Pub Date : 2024-10-24DOI: 10.1016/j.jconrel.2024.10.024
Yanhui Qin , Lan Yang , Yafeng Yang , Wenjia Gao , Kamiran Aihemaiti , Guangwei Jiang , Rong Huang , Haroon Khan , Rongqin Huang
Overcoming multiple barriers to deliver macromolecular drugs is an urgent challenge for glioma treatment. Herein, a strategy of protein corona-regulation synergizing with photoactivation based on T10 peptide-modified and indocyanine green (ICG)-loaded dendrigraft poly-L-lysines was proposed to augment prime editing therapy of glioma. First, the modified T10 peptide could escape the interference barrier of protein crown in blood via its specific binding with endogenous transferrin, thus crossing the blood-brain barrier (BBB) and achieving the targeting recognition of glioma cells. Next, the loaded ICG could weaken the tumor stromal barrier, decrease the cell membrane barrier and escape the lysosomal degradation/autophagy barrier via its photothermal and photodynamic effects. Subsequently, a therapeutic gene that could downregulate p-ERK1/2 for tumor growth inhibition and immunoregulation could be effectively delivered into the glioma cells. The glioma-targeted photo-gene combined immunotherapy effectively inhibit the glioma growth, especially co-dosing with the PD-1 antibody.
{"title":"Overcoming multiple barriers to deliver photo-gene system for glioma-targeted combined therapy","authors":"Yanhui Qin , Lan Yang , Yafeng Yang , Wenjia Gao , Kamiran Aihemaiti , Guangwei Jiang , Rong Huang , Haroon Khan , Rongqin Huang","doi":"10.1016/j.jconrel.2024.10.024","DOIUrl":"10.1016/j.jconrel.2024.10.024","url":null,"abstract":"<div><div>Overcoming multiple barriers to deliver macromolecular drugs is an urgent challenge for glioma treatment. Herein, a strategy of protein corona-regulation synergizing with photoactivation based on T10 peptide-modified and indocyanine green (ICG)-loaded dendrigraft poly-L-lysines was proposed to augment prime editing therapy of glioma. First, the modified T10 peptide could escape the interference barrier of protein crown in blood via its specific binding with endogenous transferrin, thus crossing the blood-brain barrier (BBB) and achieving the targeting recognition of glioma cells. Next, the loaded ICG could weaken the tumor stromal barrier, decrease the cell membrane barrier and escape the lysosomal degradation/autophagy barrier via its photothermal and photodynamic effects. Subsequently, a therapeutic gene that could downregulate p-ERK1/2 for tumor growth inhibition and immunoregulation could be effectively delivered into the glioma cells. The glioma-targeted photo-gene combined immunotherapy effectively inhibit the glioma growth, especially co-dosing with the PD-1 antibody.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 542-552"},"PeriodicalIF":10.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451857","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 : 2024-10-24DOI: 10.1016/j.jconrel.2024.10.036
Zian Liao , Diana Monsivais , Martin M. Matzuk
Endometriosis, defined by the growth of endometrial tissues outside of the uterine cavity, is a global health burden for ∼200 million women. Patients with endometriosis usually present with chronic pain and are often diagnosed with infertility. The pathogenesis of endometriosis is still an open question; however, tissue stemness and immunological and genetic factors have been extensively discussed in the establishment of endometriotic lesions. Current treatments for endometriosis can be categorized into pharmacological management of hormone levels and surgical removal of the lesions. Both approaches have limited efficacy, with recurrences often encountered; thus, there is no complete cure for the disease or its symptoms. We review the current knowledge of the etiology of endometriosis and summarize the advancement of pharmacological management of endometriosis. We also discuss our efforts in applying DNA-encoded chemistry technology (DEC-Tec) to identify bioactive molecules for the treatment of endometriosis, offering new avenues for developing non-hormonal treatment options for those patients who seek spontaneous pregnancies.
