Pub Date : 2024-11-20DOI: 10.1016/j.jconrel.2024.11.025
Wenxiang Zhang , Xue Yang , Zheng Qu , Peikai Ding , Xiangyi Kong , Xiangyu Wang , Qiang Liu , Xingsong Zhang , Ye Lu , Jing Wang , Zhengju Chen , Yi Fang
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. Recently, the deubiquitinizing enzyme ovarian tumor domain-containing 6B (OTUD6B) has been reported to play a potential role in TNBC progression. Therefore, this study investigates the role and underlying molecular mechanisms of OTUD6B in vitro and xenograft models of TNBC. Specifically, we examined the therapeutic effects of siOTUD6B and doxorubicin (DOX) co-delivery using synthesized tetrahedral DNA nanoparticles (Tds) on tumor growth and progression. Additionally, the uptake and efficacy of the siOTUD6B/DOX@Td in TNBC cells were evaluated. Notably, the siOTUD6B/DOX@Td nanoparticle demonstrated efficient cellular uptake by TNBC cells, resulting in OTUD6B knockdown and controlled release of DOX. Additionally, siOTUD6B/DOX@Td treatment enhanced apoptosis rates increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis. Moreover, in vivo experiments confirmed that siOTUD6B/DOX@Td treatment inhibited tumor growth and metastasis without damaging the primary organs. Mechanistically, OTUD6B regulates TNBC progression by stabilizing murine double minute 2 (MDM2) and degrading forkhead box O3a (FOXO3a). Conclusively, this study demonstrates the potential applicability of DNA nanoparticles loaded with DOX and siOTUD6B for TNBC treatment.
{"title":"DNA tetrahedral nanoparticles: Co-delivery of siOTUD6B/DOX against triple-negative breast cancer","authors":"Wenxiang Zhang , Xue Yang , Zheng Qu , Peikai Ding , Xiangyi Kong , Xiangyu Wang , Qiang Liu , Xingsong Zhang , Ye Lu , Jing Wang , Zhengju Chen , Yi Fang","doi":"10.1016/j.jconrel.2024.11.025","DOIUrl":"10.1016/j.jconrel.2024.11.025","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with limited targeted therapeutic options. Recently, the deubiquitinizing enzyme ovarian tumor domain-containing 6B (OTUD6B) has been reported to play a potential role in TNBC progression. Therefore, this study investigates the role and underlying molecular mechanisms of OTUD6B in vitro and xenograft models of TNBC. Specifically, we examined the therapeutic effects of siOTUD6B and doxorubicin (DOX) co-delivery using synthesized tetrahedral DNA nanoparticles (Tds) on tumor growth and progression. Additionally, the uptake and efficacy of the siOTUD6B/DOX@Td in TNBC cells were evaluated. Notably, the siOTUD6B/DOX@Td nanoparticle demonstrated efficient cellular uptake by TNBC cells, resulting in OTUD6B knockdown and controlled release of DOX. Additionally, siOTUD6B/DOX@Td treatment enhanced apoptosis rates increased DOX sensitivity, and inhibited TNBC cell growth, migration, and metastasis. Moreover, in vivo experiments confirmed that siOTUD6B/DOX@Td treatment inhibited tumor growth and metastasis without damaging the primary organs. Mechanistically, OTUD6B regulates TNBC progression by stabilizing murine double minute 2 (MDM2) and degrading forkhead box O3a (FOXO3a). Conclusively, this study demonstrates the potential applicability of DNA nanoparticles loaded with DOX and siOTUD6B for TNBC treatment.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 197-211"},"PeriodicalIF":10.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.jconrel.2024.11.039
Marianna Abate, Manuela Porru, Virginia Campani, Carlo Leonetti, Valeria Nele, Rossella Di Paola, Marco De Martino, Margherita Russo, Madhura Tathode, Alessia Maria Cossu, Marco Bocchetti, Alessia Angelillo, Monica Ianniello, Nadia Petrillo, Giovanni Savarese, Rosa Della Monica, Lorenzo Chiariotti, Raffaele Addeo, Michele Caraglia, Giuseppe De Rosa, Silvia Zappavigna
Glioblastoma (GBM) is a highly aggressive brain cancer with poor clinical outcome. Unfortunately, chemotherapy with temozolomide (TMZ) has a limited efficacy due to resistance mainly attributed to O6-methylguanine methyl transferase (MGMT) activity. Recently, miR-603 and miR-221 have been identified to target MGMT, thus improving the efficacy of temozolomide (TMZ) in the treatment of GBM. Previously, self-assembling nanoparticles (SANPs) have been proposed to deliver miRNAs into the brain. Here, SANP co-encapsulating miRNA-603 (miR-603) and miRNA-221 (miR-221) have been developed to enhance the efficacy of TMZ in the treatment of GBM by preventing the occurrence of chemoresistance. Preliminarily, SANPs encapsulating miRNAs were optimized in terms of lipid composition to assure physical stability and no hemolytic activity. Subsequently, SANPs with the lowest cytotoxicity and excellent internalization efficiency of miRNAs were selected through MTT assay and real-time PCR, respectively. To evaluate a potential synergistic effect between TMZ and miRNAs, MTT and clonogenic assays were performed. In our biological model, miRNA delivery via SANPs in combination with TMZ treatment strongly reduced cell viability and tumorigenic potential. Finally, in vivo assays were carried out on orthotopic xenograft mouse models. The treatment with SANPs encapsulating both miRNAs in combination with TMZ greatly decreased tumour growth, and even more significantly increased animal survival. In conclusion, this strategy provides the rationale for the development of new therapeutic approaches based on SANP technology to deliver miRNAs that play a key role in suppressing tumour.
