxia Zhang , Lihong Sun , Shuyu Xu , Shiti Sha Ma , Haonan Wang , Xiaoda Li , Qiong Xiang , Ligang Cui , Xiaolong Liang","doi":"10.1016/j.jconrel.2025.02.019","DOIUrl":"10.1016/j.jconrel.2025.02.019","url":null,"abstract":"<div><div>Hypoxia is a common feature of malignant tumors, which can accelerate tumor growth and reduce the sensitivity of chemotherapy and sonodynamic therapy by activating the hypoxia-inducible factor (HIF) signaling pathway. In HER2-positive gastric cancer, HER2 overexpression enhances HIF-1α synthesis, exacerbating hypoxia and impairing sonodynamic therapy. It also reduces trastuzumab-mediated antibody-dependent cytotoxicity, significantly compromising therapeutic outcomes. Herein, pyropheophorbide-conjugated lipid (pyropheophorbide-lipid, PL) and trastuzumab were fabricated into targeted nanoparticles (TP NPs) for loading perfluorobromooctane (PFOB) carrying oxygen (TPPO NPs), thus enabling oxygen self-supplied sonodynamic and antibody therapies. <em>In vitro</em> experiments showed that antibody targeting significantly increased the cellular uptake of sonosensitizers, and the controlled release of oxygen was dependent on ultrasound parameters, greatly enhancing the killing effects of SDT and antibody therapy. <em>In vivo</em> animal experiments showed that TPPO NPs-mediated enhanced permeation and retention (EPR) effects, along with antibody targeting, improved the enrichment of sonosensitizers in tumors. Notably, ultrasound-triggered topical delivery of oxygen significantly alleviated tumor hypoxia and further improved the efficacy of SDT and antibody therapy. Given the good biosafety profile of TPPO NPs, this system holds great promise for future clinical applications in gastric cancer.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 736-750"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414366","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 : 2025-02-18DOI: 10.1016/j.jconrel.2025.02.035
Tulin Ozbek , Hatice Demir , Senanur Dokuz , Semra Tasdurmazli , Utku Ozbey , Mehmet Ozbil , Murat Topuzogullari , Irfan Cinar , Murat Karamese , Selina Aksak Karamese , Serap Acar , Omer Faruk Bayrak , Elif Cadirci
The rapid increase in bacterial resistance to existing treatments underscores the critical need for novel therapeutic strategies. Here, an innovative approach using targeted nanocarrier systems that mimic phage-bacteria interactions through phage receptor binding protein (Gp45 from the ϕ11 lysogenic phage) or derived peptides (P1, P2, P3, P4, P5), are introduced. These nanodrugs, exhibited receptor-ligand specificity and strong binding affinity, for the first time, were employed for the precise delivery and targeting of antibiotics within living organisms. The actively targeted micelles via two methods were produced; conjugating GP45 to dual antibiotic-loaded PLGA-b-PEG micelles (MiGp45) and the synthesis of peptide-conjugated micelles with dual antibiotic-loaded PLGA-b-PEG-peptide triblock copolymers. The untargeted nano-drug reduced MIC values by 2–10 times for vancomycin and 9–75 times for oxacillin, resulting in a synergistic effect. MiGp45 and MiP1-targeted micelles further reduced MIC values at least twofold, up to ninefold in resistant strains, indicating significant antibacterial improvement. In a mouse model of sepsis by S. aureus, MiGp45 treatment resulted in complete recovery as opposed to death in the untreated group, significantly reduced bacterial load, pro-inflammatory cytokine expression, lung injury, and normalized oxidative stress. The phage-based nanodrugs show tremendous promise as a highly effective antimicrobial treatment targeting multidrug- resistant pathogens.
{"title":"Phage-inspired targeting of antibiotic-loaded polymeric micelles for enhanced therapeutic efficacy against monomicrobial sepsis","authors":"Tulin Ozbek , Hatice Demir , Senanur Dokuz , Semra Tasdurmazli , Utku Ozbey , Mehmet Ozbil , Murat Topuzogullari , Irfan Cinar , Murat Karamese , Selina Aksak Karamese , Serap Acar , Omer Faruk Bayrak , Elif Cadirci","doi":"10.1016/j.jconrel.2025.02.035","DOIUrl":"10.1016/j.jconrel.2025.02.035","url":null,"abstract":"<div><div>The rapid increase in bacterial resistance to existing treatments underscores the critical need for novel therapeutic strategies. Here, an innovative approach using targeted nanocarrier systems that mimic phage-bacteria interactions through phage receptor binding protein (Gp45 from the ϕ11 lysogenic phage) or derived peptides (P1, P2, P3, P4, P5), are introduced. These nanodrugs, exhibited receptor-ligand specificity and strong binding affinity, for the first time, were employed for the precise delivery and targeting of antibiotics within living organisms. The actively targeted micelles via two methods were produced; conjugating GP45 to dual antibiotic-loaded PLGA-b-PEG micelles (MiGp45) and the synthesis of peptide-conjugated micelles with dual antibiotic-loaded PLGA-b-PEG-peptide triblock copolymers. The untargeted nano-drug reduced MIC values by 2–10 times for vancomycin and 9–75 times for oxacillin, resulting in a synergistic effect. MiGp45 and MiP1-targeted micelles further reduced MIC values at least twofold, up to ninefold in resistant strains, indicating significant antibacterial improvement. In a mouse model of sepsis by <em>S. aureus</em>, MiGp45 treatment resulted in complete recovery as opposed to death in the untreated group, significantly reduced bacterial load, pro-inflammatory cytokine expression, lung injury, and normalized oxidative stress. The phage-based nanodrugs show tremendous promise as a highly effective antimicrobial treatment targeting multidrug- resistant pathogens.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"380 ","pages":"Pages 773-786"},"PeriodicalIF":10.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427610","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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