子宫内膜异位症是指子宫内膜组织在子宫腔外生长，是全球约 2 亿妇女的健康负担。子宫内膜异位症患者通常伴有慢性疼痛，并经常被诊断为不孕症。子宫内膜异位症的发病机制仍是一个未解之谜；然而，组织干性、免疫学和遗传学因素在子宫内膜异位症病变的形成过程中已被广泛讨论。目前治疗子宫内膜异位症的方法可分为激素水平药物治疗和手术切除病灶。这两种方法的疗效都很有限，而且经常会复发；因此，目前还没有完全治愈这种疾病或其症状的方法。我们回顾了目前对子宫内膜异位症病因的认识，总结了子宫内膜异位症药物治疗的进展。我们还讨论了我们在应用 DNA 编码化学技术（DEC-Tec）鉴定治疗子宫内膜异位症的生物活性分子方面所做的努力，这为寻求自然怀孕的患者提供了开发非激素治疗方案的新途径。
{"title":"The long road of drug development for endometriosis – Pains, gains, and hopes","authors":"Zian Liao , Diana Monsivais , Martin M. Matzuk","doi":"10.1016/j.jconrel.2024.10.036","DOIUrl":"10.1016/j.jconrel.2024.10.036","url":null,"abstract":"<div><div>Endometriosis, defined by the growth of endometrial tissues outside of the uterine cavity, is a global health burden for ∼200 million women. Patients with endometriosis usually present with chronic pain and are often diagnosed with infertility. The pathogenesis of endometriosis is still an open question; however, tissue stemness and immunological and genetic factors have been extensively discussed in the establishment of endometriotic lesions. Current treatments for endometriosis can be categorized into pharmacological management of hormone levels and surgical removal of the lesions. Both approaches have limited efficacy, with recurrences often encountered; thus, there is no complete cure for the disease or its symptoms. We review the current knowledge of the etiology of endometriosis and summarize the advancement of pharmacological management of endometriosis. We also discuss our efforts in applying DNA-encoded chemistry technology (DEC-Tec) to identify bioactive molecules for the treatment of endometriosis, offering new avenues for developing non-hormonal treatment options for those patients who seek spontaneous pregnancies.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 429-440"},"PeriodicalIF":10.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466610","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 : 2024-10-24DOI: 10.1016/j.jconrel.2024.10.035
Seyyed Majid Eslami, Xiuling Lu
The high prevalence of drug resistance, relapse, and unfavorable response rate of conventional cancer therapies necessitate the development of more efficient treatment modalities. Immunotherapy represents a novel therapeutic approach to cancer treatment in which the immune system's potential is harnessed to recognize and eliminate tumor cells. mRNA cancer vaccines, as a burgeoning field of immunotherapy, have recently drawn particular attention, and among mRNAs encoding tumor-associated antigens, tumor-specific antigens, and immune stimulatory factors, the latter has been relatively less explored. These immunostimulatory mRNAs encode a range of proteins, including stimulatory ligands, receptors, enzymes, pro-inflammatory cytokines, and inhibitory binding proteins, which collectively augment the host immune system's ability against cancerous cells. In this review, we aimed to provide a comprehensive account of mRNA-based cancer vaccines encoding immune stimulants, encompassing their current status, mechanisms of action, delivery strategies employed, as well as recent advances in preclinical and clinical studies. The potential challenges, strategies and future perspectives have also been discussed.
{"title":"Recent advances in mRNA-based cancer vaccines encoding immunostimulants and their delivery strategies","authors":"Seyyed Majid Eslami, Xiuling Lu","doi":"10.1016/j.jconrel.2024.10.035","DOIUrl":"10.1016/j.jconrel.2024.10.035","url":null,"abstract":"<div><div>The high prevalence of drug resistance, relapse, and unfavorable response rate of conventional cancer therapies necessitate the development of more efficient treatment modalities. Immunotherapy represents a novel therapeutic approach to cancer treatment in which the immune system's potential is harnessed to recognize and eliminate tumor cells. mRNA cancer vaccines, as a burgeoning field of immunotherapy, have recently drawn particular attention, and among mRNAs encoding tumor-associated antigens, tumor-specific antigens, and immune stimulatory factors, the latter has been relatively less explored. These immunostimulatory mRNAs encode a range of proteins, including stimulatory ligands, receptors, enzymes, pro-inflammatory cytokines, and inhibitory binding proteins, which collectively augment the host immune system's ability against cancerous cells. In this review, we aimed to provide a comprehensive account of mRNA-based cancer vaccines encoding immune stimulants, encompassing their current status, mechanisms of action, delivery strategies employed, as well as recent advances in preclinical and clinical studies. The potential challenges, strategies and future perspectives have also been discussed.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 413-428"},"PeriodicalIF":10.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488232","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 : 2024-10-24DOI: 10.1016/j.jconrel.2024.10.027