{"title":"Self-assembling nanoparticles for delivery of miR-603 and miR-221 in glioblastoma as a new strategy to overcome resistance to temozolomide.","authors":"Marianna Abate, Manuela Porru, Virginia Campani, Carlo Leonetti, Valeria Nele, Rossella Di Paola, Marco De Martino, Margherita Russo, Madhura Tathode, Alessia Maria Cossu, Marco Bocchetti, Alessia Angelillo, Monica Ianniello, Nadia Petrillo, Giovanni Savarese, Rosa Della Monica, Lorenzo Chiariotti, Raffaele Addeo, Michele Caraglia, Giuseppe De Rosa, Silvia Zappavigna","doi":"10.1016/j.jconrel.2024.11.039","DOIUrl":"https://doi.org/10.1016/j.jconrel.2024.11.039","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly aggressive brain cancer with poor clinical outcome. Unfortunately, chemotherapy with temozolomide (TMZ) has a limited efficacy due to resistance mainly attributed to O6-methylguanine methyl transferase (MGMT) activity. Recently, miR-603 and miR-221 have been identified to target MGMT, thus improving the efficacy of temozolomide (TMZ) in the treatment of GBM. Previously, self-assembling nanoparticles (SANPs) have been proposed to deliver miRNAs into the brain. Here, SANP co-encapsulating miRNA-603 (miR-603) and miRNA-221 (miR-221) have been developed to enhance the efficacy of TMZ in the treatment of GBM by preventing the occurrence of chemoresistance. Preliminarily, SANPs encapsulating miRNAs were optimized in terms of lipid composition to assure physical stability and no hemolytic activity. Subsequently, SANPs with the lowest cytotoxicity and excellent internalization efficiency of miRNAs were selected through MTT assay and real-time PCR, respectively. To evaluate a potential synergistic effect between TMZ and miRNAs, MTT and clonogenic assays were performed. In our biological model, miRNA delivery via SANPs in combination with TMZ treatment strongly reduced cell viability and tumorigenic potential. Finally, in vivo assays were carried out on orthotopic xenograft mouse models. The treatment with SANPs encapsulating both miRNAs in combination with TMZ greatly decreased tumour growth, and even more significantly increased animal survival. In conclusion, this strategy provides the rationale for the development of new therapeutic approaches based on SANP technology to deliver miRNAs that play a key role in suppressing tumour.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.jconrel.2024.11.018
Dong Chen, Xiaoli Ling, Yashi Wang, Qiang Zhang, Xuan He, Ziyan Dong, Man Li, Qin He
Lymph node (LN) targeting and antigen presentation by antigen-presenting cells (APCs) are critical factors affecting the immune responses induced by tumor vaccines. Autophagy activation promotes MHC class I and II antigen presentation in APCs. To enhance antigen presentation in LNs, we developed an aluminum hydroxide nanovaccine that simultaneously incorporates the autophagy-activating peptide Beclin-1 and the antigenic protein OVA (B/O@AN nanovaccine) through layer-by-layer electrostatic interaction. B/O@AN has a particle size of approximately 80 nm and efficiently targets lymph nodes following subcutaneous administration. The combination of the Beclin-1 peptide with the aluminum hydroxide nanovaccine promotes dendritic cell (DC) maturation. More importantly, B/O@AN facilitates antigen cross-presentation by promoting lysosomal escape and autophagy induction. After immunization, compared to O/@AN without Beclin-1, B/O@AN significantly augments antigen-specific cellular immune responses, leading to substantial increases in cytotoxic T lymphocytes (CTLs), T-helper 1 (Th1) cells, as well as serum antibody levels, thereby impeding melanoma development and progression in both prophylactic and therapeutic settings. These results provide evidence that autophagy activation strengthens antigen presentation and augments the antigen-specific immune responses of the aluminum hydroxide nanovaccine.
