Pub Date : 2025-04-03DOI: 10.1016/j.jconrel.2025.113686
Juan Sun, Jiangtao Yang, Jiakun Guo, Lei Tao, Bin Xu, Guanglin Wang, Fenghua Meng, Zhiyuan Zhong
Alpha radionuclide with a high emitting energy and short emitting range has emerged as a new tool for the treatment of advanced tumors; however, its clinical usage stringently depends on delivery vehicle. Here, we report on Sigma-1 receptor and PSMA dual-specific peptide with efficient 225‑actinium labeling (225Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. 225Ac-S1R/PSMA-P with a high specific activity and radiostability exhibited upgraded cell binding and uptake while diminished efflux in RM1-PSMA+ cancer cells. Intriguingly, 225Ac-S1R/PSMA-P afforded a peak uptake of 34.7 ± 3.2 %ID/g and elevated the radioactivity in the tumor over 7 days, with a tumor/kidney ratio of 12.2 ± 1.2 and minimal deposition in blood and other normal tissues like liver and muscle. A single injection of 225Ac-S1R/PSMA-P effectively shrank large LNCaP-FGC tumors at 1.85 or 5.5 kBq, and completely eradicated highly malignant murine RM1-PSMA+/RM1 tumors at 33.3 kBq. We further showed that 225Ac-S1R/PSMA-P at a low dose of 3.7 kBq could boost immune checkpoint blockade therapy of murine RM1-PSMA+/RM1 tumor, leading to 5 out of 7 mice tumor-free that showed durable antitumor immune memory. 225Ac-S1R/PSMA-P with excellent targeting and immune activation ability has a great clinical potential for treating advanced prostate cancer patients.
{"title":"Dual-targeted alpha therapy mitigates prostate cancer and boosts immune checkpoint blockade therapy","authors":"Juan Sun, Jiangtao Yang, Jiakun Guo, Lei Tao, Bin Xu, Guanglin Wang, Fenghua Meng, Zhiyuan Zhong","doi":"10.1016/j.jconrel.2025.113686","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113686","url":null,"abstract":"Alpha radionuclide with a high emitting energy and short emitting range has emerged as a new tool for the treatment of advanced tumors; however, its clinical usage stringently depends on delivery vehicle. Here, we report on Sigma-1 receptor and PSMA dual-specific peptide with efficient 225‑actinium labeling (<sup>225</sup>Ac-S1R/PSMA-P) for targeted alpha therapy and alpha-immunotherapy of murine prostate tumor. <sup>225</sup>Ac-S1R/PSMA-P with a high specific activity and radiostability exhibited upgraded cell binding and uptake while diminished efflux in RM1-PSMA<sup>+</sup> cancer cells. Intriguingly, <sup>225</sup>Ac-S1R/PSMA-P afforded a peak uptake of 34.7 ± 3.2 %ID/g and elevated the radioactivity in the tumor over 7 days, with a tumor/kidney ratio of 12.2 ± 1.2 and minimal deposition in blood and other normal tissues like liver and muscle. A single injection of <sup>225</sup>Ac-S1R/PSMA-P effectively shrank large LNCaP-FGC tumors at 1.85 or 5.5 kBq, and completely eradicated highly malignant murine RM1-PSMA<sup>+</sup>/RM1 tumors at 33.3 kBq. We further showed that <sup>225</sup>Ac-S1R/PSMA-P at a low dose of 3.7 kBq could boost immune checkpoint blockade therapy of murine RM1-PSMA<sup>+</sup>/RM1 tumor, leading to 5 out of 7 mice tumor-free that showed durable antitumor immune memory. <sup>225</sup>Ac-S1R/PSMA-P with excellent targeting and immune activation ability has a great clinical potential for treating advanced prostate cancer patients.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"32 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766322","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}
Polymersomes, which are polymer vesicles containing an aqueous cavity enclosed in a polymer membrane, hold enormous potential for biomedical applications. In recent years, enzyme-loaded polymersomes, serving as therapeutic nanoreactors, have drawn substantial interest. A crucial requirement for effective catalytic function is to impart semipermeability to the vesicular membrane while maintaining its role as a protective barrier for encapsulated enzymes. However, achieving both long-term stability and optimal membrane permeability for sustained functionality remains a challenge in many reported examples. In this study, we introduce ROS-responsive polyion complex vesicles (PICsomes) loaded with antioxidant enzymes (catalase) as antioxidative nanoreactors. The intrinsic semipermeability and crosslinked network structure of the membrane enable long-lasting catalytic function of catalase. The nanoreactor exhibits inherent cell-protective properties against oxidative stress in fibroblasts due to the ROS-scavenging ability of polymers. Notably, triggered by ROS, the nanoreactor demonstrates autoregulatory control of redox homeostasis. This is because the cysteamine released by PICsomes not only acts as a free radical scavenger but also facilitates the transport of L-cysteine into cells, thereby enhancing glutathione (GSH) biosynthesis. The results further demonstrate significant long blood circulation of PICsomes loaded with catalase and strong protection effects against bloodstream oxidative stress, paving the way for the further development of truly effective in vivo therapeutics. These findings underscore the potential of the engineered antioxidative nanoreactor with durable functionality as synthetic organelles for cellular protection against oxidative stress.