Chinmay M. Jogdeo , Sudipta Panja , Neha Kumari , Weimin Tang , Ekta Kapoor , Kasturi Siddhanta , Ashish Das , Erika I. Boesen , Kirk W. Foster , David Oupický
RNA interference has emerged as a promising therapeutic strategy to tackle acute kidney injury (AKI). Development of targeted delivery systems is highly desired for selective renal delivery of RNA and improved therapeutic outcomes in AKI. Inulin is a plant polysaccharide traditionally employed to measure glomerular filtration rate. Here, we describe the synthesis of inulin modified with α-cyclam-p-toluic acid (CPTA) to form a novel renal-targeted polymer, Inulin-CPTA (IC), which is capable of selective siRNA delivery to the injured kidneys. We show that conjugating CPTA to inulin imparts IC with targeting properties for cells that overexpress the C-X-C chemokine receptor 4 (CXCR4). Self-assembled IC/siRNA nanoparticles (polyplexes) demonstrated rapid accumulation in the injured kidneys with selective uptake and prolonged retention in injured renal tubules overexpressing the CXCR4 receptor. Tumor-suppressor protein p53 contributes significantly to the pathogenesis of AKI. siRNA-induced silencing of p53 has shown therapeutic potential in several preclinical studies, making it an important target in the treatment of AKI. Systemically administered nanoparticles formulated using IC and siRNA against p53 selectively accumulated in the injured kidneys and potently silenced p53 expression. Selective p53 knockdown led to positive therapeutic outcomes in mice with cisplatin-induced AKI, as seen by reduced tubular cell death, renal injury, inflammation, and overall improved renal function. These findings indicate that IC is a promising new carrier for renal-targeted delivery of RNA for the treatment of AKI.
RNA 干扰已成为应对急性肾损伤（AKI）的一种前景广阔的治疗策略。为了选择性地向肾脏输送 RNA 并改善 AKI 的治疗效果，开发靶向输送系统是非常必要的。菊粉是一种植物多糖，传统上用于测量肾小球滤过率。在这里，我们描述了菊粉与α-环戊酸（CPTA）的合成，从而形成一种新型肾脏靶向聚合物--菊粉-CPTA（IC），它能够选择性地将 siRNA 运送到受伤的肾脏。我们的研究表明，将 CPTA 与菊粉共轭可使 IC 对过度表达 C-X-C 趋化因子受体 4（CXCR4）的细胞具有靶向特性。自组装的IC/siRNA纳米颗粒（多聚体）在损伤的肾脏中迅速积累，并在过度表达CXCR4受体的损伤肾小管中被选择性摄取和长时间保留。siRNA 诱导的 p53 沉默已在多项临床前研究中显示出治疗潜力，使其成为治疗 AKI 的重要靶点。使用 IC 和 siRNA 针对 p53 配制的全身给药纳米颗粒可选择性地在损伤的肾脏中聚集，并有效地抑制 p53 的表达。在顺铂诱导的 AKI 小鼠中，选择性地敲除 p53 会带来积极的治疗效果，表现为肾小管细胞死亡、肾损伤、炎症的减少以及肾功能的整体改善。这些研究结果表明，IC 是一种很有前景的新载体，可用于肾脏靶向递送 RNA 以治疗 AKI。
{"title":"Inulin-based nanoparticles for targeted siRNA delivery in acute kidney injury","authors":"Chinmay M. Jogdeo , Sudipta Panja , Neha Kumari , Weimin Tang , Ekta Kapoor , Kasturi Siddhanta , Ashish Das , Erika I. Boesen , Kirk W. Foster , David Oupický","doi":"10.1016/j.jconrel.2024.10.027","DOIUrl":"10.1016/j.jconrel.2024.10.027","url":null,"abstract":"<div><div>RNA interference has emerged as a promising therapeutic strategy to tackle acute kidney injury (AKI). Development of targeted delivery systems is highly desired for selective renal delivery of RNA and improved therapeutic outcomes in AKI. Inulin is a plant polysaccharide traditionally employed to measure glomerular filtration rate. Here, we describe the synthesis of inulin modified with α-cyclam-<em>p</em>-toluic acid (CPTA) to form a novel renal-targeted polymer, Inulin-CPTA (IC), which is capable of selective siRNA delivery to the injured kidneys. We show that conjugating CPTA to inulin imparts IC with targeting properties for cells that overexpress the C-X-C chemokine receptor 4 (CXCR4). Self-assembled IC/siRNA nanoparticles (polyplexes) demonstrated rapid accumulation in the injured kidneys with selective uptake and prolonged retention in injured renal tubules overexpressing the CXCR4 receptor. Tumor-suppressor protein p53 contributes significantly to the pathogenesis of AKI. siRNA-induced silencing of p53 has shown therapeutic potential in several preclinical studies, making it an important target in the treatment of AKI. Systemically administered nanoparticles formulated using IC and siRNA against p53 selectively accumulated in the injured kidneys and potently silenced p53 expression. Selective p53 knockdown led to positive therapeutic outcomes in mice with cisplatin-induced AKI, as seen by reduced tubular cell death, renal injury, inflammation, and overall improved renal function. These findings indicate that IC is a promising new carrier for renal-targeted delivery of RNA for the treatment of AKI.