淋巴结（LN）靶向和抗原呈递细胞（APC）的抗原呈递是影响肿瘤疫苗诱导的免疫反应的关键因素。自噬激活可促进抗原呈递细胞中的 MHC I 类和 II 类抗原呈递。为了增强 LN 中的抗原呈递，我们开发了一种氢氧化铝纳米疫苗，它通过逐层静电作用同时结合了自噬激活肽 Beclin-1 和抗原蛋白 OVA（B/O@AN 纳米疫苗）。B/O@AN 的粒径约为 80 纳米，皮下注射后可有效靶向淋巴结。Beclin-1肽与氢氧化铝纳米疫苗的结合可促进树突状细胞（DC）成熟。更重要的是，B/O@AN 通过促进溶酶体逸出和自噬诱导来促进抗原交叉呈递。免疫后，与不含Beclin-1的O/@AN相比，B/O@AN能显著增强抗原特异性细胞免疫反应，导致细胞毒性T淋巴细胞（CTL）、T-helper 1（Th1）细胞以及血清抗体水平的大幅提高，从而在预防和治疗过程中阻止黑色素瘤的发展和恶化。这些结果提供了证据，证明自噬激活可加强抗原递呈，并增强氢氧化铝纳米疫苗的抗原特异性免疫反应。
{"title":"Autophagy-activating aluminum hydroxide nanovaccine for enhanced antigen presentation and anti-tumor immunity","authors":"Dong Chen, Xiaoli Ling, Yashi Wang, Qiang Zhang, Xuan He, Ziyan Dong, Man Li, Qin He","doi":"10.1016/j.jconrel.2024.11.018","DOIUrl":"10.1016/j.jconrel.2024.11.018","url":null,"abstract":"<div><div>Lymph node (LN) targeting and antigen presentation by antigen-presenting cells (APCs) are critical factors affecting the immune responses induced by tumor vaccines. Autophagy activation promotes MHC class I and II antigen presentation in APCs. To enhance antigen presentation in LNs, we developed an aluminum hydroxide nanovaccine that simultaneously incorporates the autophagy-activating peptide Beclin-1 and the antigenic protein OVA (B/O@AN nanovaccine) through layer-by-layer electrostatic interaction. B/O@AN has a particle size of approximately 80 nm and efficiently targets lymph nodes following subcutaneous administration. The combination of the Beclin-1 peptide with the aluminum hydroxide nanovaccine promotes dendritic cell (DC) maturation. More importantly, B/O@AN facilitates antigen cross-presentation by promoting lysosomal escape and autophagy induction. After immunization, compared to O/@AN without Beclin-1, B/O@AN significantly augments antigen-specific cellular immune responses, leading to substantial increases in cytotoxic T lymphocytes (CTLs), T-helper 1 (Th1) cells, as well as serum antibody levels, thereby impeding melanoma development and progression in both prophylactic and therapeutic settings. These results provide evidence that autophagy activation strengthens antigen presentation and augments the antigen-specific immune responses of the aluminum hydroxide nanovaccine.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 223-235"},"PeriodicalIF":10.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1016/j.jconrel.2024.11.043
Fabian Doktor, Rebeca Lopes Figueira, Victoria Fortuna, George Biouss, Kaya Stasiewicz, Mikal Obed, Kasra Khalaj, Lina Antounians, Augusto Zani
Oligohydramnios (decreased amniotic fluid volume for gestational age) is a severe condition associated with high morbidity and mortality mainly due to fetal pulmonary hypoplasia. Currently, there are limited treatment options to promote fetal lung development. Administration of stem cells and their derivates have shown promising regenerative properties for several fetal and neonatal diseases related to arrested lung development. Herein, we first characterized pulmonary hypoplasia secondary to oligohydramnios in a surgical rat model. Experimental induction of oligohydramnios led to impaired lung growth, branching morphogenesis (fewer airspaces with decreased Fgf10, Nrp1, Ctnnb1 expression), proximal/distal progenitor cell patterning (decreased Sox2 and Sox9 expression), and TGF-β signaling. We then tested antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs). In oligohydramnios lungs, AFSC-EV administration improved lung branching morphogenesis and airway progenitor cell patterning at least in part through the release of miR-93-5p. Our experiments suggest that AFSC-EV miR-93-5p blocked SMAD 7, resulting in upregulation of pSMAD2/3 and restoration of TGF-β signaling. Conversely, oligohydramnios lungs treated with antagomir 93-5p transfected AFSC-EVs had decreased branching morphogenesis and TGF-β signaling. This is the first study reporting that antenatal administration of stem cell derivatives could be a potential therapy to rescue lung development in fetuses with oligohydramnios.