{"title":"Engineering durable antioxidative nanoreactors as synthetic organelles for autoregulatory cellular protection against oxidative stress","authors":"Panyue Wen, Anjaneyulu Dirisala, Haocheng Guo, Xueying Liu, Shingo Kobayashi, Hiroaki Kinoh, Takahisa Anada, Masaru Tanaka, Kazunori Kataoka, Junjie Li","doi":"10.1016/j.jconrel.2025.113683","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113683","url":null,"abstract":"Polymersomes, which are polymer vesicles containing an aqueous cavity enclosed in a polymer membrane, hold enormous potential for biomedical applications. In recent years, enzyme-loaded polymersomes, serving as therapeutic nanoreactors, have drawn substantial interest. A crucial requirement for effective catalytic function is to impart semipermeability to the vesicular membrane while maintaining its role as a protective barrier for encapsulated enzymes. However, achieving both long-term stability and optimal membrane permeability for sustained functionality remains a challenge in many reported examples. In this study, we introduce ROS-responsive polyion complex vesicles (PICsomes) loaded with antioxidant enzymes (catalase) as antioxidative nanoreactors. The intrinsic semipermeability and crosslinked network structure of the membrane enable long-lasting catalytic function of catalase. The nanoreactor exhibits inherent cell-protective properties against oxidative stress in fibroblasts due to the ROS-scavenging ability of polymers. Notably, triggered by ROS, the nanoreactor demonstrates autoregulatory control of redox homeostasis. This is because the cysteamine released by PICsomes not only acts as a free radical scavenger but also facilitates the transport of L-cysteine into cells, thereby enhancing glutathione (GSH) biosynthesis. The results further demonstrate significant long blood circulation of PICsomes loaded with catalase and strong protection effects against bloodstream oxidative stress, paving the way for the further development of truly effective in vivo therapeutics. These findings underscore the potential of the engineered antioxidative nanoreactor with durable functionality as synthetic organelles for cellular protection against oxidative stress.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"58 20 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758145","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 : 2025-04-02DOI: 10.1016/j.jconrel.2025.113672
Chia-Yu Chang, Shih-Hsun Huang, Chong-Yan Chen, Cheng-Bang Jian, Ching-Chung Chang, Yu-Yao Chang, Mira Jung, Hsien-Ming Lee, Bill Cheng
In current drug delivery strategies, the efficiency of most carriers still largely depends on their ability to passively infiltrate target tissues. To overcome this limitation, we developed monocyte-adhesive peptidyl liposomes, termed monocyte-mediated drug carriers (MMDCs). These carriers are designed to exploit the innate chemotactic properties of monocytes, which actively home to diseased tissues. MMDCs were shown to effectively hitchhike on circulating monocytes (THP-1 cells) under physiological flow conditions. Their targeting specificity was further demonstrated in a 3D microfluidic culture system consisting of human breast cancer spheroids (MDA-MB-231) embedded in a collagen matrix, overlaid with a human endothelial cell-derived barrier. MMDCs underwent trans-endothelial migration via monocyte hitchhiking and selectively recognized collagen matrices containing MDA-MB-231 cells, but not those embedded with non-cancerous cells. In vitro assays revealed that doxorubicin encapsulated in MMDCs was released into the extracellular environment following phagocytosis of the carriers by THP-1-derived macrophages. In a xenograft mouse model, MMDCs exhibited high tumor-targeting efficiency. By harnessing the homing capability of monocytes, MMDCs significantly improved drug biodistribution at the disease site, thereby enhancing the therapeutic efficacy of the encapsulated agents.
