Journal of Controlled Release最新文献

{"title":"Hydrophobic ion pairing enables co-loading of water-soluble drugs in polymeric micelles","authors":"Armin Azadkhah Shalmani, Rasika Daware, Asmaa Said Elshafei, Federica De Lorenzi, Diana Moeckel, Eva M. Buhl, Barbara Mara Klinkhammer, Peter Boor, Srinivas Banala, Alina Adams, Fabian Kiessling, Gert Storm, Josbert M. Metselaar, Alexandros Marios Sofias, Yang Shi, Twan Lammers, Quim Peña, Tarun Ojha","doi":"10.1016/j.jconrel.2025.113748","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113748","url":null,"abstract":"Polymeric micelles are widely used for the delivery of hydrophobic drugs. However, several highly potent and ubiquitously used anticancer drugs are water-soluble, complicating their (<em>co</em>-) formulation in polymeric micelles without having to chemically modify them. We here explore hydrophobic ion pairing to enable the co-delivery of the water-soluble anthracycline chemotherapy drug doxorubicin and the angiotensin II receptor antagonist telmisartan (a clinically used antihypertensive drug that has shown promising (pre-) clinical outcomes in combination with anthracyclines). We show that hydrophobic ion pairing of doxorubicin and telmisartan promotes the <em>co</em>-encapsulation of both drugs in π electron-stabilized [PEG-<em>b</em>-p(HPMAm-Bz)]-based polymeric micelles. The cytotoxic activity of doxorubicin is retained, and the dual drug-loaded micelles display enhanced antitumor activity in vivo as compared to the combination of the free drugs, while also exhibiting good tolerability. Taken together, this work provides proof-of-concept for hydrophobic ion pairing as a promising formulation strategy to promote multidrug nanomedicine and drug combination therapy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"42 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841101","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}

{"title":"Local controlled release of stabilized monoclonal antibodies","authors":"Rae Sung Chang, Jennifer Walker, Anzar A. Mujeeb, Padma Kadiyala, Karthik Pisupati, Jeffrey Jamison, Anna Schwendeman, Yusuf Haggag, David A. Antonetti, Maria G. Castro, Steven P. Schwendeman","doi":"10.1016/j.jconrel.2025.113743","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113743","url":null,"abstract":"Monoclonal antibody (mAb) therapeutics have become widely successful for treatment of any number of diseases. However, for certain hard-to-reach tissues, e.g., eye, brain, tumors, and joints, local delivery is desired and long-term controlled release is necessary to avoid frequent injections and poor patient compliance. If local and sustained exposure of mAbs (or their Fab or nanobody fragments) could be accomplished by injectable polymer long-acting release (LAR) systems, the incredible potential of mAb therapeutics could be extended to additional diseases, e.g., neovascular age-related macular degeneration (wet AMD) and glioblastoma multiforme (GBM). In prior studies, long-acting delivery of mAbs has been limited by the inability to design a delivery system prepared from a biodegradable polymer used in FDA-approved LARs that achieves long-term continuous release of structurally stable and immunoreactive mAb with a low initial burst release that is easily injectable and avoids material build-up upon repeated injection. Here, we present for the first time a long-acting delivery system capable of delivering several different mAbs for multiple indications by developing a novel process to stabilize mAbs through the combination of formulation, micronization and encapsulation conditions, and to control stabilized mAb exposure in vivo for months by formulation with an appropriate biodegradable polymer (poly(lactic-<em>co</em>-glycolic acid) (PLGA)), utilization of a pH- and pore-modifying agent, and development of a novel PLGA coating layer to control osmotic pressure induced by elevated levels of critical co-encapsulated stabilizers, particularly mAb-stabilizing-trehalose. The resulting implants showed long-term efficacy in animal models for both wet AMD and GBM after single local injections. Although much more work needs to be done before their clinical application to these two diseases, the injectable PLGA platform meets several important benchmarks for controlled mAb delivery and can be developed further for delivery of a wide array of mAbs and other cofactors, offering an improved therapeutic option for treating diseases amenable to local antibody therapy.<strong>One Sentence Summary:</strong> A generalizable injectable biodegradable PLGA implant platform for site-specific and long-term slow and continuous release of stabilized monoclonal antibody drugs demonstrates improved in vivo efficacy for wet AMD and glioblastoma.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"35 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841103","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}