{"title":"Amniotic fluid stem cell extracellular vesicles promote lung development via TGF-beta modulation in a fetal rat model of oligohydramnios.","authors":"Fabian Doktor, Rebeca Lopes Figueira, Victoria Fortuna, George Biouss, Kaya Stasiewicz, Mikal Obed, Kasra Khalaj, Lina Antounians, Augusto Zani","doi":"10.1016/j.jconrel.2024.11.043","DOIUrl":"https://doi.org/10.1016/j.jconrel.2024.11.043","url":null,"abstract":"<p><p>Oligohydramnios (decreased amniotic fluid volume for gestational age) is a severe condition associated with high morbidity and mortality mainly due to fetal pulmonary hypoplasia. Currently, there are limited treatment options to promote fetal lung development. Administration of stem cells and their derivates have shown promising regenerative properties for several fetal and neonatal diseases related to arrested lung development. Herein, we first characterized pulmonary hypoplasia secondary to oligohydramnios in a surgical rat model. Experimental induction of oligohydramnios led to impaired lung growth, branching morphogenesis (fewer airspaces with decreased Fgf10, Nrp1, Ctnnb1 expression), proximal/distal progenitor cell patterning (decreased Sox2 and Sox9 expression), and TGF-β signaling. We then tested antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs). In oligohydramnios lungs, AFSC-EV administration improved lung branching morphogenesis and airway progenitor cell patterning at least in part through the release of miR-93-5p. Our experiments suggest that AFSC-EV miR-93-5p blocked SMAD 7, resulting in upregulation of pSMAD2/3 and restoration of TGF-β signaling. Conversely, oligohydramnios lungs treated with antagomir 93-5p transfected AFSC-EVs had decreased branching morphogenesis and TGF-β signaling. This is the first study reporting that antenatal administration of stem cell derivatives could be a potential therapy to rescue lung development in fetuses with oligohydramnios.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692887","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}
Breast cancer holds the highest incidence rate among women. Doxorubicin (DOX) is a potent frontline drug for the treatment of breast cancer. The anticancer mechanisms of DOX include inducing immunogenic cell death in tumor cells, causing damage to tumor DNA, and generating free radicals. However, its pharmacological efficacy and wide use are restricted by its substantial dose-dependent side effects. We have recently revealed that 1,7-Heptanediol (1,7-Hept) severely impairs the bioenergetics and metabolism of aggressive human cancer cells. In the present work, we prepared liposomes co-loaded with DOX and 1,7-Hept (DOX/1,7-Hept-lipo) and assessed their potential synergistic anti-tumor effects. In vitro studies demonstrated that 4T1 cells (the mouse breast cancer cell) exhibited higher sensitivity to 1,7-Hept and DOX/1,7-Hept-lipo could induce ICD of 4T1 cells. Cell viability was markedly reduced when 4T1 cells were treated with a combination of DOX and 1,7-Hept. In a mouse breast cancer model, the DOX/1,7-Hept-lipo exhibited superior anti-tumor efficacy compared to liposomes loaded with individual drugs, resulting in almost total elimination of the tumors at lower doses of DOX with reduced systemic toxicity. Notably, the number of immune cells significantly increased in the tumor microenvironment, and macrophages were more transformed into the anti-tumor M1 phenotype. Our findings suggest strong synergistic anti-tumor effects of DOX and 1,7-Hept, enhancing the efficacy of tumor immunotherapy and mitigating the toxic side effects of DOX.