{"title":"Monocyte-adhesive peptidyl liposomes for harnessing monocyte homing to tumor tissues","authors":"Chia-Yu Chang, Shih-Hsun Huang, Chong-Yan Chen, Cheng-Bang Jian, Ching-Chung Chang, Yu-Yao Chang, Mira Jung, Hsien-Ming Lee, Bill Cheng","doi":"10.1016/j.jconrel.2025.113672","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113672","url":null,"abstract":"In current drug delivery strategies, the efficiency of most carriers still largely depends on their ability to passively infiltrate target tissues. To overcome this limitation, we developed monocyte-adhesive peptidyl liposomes, termed monocyte-mediated drug carriers (MMDCs). These carriers are designed to exploit the innate chemotactic properties of monocytes, which actively home to diseased tissues. MMDCs were shown to effectively hitchhike on circulating monocytes (THP-1 cells) under physiological flow conditions. Their targeting specificity was further demonstrated in a 3D microfluidic culture system consisting of human breast cancer spheroids (MDA-MB-231) embedded in a collagen matrix, overlaid with a human endothelial cell-derived barrier. MMDCs underwent trans-endothelial migration <em>via</em> monocyte hitchhiking and selectively recognized collagen matrices containing MDA-MB-231 cells, but not those embedded with non-cancerous cells. <em>In vitro</em> assays revealed that doxorubicin encapsulated in MMDCs was released into the extracellular environment following phagocytosis of the carriers by THP-1-derived macrophages. In a xenograft mouse model, MMDCs exhibited high tumor-targeting efficiency. By harnessing the homing capability of monocytes, MMDCs significantly improved drug biodistribution at the disease site, thereby enhancing the therapeutic efficacy of the encapsulated agents.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"58 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766379","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 : 2025-04-02DOI: 10.1016/j.jconrel.2025.113681
Andrew McLain, Amanda Kowalczyk, Paulina Baran-Rachwalska, Flavia Maria Sutera, Louise J. Robertson, Nadia Sukusu Nielsen, Jan J. Enghild, Diego Cobice, Filippo Bonelli, Vanessa Barbaro, Stefano Ferrari, Benjamin Patterson, Luca Moore, John Marshall, M. Andrew Nesbit, Tara Moore
In recent years, success has been achieved in treating several eye conditions with oligonucleotide-based therapies. Herein, we outline the experimentation involved in progressing selection and development of a lead therapeutic siRNA for R124H mutation of TGFBI gene which causes Granular Corneal Dystrophy Type 2 (GCD2/Avellino CD). Firstly, a series of siRNA designs, generated by a gene walk across the R124H TGFBI mutation site, were tested and a lead siRNA identified. The lead siRNA was delivered into an immortalised human corneal epithelial cell line to assess on-target efficacy and off-target effects. The in vivo efficacy of the lead R124H TGFBI siRNA, complexed with Bio-Courier technology, silicon stabilized hybrid lipid nanoparticles (sshLNP), was assessed in a mouse model of GCD2 which expressed the human R124H TGFBI transgene. Following topical siRNA application for 5 consecutive days, expression of the R124H mutant TGFBI transgene was measured and shown to be reduced by 22.4 % (± 15.7 %, p < 0.05).We investigated gene expression in the mouse cornea and showed expression of murine Tgfbi was 20-fold lower than TGFBI in human cornea, and expression of the mutant TGFBI transgene was a further 3-fold lower. This estimated 60-fold lower mutant transgene expression may explain the low frequency of corneal deposits observed in this mouse model, limiting its usefulness to test whether siRNA silencing is capable of phenotypic improvement or regression of GCD2/Avellino corneal dystrophy.We assessed WT TGFBI silencing in human primary corneal epithelial cells (PCEC) derived from human corneal limbal biopsy material, which express TGFBI at a similar level to human corneal biopsy. We demonstrated that a single 100 nM siRNA treatment, delivered by the sshLNP to the primary human corneal epithelial cells, gave 26.6 % (± 6.6 %, p < 0.001) reduction in TGFBI mRNA and a 15.4 % (±10.5 %, p < 0.05 %) reduction in TGFBi protein after 48 h. In consideration of the mutant gene expression levels in existing models of GCD2 disease, an ex vivo model of mutation-expressing primary corneal epithelial cells generated from corneal limbal biopsies from GCD2 patients would be more suitable than existing transgenic mouse models for future pre-clinical work in the development of gene silencing therapies for corneal dystrophies.