{"title":"Fate reversal: Exosome-driven macrophage rejuvenation and bacterial-responsive drug release for infection immunotherapy in diabetes","authors":"Jiaxuan Zou, Wushi Cui, Niping Deng, Congsun Li, Weinan Yang, Xiaojun Ye, Feng Yao, Tao Zhang, Jian Xiao, Chiyuan Ma, Lingfeng Wu, Dahai Dong, Jing Chen, Chengchen Guo, An Liu, Haobo Wu","doi":"10.1016/j.jconrel.2025.113730","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113730","url":null,"abstract":"Superficial surgical site infection (SSI) is a significant risk factor for the development of periprosthetic joint infection (PJI), particularly in diabetic patients. A high-glucose microenvironment is observed to compromise phagocytosis by inducing cellular senescence, which leads to impaired antibacterial immune function. Exosomes derived from umbilical cord stem cells (H-Exos) can reverse the immunosuppressive microenvironment by rejuvenating senescent cells, thereby terminating excessive, persistent, and ineffective inflammatory responses. Thus, a novel exosome-based immunotherapeutic antibacterial strategy to reverse fate is proposed. Vancomycin &amp; lysostaphin-loaded exosomes are incorporated in a customizable microneedle patch (ExoV-ExoL@MN) for controlled release, enabling tailored treatments for diverse clinical scenarios. While rejuvenating macrophage senescent phenotype, the antibiotics encapsulated within exosomes can be responsively released by the hemolysin secreted by bacteria, triggering rapid bacterial killing. Post-infection clearance, they induce a shift from M1 to M2 macrophage polarization, thereby enhancing anti-inflammatory and reparative responses. Furthermore, the components can be mixed on demand and at any time, allowing for real-time customization and fabrication directly at the clinic (fabrication@clinic). This strategy reverses the immunosuppressive microenvironment by rejuvenating senescent macrophages and effectively combats bacterial invasion into deep tissues through bacteria-responsive antibiotic release, providing a promising approach for preventing and treating SSI-induced PJI.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"74 3 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837504","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}

{"title":"Tough and waterproof microneedles overcome mucosal immunotolerance by modulating antigen release patterns","authors":"Penghui He ,&nbsp;Chunting He ,&nbsp;Rong Guo,&nbsp;Yangsen Ou,&nbsp;Yu Chang,&nbsp;Zhiqiang Xie,&nbsp;Xue Tang,&nbsp;Yanhua Xu,&nbsp;Yuanhao Zhao,&nbsp;Hairui Wang,&nbsp;Zhaofei Guo,&nbsp;Shuting Bai,&nbsp;Zhengjun Chen,&nbsp;Fan Fan,&nbsp;Guangsheng Du,&nbsp;Xun Sun","doi":"10.1016/j.jconrel.2025.113740","DOIUrl":"10.1016/j.jconrel.2025.113740","url":null,"abstract":"<div><div>Mucosal vaccines are considered an ideal choice for combating mucosal pathogens due to their ability to neutralize pathogens at the first line of defense. However, the development of mucosal subunit vaccines is constricted by rigorous challenges, such as low immunogenicity, poor antigen delivery efficiency, and mucosal tolerance. Here, a buccal microneedle patch incorporated with engineered nanoparticles loaded with urease B subunit (rUreB) was developed to overcome the above challenges. Specifically, an engineered nanocarrier was developed to protect the antigen and modulate its release profile. Then, the nanoparticles were enriched to form microneedle tips with superior mechanical and waterproof properties, allowing effective penetration of the buccal mucosa and resistance to salivary washout. Besides, the microneedles demonstrated an S-curve antigen release pattern which was crucial for the recruitment of antigen presenting cells (APCs) and the downregulation of mucosal tolerogenic DCs and Treg cells. The buccal microneedle vaccine without any immune stimulators induced potent systemic and mucosal immune responses, resulting in superior protection of mice from the oral challenge of <em>Helicobacter pylori</em>. These results suggested that the rationally designed buccal microneedle vaccine can effectively overcome mucosal delivery barriers and mucosal tolerance, providing a promising alternative strategy for mucosal vaccination of subunit antigens.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"382 ","pages":"Article 113740"},"PeriodicalIF":10.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143841102","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}