{"title":"Synergistic in vivo anticancer effects of 1,7-heptanediol and doxorubicin co-loadedliposomes in highly aggressive breast cancer","authors":"Muge Gu , Wei Yu , Sílvio Terra Stefanello , Jiayu Wang , Xiangqi Zhang , Yihui Zhang , Wenkai Zhang , Yuanye Guan , Victor Shahin , Yun Qian , Wei-En Yuan","doi":"10.1016/j.jconrel.2024.11.012","DOIUrl":"10.1016/j.jconrel.2024.11.012","url":null,"abstract":"<div><div>Breast cancer holds the highest incidence rate among women. Doxorubicin (DOX) is a potent frontline drug for the treatment of breast cancer. The anticancer mechanisms of DOX include inducing immunogenic cell death in tumor cells, causing damage to tumor DNA, and generating free radicals. However, its pharmacological efficacy and wide use are restricted by its substantial dose-dependent side effects. We have recently revealed that 1,7-Heptanediol (1,7-Hept) severely impairs the bioenergetics and metabolism of aggressive human cancer cells. In the present work, we prepared liposomes co-loaded with DOX and 1,7-Hept (DOX/1,7-Hept-lipo) and assessed their potential synergistic anti-tumor effects. In vitro studies demonstrated that 4T1 cells (the mouse breast cancer cell) exhibited higher sensitivity to 1,7-Hept and DOX/1,7-Hept-lipo could induce ICD of 4T1 cells. Cell viability was markedly reduced when 4T1 cells were treated with a combination of DOX and 1,7-Hept. In a mouse breast cancer model, the DOX/1,7-Hept-lipo exhibited superior anti-tumor efficacy compared to liposomes loaded with individual drugs, resulting in almost total elimination of the tumors at lower doses of DOX with reduced systemic toxicity. Notably, the number of immune cells significantly increased in the tumor microenvironment, and macrophages were more transformed into the anti-tumor M1 phenotype. Our findings suggest strong synergistic anti-tumor effects of DOX and 1,7-Hept, enhancing the efficacy of tumor immunotherapy and mitigating the toxic side effects of DOX.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 174-185"},"PeriodicalIF":10.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.jconrel.2024.11.021
Yan Wang , Andrew Otte , Haesun Park , Kinam Park
In vitro-in vivo correlation (IVIVC), linking in vitro drug release to in vivo drug release or in vivo drug absorption, has been explored chiefly for oral extended-release dosage forms. Currently, there are no official guidelines on IVIVC development for non-oral drug delivery systems. Recently, many long-acting injectable (LAI) formulations based on poly(lactide-co-glycolide) (PLGA) have been developed to deliver various drugs, ranging from small molecules to peptides and proteins, for up to 6 months. The circumstances involved in the LAI formulations are drastically different from those in oral formulations, which generally deliver drugs for a maximum of 24 h. This article examines 37 IVIVC studies of PLGA microparticle formulations available in the literature. Understanding and establishing an IVIVC of LAI formulations requires more than merely plotting the percentage in vitro drug release against the percentage in vivo absorption. In vivo drug absorption (or release) should be measured to provide a complete pharmacokinetic profile when feasible. Accelerated in vitro release methods need to be respective of the real-time measurements by sharing the same release mechanism. Obtaining meaningful IVIVCs with predictive capability will be highly useful for future regulatory actions and for developing generic and new formulations.
{"title":"In vitro-in vivo correlation (IVIVC) development for long-acting injectable drug products based on poly(lactide-co-glycolide)","authors":"Yan Wang , Andrew Otte , Haesun Park , Kinam Park","doi":"10.1016/j.jconrel.2024.11.021","DOIUrl":"10.1016/j.jconrel.2024.11.021","url":null,"abstract":"<div><div><em>In vitro-in vivo</em> correlation (IVIVC), linking <em>in vitro</em> drug release to <em>in vivo</em> drug release or <em>in vivo</em> drug absorption, has been explored chiefly for oral extended-release dosage forms. Currently, there are no official guidelines on IVIVC development for non-oral drug delivery systems. Recently, many long-acting injectable (LAI) formulations based on poly(lactide-<em>co</em>-glycolide) (PLGA) have been developed to deliver various drugs, ranging from small molecules to peptides and proteins, for up to 6 months. The circumstances involved in the LAI formulations are drastically different from those in oral formulations, which generally deliver drugs for a maximum of 24 h. This article examines 37 IVIVC studies of PLGA microparticle formulations available in the literature. Understanding and establishing an IVIVC of LAI formulations requires more than merely plotting the percentage <em>in vitro</em> drug release against the percentage <em>in vivo</em> absorption. <em>In vivo</em> drug absorption (or release) should be measured to provide a complete pharmacokinetic profile when feasible. Accelerated <em>in vitro</em> release methods need to be respective of the real-time measurements by sharing the same release mechanism. Obtaining meaningful IVIVCs with predictive capability will be highly useful for future regulatory actions and for developing generic and new formulations.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 186-196"},"PeriodicalIF":10.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621399","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}
Long-acting injectable formulations of dexamethasone with minimal invasiveness are highly desired to manage chronic ocular inflammatory conditions. Here, we applied microcrystals (MCs) of a hydrophobic acetone-based ketal-linked prodrug of dexamethasone (SKD) to treat postoperative ocular inflammation. We compared the efficacy and safety of SKD MCs through subconjunctival (SC) injection with that of Maxidex (a topical suspension of dexamethasone MCs) through SC injection and eye drops in the phacoemulsification combined with intraocular lens implantation (Phaco-IOL) rabbit model. In Phaco-IOL rabbit eyes, a single SC injection of SKD MCs (0.4 mg dexamethasone equiv.) showed anti-inflammatory effects comparable to Maxidex eye drops and completely alleviated the inflammation within 28 days, while an SC injection of Maxidex at the same dose only provided anti-inflammatory effects for 7 days. The study on the dose-dependent anti-inflammatory effects of SKD MCs showed no significant difference in anti-inflammatory effects for the high dosage (0.8 mg dexamethasone equiv.) and the low dosage (0.4 mg dexamethasone equiv.) in 28 days. Nevertheless, systematic drug distribution of SKD MCs and Maxidex in normal rabbits after SC injection demonstrates that the drug concentration in conjunctiva was higher for the high dosage and that a considerable amount of prodrug and dexamethasone could still be detected in the cornea and iris-ciliary body at least 84 days for SKD MCs at high dosage. Furthermore, no persistent elevated intraocular pressure and abnormality in retinal structure and thickness were observed, confirming the excellent safety of long-acting SKD MCs post-SC injection. Our findings provide valuable insights into using prodrug-based MCs for treating ocular postoperative inflammation, and the detailed drug distribution analysis would promote the clinical translation of these MCs in ocular diseases.