{"title":"TGFBI R124H mutant allele silencing in granular corneal dystrophy type 2 using topical siRNA delivery","authors":"Andrew McLain, Amanda Kowalczyk, Paulina Baran-Rachwalska, Flavia Maria Sutera, Louise J. Robertson, Nadia Sukusu Nielsen, Jan J. Enghild, Diego Cobice, Filippo Bonelli, Vanessa Barbaro, Stefano Ferrari, Benjamin Patterson, Luca Moore, John Marshall, M. Andrew Nesbit, Tara Moore","doi":"10.1016/j.jconrel.2025.113681","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113681","url":null,"abstract":"In recent years, success has been achieved in treating several eye conditions with oligonucleotide-based therapies. Herein, we outline the experimentation involved in progressing selection and development of a lead therapeutic siRNA for R124H mutation of <em>TGFBI</em> gene which causes Granular Corneal Dystrophy Type 2 (GCD2/Avellino CD). Firstly, a series of siRNA designs, generated by a gene walk across the R124H <em>TGFBI</em> mutation site, were tested and a lead siRNA identified. The lead siRNA was delivered into an immortalised human corneal epithelial cell line to assess on-target efficacy and off-target effects. The <em>in vivo</em> efficacy of the lead R124H <em>TGFBI</em> siRNA, complexed with Bio-Courier technology, silicon stabilized hybrid lipid nanoparticles (sshLNP), was assessed in a mouse model of GCD2 which expressed the human R124H <em>TGFBI</em> transgene. Following topical siRNA application for 5 consecutive days, expression of the R124H mutant <em>TGFB</em>I transgene was measured and shown to be reduced by 22.4 % (± 15.7 %, <em>p</em> < 0.05).We investigated gene expression in the mouse cornea and showed expression of murine <em>Tgfbi</em> was 20-fold lower than TGFBI in human cornea, and expression of the mutant <em>TGFBI</em> transgene was a further 3-fold lower. This estimated 60-fold lower mutant transgene expression may explain the low frequency of corneal deposits observed in this mouse model, limiting its usefulness to test whether siRNA silencing is capable of phenotypic improvement or regression of GCD2/Avellino corneal dystrophy.We assessed WT TGFBI silencing in human primary corneal epithelial cells (PCEC) derived from human corneal limbal biopsy material, which express TGFBI at a similar level to human corneal biopsy. We demonstrated that a single 100 nM siRNA treatment, delivered by the sshLNP to the primary human corneal epithelial cells, gave 26.6 % (± 6.6 %, <em>p</em> < 0.001) reduction in TGFBI mRNA and a 15.4 % (±10.5 %, <em>p</em> < 0.05 %) reduction in TGFBi protein after 48 h. In consideration of the mutant gene expression levels in existing models of GCD2 disease, an <em>ex vivo</em> model of mutation-expressing primary corneal epithelial cells generated from corneal limbal biopsies from GCD2 patients would be more suitable than existing transgenic mouse models for future pre-clinical work in the development of gene silencing therapies for corneal dystrophies.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758146","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 : 2025-04-02DOI: 10.1016/j.jconrel.2025.113677
Dennis To, Christian Steinbring, Leonie I. Weber, Fabrizio Ricci, Ilaria Polidori, Annika Postina, Markus Hartl, Andreas Bernkop-Schnürch
Hypothesis
Oral delivery of the proliferation-inhibiting brain acid-soluble protein 1 effector domain peptide (Myr-NT) towards MYC-dependent gastrointestinal tumors can be achieved by forming hydrophobic ion pairs (HIPs) and incorporating them into lipid-based formulations.
Experiments
Hydrophobic ion pairing of fluorescently-labelled Myr-NT (Myr-NT-TAMRA) was performed, increase in lipophilicity was assessed, and the most promising HIP was subsequently incorporated into a nanoemulsion. Stability of the peptide towards degradation by trypsin was evaluated. Anti-proliferative and anti-invasive measurements were performed upon application of the loaded nanoemulsion on various MYC-dependent human cancer cell lines. Cellular uptake and molecular effect were complementary investigated by confocal laser scanning microscopy (CLSM) and by immunoblot analyses, respectively.
Findings
HIPs of Myr-NT-TAMRA exhibited up to 10,000-fold increase in lipophilicity, thereby enabling incorporation into a nanoemulsion. The formulation significantly boosted stability of incorporated peptide towards enzymatic degradation by trypsin. Furthermore, anti-proliferative measurements on human cancer cell lines revealed superior biological activity of the loaded nanoemulsion compared to the native peptide particularly in lymphoma cells, but also in colorectal cancer cells. Thereby, a correlation with proliferation inhibition as well as differences in MYC protein expression were observed. Finally, CLSM imaging revealed up to 15-fold increased cellular uptake of Myr-NT-TAMRA from the nanoemulsion confirming efficient intracellular delivery of the peptide.