{"title":"Linoleic acid co-administration promotes oral delivery of exenatide-loaded butyrate-decorated nanocapsules","authors":"Haoyang Yuan, Peifu Xiao, Fan Wang, Chen Guo, Shu Pan, Mai Jiang, Shicheng Hou, Yunong Sun, Yibo Wang, Yu Zhang, Tian Yin, Haibing He, Jingxin Gou, Xing Tang","doi":"10.1016/j.jconrel.2025.113744","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113744","url":null,"abstract":"Epithelial cell entrance and trans-epithelial transport are two essential processes that directly affect the efficacy of oral delivery of nanocarriers. Herein, a hydroxyethyl starch-based nanocapsule dual decorated with butyrate and octadecylamine (ODA) was first constructed to enhance transporter-mediated endocytosis and trans-epithelial transport, while reducing exenatide (EXT) loss during absorption. The epithelial barrier was then treated with linoleic acid (LA), which functioned as a cell membrane fluidity regulator. This treatment further improved oral delivery efficiency by lowering the energy cost of endocytosis through fluidizing of the cell membrane and increasing monocarboxylate transporter 1 (MCT1) expression on cell surfaces. The findings revealed that LA upregulated MCT1 expression by 3.26-fold, increased the cellular uptake of nanocapsules co-modified with butyrate and ODA by 4.52-fold, decreased ATP consumption for uptake in LA-pretreated Caco-2 cells to only 18.64 % of that in untreated Caco-2 cells, and increased their transcellular transport by 1.72-fold in a Caco-2/HT29-MTX-E12 co-culture monolayer. Therefore, the oral administration of EXT-loaded Bu-PEG-ODA NCs with LA significantly enhanced the oral bioavailability of EXT (Bu-PEG-ODA NCs group: 10.10 %, Bu-PEG-ODA NCs + LA group: 14.84 %), leading to a significant hypoglycemic effect with a 16.06 % relative pharmacological availability. This dosing strategy exhibited efficacious blood glucose control and pancreatic function recovery capabilities in the type 2 diabetes rat model. This study presents a unique co-optimization strategy based on two key processes in the oral absorption of nanocarriers, yielding significant advancements in the oral bioavailability of nanomedicines and improving their therapeutic efficacy.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"22 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143837471","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}

{"title":"Potent therapeutic efficacy of intranasally deliverable paclitaxel modified with pH-sensitive and PEGylated polymeric micelle against glioblastoma","authors":"Young-Beom Kim ,&nbsp;Soo-Hwan Lee ,&nbsp;Dayananda Kasala ,&nbsp;Yuebin Zhao ,&nbsp;Ao Jiao ,&nbsp;JinWoo Hong ,&nbsp;Jin Su Kim ,&nbsp;A-Rum Yoon ,&nbsp;Chae-Ok Yun","doi":"10.1016/j.jconrel.2025.113711","DOIUrl":"10.1016/j.jconrel.2025.113711","url":null,"abstract":"<div><div>Glioblastoma multiforme (GBM) is the most aggressive and common type of brain tumor. Conventional therapies for GBM, such as surgery or radiotherapy, have shown inadequate therapeutic effect. Similarly, a large fraction of chemotherapeutics are ineffective against GBM due to the blood-brain barrier (BBB) preventing effective delivery of these drugs to the brain. To overcome these obstacles, an intranasally administrable and multifunctional drug-loaded polymeric micelle composed of a pH-sensitive PPCBA-PEI-Arg (PPA) polymer conjugated with PEGylated paclitaxel (PEG-PTX; PPP) was synthesized to treat GBM. PPP was more soluble in an aqueous solution than parental PTX and was more effectively internalized into the GBM cells. Further, PPP elicited a more potent cancer cell killing effect than PTX under physiological pH condition, which was further augmented under the mildly acidic condition that emulated the tumor microenvironment. Intranasal administration of PPP into orthotopic GBM tumor xenograft-bearing mice led to more efficient delivery of the drug to the brain tissues compared to parental PTX delivered via intranasal or intravenous route, thus resulting in superior inhibition of GBM growth. Collectively, these findings demonstrated that intranasal delivery of PTX via pH-sensitive and PEGylated polymeric micelles can be an effective approach for the treatment of aggressive GBM.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"382 ","pages":"Article 113711"},"PeriodicalIF":10.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143819320","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}