{"title":"Subconjunctival injection of microcrystalline prodrug of dexamethasone for long-acting anti-inflammation after phacoemulsification surgery.","authors":"Xueyan Zhou, Zunkai Xu, Yanliang Dong, Maoyu Cai, Zhixia Chen, Jingqing Mu, Bo Yuan, Xia Hua, Xiaoyong Yuan, Shutao Guo","doi":"10.1016/j.jconrel.2024.11.046","DOIUrl":"https://doi.org/10.1016/j.jconrel.2024.11.046","url":null,"abstract":"<p><p>Long-acting injectable formulations of dexamethasone with minimal invasiveness are highly desired to manage chronic ocular inflammatory conditions. Here, we applied microcrystals (MCs) of a hydrophobic acetone-based ketal-linked prodrug of dexamethasone (SKD) to treat postoperative ocular inflammation. We compared the efficacy and safety of SKD MCs through subconjunctival (SC) injection with that of Maxidex (a topical suspension of dexamethasone MCs) through SC injection and eye drops in the phacoemulsification combined with intraocular lens implantation (Phaco-IOL) rabbit model. In Phaco-IOL rabbit eyes, a single SC injection of SKD MCs (0.4 mg dexamethasone equiv.) showed anti-inflammatory effects comparable to Maxidex eye drops and completely alleviated the inflammation within 28 days, while an SC injection of Maxidex at the same dose only provided anti-inflammatory effects for 7 days. The study on the dose-dependent anti-inflammatory effects of SKD MCs showed no significant difference in anti-inflammatory effects for the high dosage (0.8 mg dexamethasone equiv.) and the low dosage (0.4 mg dexamethasone equiv.) in 28 days. Nevertheless, systematic drug distribution of SKD MCs and Maxidex in normal rabbits after SC injection demonstrates that the drug concentration in conjunctiva was higher for the high dosage and that a considerable amount of prodrug and dexamethasone could still be detected in the cornea and iris-ciliary body at least 84 days for SKD MCs at high dosage. Furthermore, no persistent elevated intraocular pressure and abnormality in retinal structure and thickness were observed, confirming the excellent safety of long-acting SKD MCs post-SC injection. Our findings provide valuable insights into using prodrug-based MCs for treating ocular postoperative inflammation, and the detailed drug distribution analysis would promote the clinical translation of these MCs in ocular diseases.</p>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":" ","pages":""},"PeriodicalIF":10.5,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687209","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}
Ionizable lipids are widely recognized as the crucial component of lipid nanoparticles (LNPs). They enable mRNA encapsulation, shield it from enzymatic degradation, facilitate cellular uptake, and foster its cytosolic release for subsequent translation into proteins. In addition, PEGylated lipids are added to stabilize the particles in storage and in vivo. In this study, we investigate the potency of LNPs prepared using commonly adopted ionizable and pegylated lipids in vitro (using HEK293 cells) and in vivo (mouse studies) to consider the impact of structure on potency. LNPs were prepared using a fixed molar ratio of DSPC: Cholesterol: ionizable/cationic lipid: PEG lipid (10:38.5:50:1.5 mol%). All LNP formulations exhibited similar critical quality attributes (CQAs), including particle size <100 nm, low PDI (<0.2), near-neutral zeta potential, and high encapsulation efficiency (>90%). However, the potency of these LNPs, as measured by in vitro mRNA expression and in vivo expression following intramuscular injection in mice varied significantly. LNPs formulated with SM-102 exhibited the highest expression in vitro, whilst in vivo SM-102 and ALC-0315 LNPs showed significantly higher mRNA expression than DLin-MC3-DMA (MC3), DODAP and DOTAP LNPs. We also investigated the effect of PEG lipid choice (ALC-0159, DMG-PEG2k, and DSPE-PEG2k), which did not impact LNP CQAs, nor their clearance from the injection site. However, PEG lipid choice significantly influenced mRNA expression with the incorporation of DSPE-PEG2k reducing expression. This work contributes valuable insights to the evolving landscape of mRNA research, emphasizing that CQAs are a marker of the quality of the LNP production process, but not discriminatory regarding LNP potency. Similarly, standard in vitro studies do not provide insights into in vivo potency. These results further emphasize the intricacies of formulation design and the importance of bridging gaps between experimental outcomes in different settings.