Conclusion
Myr-NT can be efficiently delivered into intestinal tumor cells using orally administered lipid-based formulations.
{"title":"Design of lipid-based formulations for oral delivery of a BASP1 peptide targeting MYC-dependent gastrointestinal cancer cells","authors":"Dennis To, Christian Steinbring, Leonie I. Weber, Fabrizio Ricci, Ilaria Polidori, Annika Postina, Markus Hartl, Andreas Bernkop-Schnürch","doi":"10.1016/j.jconrel.2025.113677","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113677","url":null,"abstract":"<h3>Hypothesis</h3>Oral delivery of the proliferation-inhibiting brain acid-soluble protein 1 effector domain peptide (Myr-NT) towards MYC-dependent gastrointestinal tumors can be achieved by forming hydrophobic ion pairs (HIPs) and incorporating them into lipid-based formulations.<h3>Experiments</h3>Hydrophobic ion pairing of fluorescently-labelled Myr-NT (Myr-NT-TAMRA) was performed, increase in lipophilicity was assessed, and the most promising HIP was subsequently incorporated into a nanoemulsion. Stability of the peptide towards degradation by trypsin was evaluated. Anti-proliferative and anti-invasive measurements were performed upon application of the loaded nanoemulsion on various MYC-dependent human cancer cell lines. Cellular uptake and molecular effect were complementary investigated by confocal laser scanning microscopy (CLSM) and by immunoblot analyses, respectively.<h3>Findings</h3>HIPs of Myr-NT-TAMRA exhibited up to 10,000-fold increase in lipophilicity, thereby enabling incorporation into a nanoemulsion. The formulation significantly boosted stability of incorporated peptide towards enzymatic degradation by trypsin. Furthermore, anti-proliferative measurements on human cancer cell lines revealed superior biological activity of the loaded nanoemulsion compared to the native peptide particularly in lymphoma cells, but also in colorectal cancer cells. Thereby, a correlation with proliferation inhibition as well as differences in MYC protein expression were observed. Finally, CLSM imaging revealed up to 15-fold increased cellular uptake of Myr-NT-TAMRA from the nanoemulsion confirming efficient intracellular delivery of the peptide.<h3>Conclusion</h3>Myr-NT can be efficiently delivered into intestinal tumor cells using orally administered lipid-based formulations.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"3 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758147","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 : 2025-04-02DOI: 10.1016/j.jconrel.2025.113684
Xucheng Hou, Chang Wang, Yichen Zhong, Leiming Wang, Diana D. Kang, Gabrielle Lubitz, Yonger Xue, Zhengwei Liu, Siyu Wang, Haoyuan Li, Meng Tian, Dinglingge Cao, Kaiyuan Guo, Binbin Deng, David W. McComb, Thomas Marron, Brian D. Brown, Miriam Merad, Joshua D. Brody, Yizhou Dong
Dendritic cells (DCs) are essential for inducing effective antitumor T cell responses. However, the immunosuppressive tumor microenvironment (TME) hinders DC recruitment and maturation, facilitating tumor progression and spread. This study investigates the synergistic potential of immunogenic cell death (ICD), triggered by chemotherapeutic-derived lipid nanoparticles (LNPs), in combination with Flt3L and CD40L mRNA delivery to enhance DC mobilization and activation, reprogram the TME, and ultimately promote robust antitumor T cell responses. The optimized LNP formulation, GEM5Q7, efficiently delivered mRNA and induced ICD in melanoma cells. Intratumoral administration of GEM5Q7, encapsulating Flt3L and CD40L mRNAs, elevated pro-inflammatory cytokine and chemokine secretion, driving the infiltration and activation of cross-presenting DCs, which are critical for priming T cells. In a subcutaneous melanoma model, this approach led to significant tumor suppression and a 40 % complete response rate. This strategy holds promise for enhancing cancer immunotherapies by reprogramming the TME and inducing durable antitumor T cell immunity.