{"title":"Enhancing the bystander effect of antibody-drug conjugate by using a novel caspase-3 cleavable peptide linker to overcome tumor heterogeneity","authors":"Ha Kyeong Lee ,&nbsp;Byoungmo Kim ,&nbsp;Yoon Gun Ko ,&nbsp;Seung Woo Chung ,&nbsp;Wan Seob Shim ,&nbsp;So-Young Choi ,&nbsp;Se-Ra Lee ,&nbsp;Sang Yoon Kim ,&nbsp;Youngro Byun","doi":"10.1016/j.jconrel.2025.113738","DOIUrl":"10.1016/j.jconrel.2025.113738","url":null,"abstract":"<div><div>Tumor heterogeneity is a major obstacle to effective targeted therapies, including those utilizing antibody-drug conjugates (ADCs). Although some ADCs employ the bystander effect to eliminate neighboring antigen-negative cells, their efficacy often diminishes as antigen-positive cell populations decrease within heterogeneous tumors. To address this limitation in ADC therapies, we developed a novel ADC using a caspase substrate, Asp-Glu-Val-Asp (DEVD), as a linker to generate a more potent and sustained bystander effect. The DEVD ADC effectively targeted antigen-positive cells and released its payload via cathepsin B cleavage. Notably, it exhibited a significant bystander effect mediated by the caspase-3-triggered extracellular cleavage of the linker, enhancing payload release into the tumor microenvironment. In breast cancer xenograft models, the DEVD ADC maintained its efficacy and continued to exert a bystander effect even after the depletion of antigen-positive cells, thereby overcoming challenges posed by tumor heterogeneity. These findings emphasize the potential of DEVD linkers in enhancing ADC efficacy against heterogeneous solid tumors, offering a promising strategy to improve therapeutic outcomes.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"382 ","pages":"Article 113738"},"PeriodicalIF":10.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831774","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}

{"title":"Soluble-microneedle enhance three T-cell activation signals as efficient tumor vaccines for melanoma prevention and treatment","authors":"Nan Li, Weiwei Mu, Zhenxing Xia, Qingping Ma, Ruihua Feng, Panpan Gu, Qinglin Yang, Shuying Gao, Weihan Zhang, Suyun Wei, Yi Zheng, Wei Zhao, Yongjun Liu, Na Zhang","doi":"10.1016/j.jconrel.2025.113726","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113726","url":null,"abstract":"Therapeutic tumor vaccines, which activate self-T cells to eliminate tumors, hold tremendous promise in future cancer immunotherapy with high specificity and low side effects. To effectively activate T cell, dendritic cells (DCs) need simultaneously provide three indispensable signals to naive T cells, including MHC-antigen signal, costimulation signal and cytokine stimulation. However, current marketed therapeutic tumor vaccines still suffer from lacking the ability to activate three stimulation signals at the same time, which resulted to the low response rate and unsatisfied therapeutic efficiency. Here, we proposed a soluble microneedle-based tumor vaccines (TR-12@LGMN) which facilitate triple activation of antigen presentation and induce high immune response rate. First, the melanoma-specific antigen tyrosinaserelated protein-2 (Trp2), Resiquimod (R848), and IL-12 mRNA co-loaded liposomes (TR-12@LIPO) was prepared. The TR-12@LIPO ensured triple-activating three essential signals of antigen presentation through enhancing the binding of MHC I-antigen peptides to T cell receptor (TCR), the binding of CD80/86 on DCs to CD28 on T cells, and the release of cytokines for T cells activation. Second, TR-12@LIPO was <em>co</em>-dispersed in polyvinylpyrrolidone-polyvinyl alcohol (PVP-PVA) matrix with granulocyte-macrophage colony stimulating factor (GM-CSF) to prepare TR-12@LGMN by mold method. The TR-12@LGMN was quadrilateral shape with sufficient mechanical strength for skin piercing. After skin insertion, TR-12@LGMN dissolved in the skin interstitial fluid to release GM-CSF and TR-12@LIPO. DCs were recruited by GM-CSF and uptaked TR-12@LIPO. TR-12@LIPO showed enhancement of cross-presentation by antigen cytoplasmic delivery, DCs maturation and IL-12 secretion. In vivo results showed that TR-12@LGMN could efficiently activate CD8⁺ T cells, induce antigen-specific cytotoxic T cells (CTLs) and memory T cell (T_m). Ultimately, strong anti-tumor immunity and long-term durable tumor control were achieved in the B16F10 tumor prevention and treatment model. Overall, our work proposes a triple-activated antigen presentation strategy and designs a microneedle-based tumor vaccine for skin delivery, revealing a potential promising direction for the development of new therapeutic tumor vaccines methods.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"27 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831791","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}