{"title":"Exploring the impact of commonly used ionizable and pegylated lipids on mRNA-LNPs: A combined in vitro and preclinical perspective","authors":"Burcu Binici , Zahra Rattray , Assaf Zinger , Yvonne Perrie","doi":"10.1016/j.jconrel.2024.11.010","DOIUrl":"10.1016/j.jconrel.2024.11.010","url":null,"abstract":"<div><div>Ionizable lipids are widely recognized as the crucial component of lipid nanoparticles (LNPs). They enable mRNA encapsulation, shield it from enzymatic degradation, facilitate cellular uptake, and foster its cytosolic release for subsequent translation into proteins. In addition, PEGylated lipids are added to stabilize the particles in storage and <em>in vivo</em>. In this study, we investigate the potency of LNPs prepared using commonly adopted ionizable and pegylated lipids <em>in vitro</em> (using HEK293 cells) and <em>in vivo</em> (mouse studies) to consider the impact of structure on potency. LNPs were prepared using a fixed molar ratio of DSPC: Cholesterol: ionizable/cationic lipid: PEG lipid (10:38.5:50:1.5 mol%). All LNP formulations exhibited similar critical quality attributes (CQAs), including particle size <100 nm, low PDI (<0.2), near-neutral zeta potential, and high encapsulation efficiency (>90%). However, the potency of these LNPs, as measured by <em>in vitro</em> mRNA expression and <em>in vivo</em> expression following intramuscular injection in mice varied significantly. LNPs formulated with SM-102 exhibited the highest expression <em>in vitro</em>, whilst <em>in vivo</em> SM-102 and ALC-0315 LNPs showed significantly higher mRNA expression than DLin-MC3-DMA (MC3), DODAP and DOTAP LNPs. We also investigated the effect of PEG lipid choice (ALC-0159, DMG-PEG2k, and DSPE-PEG2k), which did not impact LNP CQAs, nor their clearance from the injection site. However, PEG lipid choice significantly influenced mRNA expression with the incorporation of DSPE-PEG2k reducing expression. This work contributes valuable insights to the evolving landscape of mRNA research, emphasizing that CQAs are a marker of the quality of the LNP production process, but not discriminatory regarding LNP potency. Similarly, standard <em>in vitro</em> studies do not provide insights into <em>in vivo</em> potency. These results further emphasize the intricacies of formulation design and the importance of bridging gaps between experimental outcomes in different settings.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 162-173"},"PeriodicalIF":10.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.jconrel.2024.11.014
Dandan Su , Manchun Li , Yuedong Xie , Zhanxue Xu , Guowen Lv , Yaming Jiu , Jingxiong Lin , Chih-Jung Chang , Hongbo Chen , Fang Cheng
Despite gut microbiota-derived extracellular vesicles (EVs) serving as pivotal mediators in bacteria-host cell interactions, their potential role in modulating skin inflammation remains poorly understood. Here, we developed strategies for mass production of Parabacteroides goldsteinii-derived outer membrane vesicles (Pg OMVs), commonly known as EVs. We found that orally administered Pg OMVs can reach the colon, traverse the intestinal barrier, and circulate to the inflamed skin of psoriasis-like mice, resulting in reduced epidermal hyperplasia, suppressed infiltration of inflammatory cells in the skin lesions, and effective amelioration of both skin and systemic inflammation. Additionally, subcutaneous injection of thermosensitive PF-127 hydrogel loaded with Pg OMVs exerts similar immunomodulatory effects, allowing sustained release of Pg OMVs into skin cells, effectively suppressing skin inflammation and ameliorating symptoms of psoriasis. This study unveils the importance of gut microbiota-derived OMVs, which can target inflamed skin via both the gut-skin axis and local skin administration, providing a promising alternative to live bacteria therapy for the treatment of skin inflammatory diseases.