{"title":"Enhancing antitumor immunity through chemotherapeutic-derived lipid nanoparticle-induced immunogenic cell death and CD40L/Flt3L mRNA-mediated dendritic cell activation","authors":"Xucheng Hou, Chang Wang, Yichen Zhong, Leiming Wang, Diana D. Kang, Gabrielle Lubitz, Yonger Xue, Zhengwei Liu, Siyu Wang, Haoyuan Li, Meng Tian, Dinglingge Cao, Kaiyuan Guo, Binbin Deng, David W. McComb, Thomas Marron, Brian D. Brown, Miriam Merad, Joshua D. Brody, Yizhou Dong","doi":"10.1016/j.jconrel.2025.113684","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113684","url":null,"abstract":"Dendritic cells (DCs) are essential for inducing effective antitumor T cell responses. However, the immunosuppressive tumor microenvironment (TME) hinders DC recruitment and maturation, facilitating tumor progression and spread. This study investigates the synergistic potential of immunogenic cell death (ICD), triggered by chemotherapeutic-derived lipid nanoparticles (LNPs), in combination with Flt3L and CD40L mRNA delivery to enhance DC mobilization and activation, reprogram the TME, and ultimately promote robust antitumor T cell responses. The optimized LNP formulation, GEM5Q7, efficiently delivered mRNA and induced ICD in melanoma cells. Intratumoral administration of GEM5Q7, encapsulating Flt3L and CD40L mRNAs, elevated pro-inflammatory cytokine and chemokine secretion, driving the infiltration and activation of cross-presenting DCs, which are critical for priming T cells. In a subcutaneous melanoma model, this approach led to significant tumor suppression and a 40 % complete response rate. This strategy holds promise for enhancing cancer immunotherapies by reprogramming the TME and inducing durable antitumor T cell immunity.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"38 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143766323","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 : 2025-04-02DOI: 10.1016/j.jconrel.2025.113682
Jiahui Li, Hasan Al Faruque, Shannuo Li, Monika Sima, Douglas Sborov, Siwen Hu-Lieskovan, Theresa Werner, Jindřich Kopeček, Jiyuan Yang
Following successful design of polymer enhanced rituximab-epirubicin (EPI) conjugates targeted to non-Hodgkin lymphoma (Zhang et al. 2017), we developed U6244–051 that consists of anti-PD-L1 antibody (αPD-L1) and semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates (ST-P-EPI); the latter is attached to αPD-L1 via Cu-free azide/alkyne cycloaddition. This new polymer-enhanced antibody-drug conjugate (pADC) not only exhibits a high drug-to-antibody ratio (DAR ~ 30–40) but also integrates immune checkpoint blockade with long-lasting immunogenic anticancer chemotherapy, providing an innovative chemo-immuno combination modality. The biological properties of U6244-051 were evaluated using ID8-Luc murine ovarian cancer cells in vitro and in vivo. In vitro, U6244-051 treatment induced immunomodulatory changes, including upregulation of calreticulin, PD-L1, and MHC I, suggesting enhanced tumor cell visibility to the immune system. In vivo efficacy was assessed in a syngeneic murine model (C57BL/6 J mice inoculated with 5 × 106 ID8-Luc cells/mouse). U6244-051 treatment resulted in 100 % survival at day 100, despite initiation at an advanced disease stage. Treatment modulated the tumor immune microenvironment by reducing immunosuppressive populations (TAMs and MDSCs) and enhancing T cell recruitment and activation. A decrease in PD-L1 expression and increased MHC I upregulation correlated with enhanced immune-mediated tumor clearance. Additionally, reduced Treg levels and increased CD8+ T cell activation contributed to a more effective antitumor response. Repeated dosing amplified immunomodulatory effects, leading to durable immunity. These results highlight U6244–051 as a next-generation pADC with high translational potential, offering enhanced efficacy and reduced on-target, off-tumor toxicity.