{"title":"In vivo delivery of antioxidant enzymes with multi-functionalized lipid nanoparticles for sepsis therapy","authors":"Hiroyuki Koide, Shinya Hirata, Midori Watanabe, Hiroki Ochiai, Tatsuya Kobayashi, Go Yasuno, Hajime Mizuno, Eiji Sugiyama, Shohei Kojima, Takehisa Dewa, Hiromichi Egami, Sei Yonezawa, Naoto Oku, Tomohiro Asai","doi":"10.1016/j.jconrel.2025.113734","DOIUrl":"https://doi.org/10.1016/j.jconrel.2025.113734","url":null,"abstract":"Supplementing the cell with specific proteins is essential for disease prevention and therapy. However, protein permeability to the cell membrane is quite low because of the molecules large size and hydrophilic nature. Although protein delivery systems have been developing using vectors, their protein encapsulation efficiency depends on electrostatic interaction between proteins and vectors. Since proteins have a weaker net charge high affinity between vector and protein cannot be realized, and thus the encapsulation efficiency of naked proteins into vector is low. Herein, we developed a strategy for delivering target proteins into cells utilizing multifunctionalized lipid nanoparticles (MF-LNPs) prepared using several functional lipids that induce noncovalent interactions. We used two types of antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), as model proteins for inflammation therapy. MF-LNPs are prepared by combining positively charged, neutral, and hydrophobic group-functionalized lipids. Optimization of the functional lipid composition alone resulted in MF-LNPs exhibiting nM affinity for SOD and CAT. Proteins were encapsulated in each optimized MF-LNP by freeze-thawing of MF-LNP and protein complexes. Co-treatment with SOD- and CAT-encapsulated MF-LNPs significantly inhibited ROS production in vitro and in vivo. Notably, the survival rate of model mice with severe sepsis was dramatically improved following the co-administration of SOD- and CAT-encapsulated MF-LNPs through the suppression of inflammatory cytokines and improvement of ROS scavenging activities. The findings indicate that this fundamental technology could be useful information for designing protein delivery vectors.","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"23 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831783","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}

{"title":"Sonopermeation combined with stroma normalization enables complete cure using nano-immunotherapy in murine breast tumors","authors":"Constantina Neophytou ,&nbsp;Antonia Charalambous ,&nbsp;Chrysovalantis Voutouri ,&nbsp;Stella Angeli ,&nbsp;Myrofora Panagi ,&nbsp;Triantafyllos Stylianopoulos ,&nbsp;Fotios Mpekris","doi":"10.1016/j.jconrel.2025.113722","DOIUrl":"10.1016/j.jconrel.2025.113722","url":null,"abstract":"<div><div>Nano-immunotherapy shows great promise in improving patient outcomes, as seen in advanced triple-negative breast cancer, but it does not cure the disease, with median survival under two years. Therefore, understanding resistance mechanisms and developing strategies to enhance its effectiveness in breast cancer is crucial. A key resistance mechanism is the pronounced desmoplasia in the tumor microenvironment, which leads to dysfunction of tumor blood vessels and thus, to hypoperfusion, limited drug delivery and hypoxia. Ultrasound sonopermeation and agents that normalize the tumor stroma have been employed separately to restore vascular abnormalities in tumors with some success. Here, we performed in vivo studies in two murine, orthotopic breast tumor models to explore if combination of ultrasound sonopermeation with a stroma normalization drug can synergistically improve tumor perfusion and enhance the efficacy of nano-immunotherapy. We found that the proposed combinatorial treatment can drastically reduce primary tumor growth and in many cases tumors were no longer measurable. Overall survival studies showed that all mice that received the combination treatment survived and rechallenge experiments revealed that the survivors obtained immunological memory. Employing ultrasound elastography and contrast enhanced ultrasound along with proteomics analysis, flow cytometry and immunofluorescene staining, we found the combinatorial treatment reduced tumor stiffness to normal levels, restoring tumor perfusion and oxygenation. Furthermore, it increased infiltration and activity of immune cells and altered the levels of immunosupportive chemokines. Finally, using machine learning analysis, we identified that tumor stiffness, CD8⁺ T cells and M2-type macrophages were strong predictors of treatment response.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"382 ","pages":"Article 113722"},"PeriodicalIF":10.5,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831958","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}