{"title":"Gut commensal bacteria Parabacteroides goldsteinii-derived outer membrane vesicles suppress skin inflammation in psoriasis","authors":"Dandan Su , Manchun Li , Yuedong Xie , Zhanxue Xu , Guowen Lv , Yaming Jiu , Jingxiong Lin , Chih-Jung Chang , Hongbo Chen , Fang Cheng","doi":"10.1016/j.jconrel.2024.11.014","DOIUrl":"10.1016/j.jconrel.2024.11.014","url":null,"abstract":"<div><div>Despite gut microbiota-derived extracellular vesicles (EVs) serving as pivotal mediators in bacteria-host cell interactions, their potential role in modulating skin inflammation remains poorly understood. Here, we developed strategies for mass production of <em>Parabacteroides goldsteinii</em>-derived outer membrane vesicles (Pg OMVs), commonly known as EVs. We found that orally administered Pg OMVs can reach the colon, traverse the intestinal barrier, and circulate to the inflamed skin of psoriasis-like mice, resulting in reduced epidermal hyperplasia, suppressed infiltration of inflammatory cells in the skin lesions, and effective amelioration of both skin and systemic inflammation. Additionally, subcutaneous injection of thermosensitive PF-127 hydrogel loaded with Pg OMVs exerts similar immunomodulatory effects, allowing sustained release of Pg OMVs into skin cells, effectively suppressing skin inflammation and ameliorating symptoms of psoriasis. This study unveils the importance of gut microbiota-derived OMVs, which can target inflamed skin <em>via</em> both the gut-skin axis and local skin administration, providing a promising alternative to live bacteria therapy for the treatment of skin inflammatory diseases.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 127-145"},"PeriodicalIF":10.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-18DOI: 10.1016/j.jconrel.2024.11.026
Yuxin Ren , Peishan Li , Ying Xie , Jiarui Xu , Qian Luo , Ming Chen , Rui Liu , Hexuan Feng , Yuling Chen , Yixuan Liu , Chunjie Bao , Jialun Duan , Jianwei Li , Wanliang Lu
Drug delivery efficiency often affects chemotherapy outcome due to dense collagen barrier in tumor environment. Here, we report a nanoparticle capable of pH and glutathione dual-responsive drug delivery to enhance the efficacy of breast cancer chemotherapy. Maleiminated polyethylene glycol and polylactide block copolymer were synthesized as a core material, doxorubicin was encapsulated into the nanoparticle by self-assembly. Thiocollagenase and maleimide were connected on the nanoparticle surface by click chemistry, and further coated with chondroitin sulfate as a protective layer to form dual-responsive doxorubicin nanoparticle. The results showed that the nanoparticle had the ability to penetrate deep tumor tissue, to target on CD44 of cancer cell, and to release doxorubicin in cancer cell in response to pH and glutathione signals, demonstrating superior anticancer efficacy in breast cancer-bearing mice. In conclusion, the dual-responsive nanoparticle could be used as a drug carrier to enhance drug delivery in breast cancer chemotherapy.
{"title":"Dual-responsive nanoparticles for enhanced drug delivery in breast Cancer chemotherapy","authors":"Yuxin Ren , Peishan Li , Ying Xie , Jiarui Xu , Qian Luo , Ming Chen , Rui Liu , Hexuan Feng , Yuling Chen , Yixuan Liu , Chunjie Bao , Jialun Duan , Jianwei Li , Wanliang Lu","doi":"10.1016/j.jconrel.2024.11.026","DOIUrl":"10.1016/j.jconrel.2024.11.026","url":null,"abstract":"<div><div>Drug delivery efficiency often affects chemotherapy outcome due to dense collagen barrier in tumor environment. Here, we report a nanoparticle capable of pH and glutathione dual-responsive drug delivery to enhance the efficacy of breast cancer chemotherapy. Maleiminated polyethylene glycol and polylactide block copolymer were synthesized as a core material, doxorubicin was encapsulated into the nanoparticle by self-assembly. Thiocollagenase and maleimide were connected on the nanoparticle surface by click chemistry, and further coated with chondroitin sulfate as a protective layer to form dual-responsive doxorubicin nanoparticle. The results showed that the nanoparticle had the ability to penetrate deep tumor tissue, to target on CD44 of cancer cell, and to release doxorubicin in cancer cell in response to pH and glutathione signals, demonstrating superior anticancer efficacy in breast cancer-bearing mice. In conclusion, the dual-responsive nanoparticle could be used as a drug carrier to enhance drug delivery in breast cancer chemotherapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"377 ","pages":"Pages 146-161"},"PeriodicalIF":10.5,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643746","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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