{"title":"PD-L1 targeted antibody-polymer-Epirubicin conjugate prolongs survival in a preclinical murine model of advanced ovarian cancer","authors":"Jiahui Li, Hasan Al Faruque, Shannuo Li, Monika Sima, Douglas Sborov, Siwen Hu-Lieskovan, Theresa Werner, Jindřich Kopeček, Jiyuan Yang","doi":"10.1016/j.jconrel.2025.113682","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113682","url":null,"abstract":"Following successful design of polymer enhanced rituximab-epirubicin (EPI) conjugates targeted to non-Hodgkin lymphoma (Zhang et al. 2017), we developed U6244–051 that consists of anti-PD-L1 antibody (αPD-L1) and semitelechelic <em>N</em>-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-epirubicin (EPI) conjugates (ST-P-EPI); the latter is attached to αPD-L1 via Cu-free azide/alkyne cycloaddition. This new polymer-enhanced antibody-drug conjugate (pADC) not only exhibits a high drug-to-antibody ratio (DAR ~ 30–40) but also integrates immune checkpoint blockade with long-lasting immunogenic anticancer chemotherapy, providing an innovative chemo-immuno combination modality. The biological properties of U6244-051 were evaluated using ID8-Luc murine ovarian cancer cells in vitro and in vivo. In vitro, U6244-051 treatment induced immunomodulatory changes, including upregulation of calreticulin, PD-L1, and MHC I, suggesting enhanced tumor cell visibility to the immune system. In vivo efficacy was assessed in a syngeneic murine model (C57BL/6 J mice inoculated with 5 × 10<sup>6</sup> ID8-Luc cells/mouse). U6244-051 treatment resulted in 100 % survival at day 100, despite initiation at an advanced disease stage. Treatment modulated the tumor immune microenvironment by reducing immunosuppressive populations (TAMs and MDSCs) and enhancing T cell recruitment and activation. A decrease in PD-L1 expression and increased MHC I upregulation correlated with enhanced immune-mediated tumor clearance. Additionally, reduced Treg levels and increased CD8<sup>+</sup> T cell activation contributed to a more effective antitumor response. Repeated dosing amplified immunomodulatory effects, leading to durable immunity. These results highlight U6244–051 as a next-generation pADC with high translational potential, offering enhanced efficacy and reduced on-target, off-tumor toxicity.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"3 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758521","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}
Fibroblasts activated protein (FAP) appears to be a promising target for tumor theranostics. However, the development of radioiodinated probes for FAP has been slow. In this study, a progressive abumin-driven strategy was adopted to improve the FAP-targeted delivery of radioiodinated probes for tumor theranostics. A series of FAP-targeted probes (namely [131I]IPB-FAPI, [131I]IPB-FAPI-A1, [131I]IPB-FAPI-A3, [131I]FSDD3I) were synthesized by incorporating an albumin-binding moiety (4-(p-iodophenyl)butyric acid, 4-IPBA) labeled with radioiodine. The specificity and binding characteristics of the radiotracers to FAP and human serum albumin (HSA) were confirmed. SPECT imaging results showed that the [131I]FSDD3I had more prominent tumor retention property and superior target-to-non-target ratio, which were consistent with the biodistribution results. As expected, the FAP-targeted therapy with 11.1 MBq [131I]FSDD3I significantly inhibited tumor growth. In conclusion, this proof-of-concept study employed a progressive design strategy to enhance pharmacokinetics of radioiodinated FAP-targeted probes. Among these radioiodinated FAPI probes, 131I-labeled FSDD3I ([131I]FSDD3I) emerged as a standout candidate with superior competitive advantages for application in radioiodine-guided internal irradiation therapy.
{"title":"FAP-targeted delivery of radioiodinated probes: A progressive albumin-driven strategy for tumor theranostics","authors":"Huifeng Li, Dongsheng Xia, Lingxin Meng, Jingru Zhang, Xuedong Chen, Rongqiang Zhuang, Jinxiong Huang, Yesen Li, Jianyang Fang, Xianzhong Zhang, Zhide Guo","doi":"10.1016/j.jconrel.2025.113678","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113678","url":null,"abstract":"Fibroblasts activated protein (FAP) appears to be a promising target for tumor theranostics. However, the development of radioiodinated probes for FAP has been slow. In this study, a progressive abumin-driven strategy was adopted to improve the FAP-targeted delivery of radioiodinated probes for tumor theranostics. A series of FAP-targeted probes (namely [<sup>131</sup>I]IPB-FAPI, [<sup>131</sup>I]IPB-FAPI-A1, [<sup>131</sup>I]IPB-FAPI-A3, [<sup>131</sup>I]FSDD<sub>3</sub>I) were synthesized by incorporating an albumin-binding moiety (4-(<em>p</em>-iodophenyl)butyric acid, 4-IPBA) labeled with radioiodine. The specificity and binding characteristics of the radiotracers to FAP and human serum albumin (HSA) were confirmed. SPECT imaging results showed that the [<sup>131</sup>I]FSDD<sub>3</sub>I had more prominent tumor retention property and superior target-to-non-target ratio, which were consistent with the biodistribution results. As expected, the FAP-targeted therapy with 11.1 MBq [<sup>131</sup>I]FSDD<sub>3</sub>I significantly inhibited tumor growth. In conclusion, this proof-of-concept study employed a progressive design strategy to enhance pharmacokinetics of radioiodinated FAP-targeted probes. Among these radioiodinated FAPI probes, <sup>131</sup>I-labeled FSDD<sub>3</sub>I ([<sup>131</sup>I]FSDD<sub>3</sub>I) emerged as a standout candidate with superior competitive advantages for application in radioiodine-guided internal irradiation therapy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"72 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758518","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 : 2025-04-01DOI: 10.1016/j.jconrel.2025.113679
Shiyi Bi , Jieyu Shen , Yu Zhu , Lei Fan , Huangxian Ju , Ying Liu
Choosing appropriate delivery system for chemotherapeutic drugs as well as arranging the time spots for adoptive cells administrations is the key to achieve efficient combined chemo-adoptive cell therapy. Tumor-homing character makes adoptive immune cells appropriate targeting delivery carriers, but they are rarely used for chemtoxic payloads considering payloads internalization during administration which impairs adoptive cells. Herein, we frame adoptive NK cells using DNA scaffold with chemotherapeutic payloads fastened exterior, and achieves time-programmed drugs release and NK cell decapsulation to minimize side effects and enhance therapeutic effect. IL-21 nanoparticles are prepared by conjugating cytokine IL-21 with a GSH cleavable linker and act as anchor points for DNA scaffold assembly. Chemotherapeutic payloads are prepared by loading DOX/verapamil drugs to PLGA nanoparticles (PLGAdrugs NPs), and connected to the exterior of DNA scaffold with a ROS cleavable linker. Porous DNA scaffold protects NK cells functions from impairing by chemotherapeutic payloads, while guarantees efficient communication of NK cells with exterior environment to keep tumor homing capability. Reactive oxygen species (ROS) in tumor microenvironment releases PLGAdrugs NPs to perform chemotherapy, which subsequently generates a reductive environment to detach DNA scaffold for NK cell and IL-21 release to achieve combined chemo-adoptive cell therapy with enhanced therapeutic efficiency.
{"title":"DNA scaffold-framed natural killer cell with programmed drug release for chemo-adoptive cell therapy","authors":"Shiyi Bi , Jieyu Shen , Yu Zhu , Lei Fan , Huangxian Ju , Ying Liu","doi":"10.1016/j.jconrel.2025.113679","DOIUrl":"10.1016/j.jconrel.2025.113679","url":null,"abstract":"<div><div>Choosing appropriate delivery system for chemotherapeutic drugs as well as arranging the time spots for adoptive cells administrations is the key to achieve efficient combined chemo-adoptive cell therapy. Tumor-homing character makes adoptive immune cells appropriate targeting delivery carriers, but they are rarely used for chemtoxic payloads considering payloads internalization during administration which impairs adoptive cells. Herein, we frame adoptive NK cells using DNA scaffold with chemotherapeutic payloads fastened exterior, and achieves time-programmed drugs release and NK cell decapsulation to minimize side effects and enhance therapeutic effect. IL-21 nanoparticles are prepared by conjugating cytokine IL-21 with a GSH cleavable linker and act as anchor points for DNA scaffold assembly. Chemotherapeutic payloads are prepared by loading DOX/verapamil drugs to PLGA nanoparticles (PLGA<sub>drugs</sub> NPs), and connected to the exterior of DNA scaffold with a ROS cleavable linker. Porous DNA scaffold protects NK cells functions from impairing by chemotherapeutic payloads, while guarantees efficient communication of NK cells with exterior environment to keep tumor homing capability. Reactive oxygen species (ROS) in tumor microenvironment releases PLGA<sub>drugs</sub> NPs to perform chemotherapy, which subsequently generates a reductive environment to detach DNA scaffold for NK cell and IL-21 release to achieve combined chemo-adoptive cell therapy with enhanced therapeutic efficiency.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"382 ","pages":"Article 113679"},"PeriodicalIF":10.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143745532","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}
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25–30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.
{"title":"Innovative nanomedicine approaches for the management of non-alcoholic fatty liver disease","authors":"Limeng Li, Weiqi Gao, Fengyang Yao, Jiayi Li, Wei Sang, Ruiping Zhang","doi":"10.1016/j.jconrel.2025.113680","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113680","url":null,"abstract":"Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally. The prevalence of NAFLD in the general population is estimated to be 25–30 %, making it the most common chronic liver condition in China as well as worldwide. Given the escalating disease burden and the scarcity of effective therapeutic interventions, there is a pressing unmet clinical need. Consequently, the development of novel pharmaceuticals has emerged as a pivotal research focus in recent years. Moreover, the advent of nano-delivery technology offers innovative solutions for NAFLD drug therapy. This paper presents a comprehensive examination of the pathogenesis and therapeutic targets of NAFLD. It critically reviews the latest advancements in nanomedicine research pertinent to NAFLD treatment. The review synthesizes a broad range of research findings to bridge the gap between current knowledge and emerging therapeutic strategies, and aims to inform and guide future research directions in NAFLD management.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"32 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143758148","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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