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 577-592"},"PeriodicalIF":10.5,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449275","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 : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.018
Zhe Cong , Yi Wei , Huihui Chong , Dong Zhang , Ling Tong , Jingjing Zhang , Yuanmei Zhu , Zejing Gao , Huijuan Jin , Jiahan Lu , Qiuhan Lu , Ting Chen , Qiang Wei , Guanghui Ma , Yuxian He , Fangling Gong , Jing Xue
Non-adherence to antiretroviral treatment is a critical obstacle to effectively managing the progression of AIDS and reducing transmission and mortality rates. A promising strategy to address the clinical disadvantages of user-dependent dosing and decrease medication frequency is the development of long-acting antiretrovirals. In this study, we fabricated PLGA microspheres (MS) incorporating the lipopeptide LP-98 (LP-98-MS), which has previously exhibited potent anti-HIV efficacy. Our findings demonstrate that a single-dose injection of LP-98-MS in SHIV-infected rhesus macaques resulted in sustained and gradual release, maintaining antiviral effects at least 28 days. Notably, a single administration of LP-98-MS provided more than 28 days of sustained release, resulting in high-level pre-exposure prophylaxis (PrEP) for rhesus macaques, even providing complete protection when exposed to repeated intravaginal and intrarectal SHIV challenges. Overall, LP-98-MS holds significant potential in reducing medication frequency and shows promising prospects for further development.
{"title":"Prolonged release and antiviral efficacy of HIV fusion inhibitor LP-98-loaded microspheres in rhesus macaques","authors":"Zhe Cong , Yi Wei , Huihui Chong , Dong Zhang , Ling Tong , Jingjing Zhang , Yuanmei Zhu , Zejing Gao , Huijuan Jin , Jiahan Lu , Qiuhan Lu , Ting Chen , Qiang Wei , Guanghui Ma , Yuxian He , Fangling Gong , Jing Xue","doi":"10.1016/j.jconrel.2024.10.018","DOIUrl":"10.1016/j.jconrel.2024.10.018","url":null,"abstract":"<div><div>Non-adherence to antiretroviral treatment is a critical obstacle to effectively managing the progression of AIDS and reducing transmission and mortality rates. A promising strategy to address the clinical disadvantages of user-dependent dosing and decrease medication frequency is the development of long-acting antiretrovirals. In this study, we fabricated PLGA microspheres (MS) incorporating the lipopeptide LP-98 (LP-98-MS), which has previously exhibited potent anti-HIV efficacy. Our findings demonstrate that a single-dose injection of LP-98-MS in SHIV-infected rhesus macaques resulted in sustained and gradual release, maintaining antiviral effects at least 28 days. Notably, a single administration of LP-98-MS provided more than 28 days of sustained release, resulting in high-level pre-exposure prophylaxis (PrEP) for rhesus macaques, even providing complete protection when exposed to repeated intravaginal and intrarectal SHIV challenges. Overall, LP-98-MS holds significant potential in reducing medication frequency and shows promising prospects for further development.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 530-541"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.039
Jie He , Xingli Zhang , Haiyan Xing , Jiangwei Tan , Lei Zhang , Zhigang Xu , Yuejun Kang , Peng Xue
Innervation is closely linked to several biological processes that promote tumor growth, making it an increasingly promising therapeutic target. In this study, biomimetic hollow MnO2 nanocarriers camouflaged with tumor cell membranes (HMLC) are developed to encapsulate lidocaine, an innervation inhibitor, for effective antineoplastic therapy. This approach aims to suppress nerve fiber growth and induce intracellular redox imbalance. Benefiting from the tumor-homing effect, HMLC accumulates in cancerous tissue during circulation and is endocytosed by tumor cells through homologous membrane fusion. Once inside the cells, MnO2 can be degraded by the overproduced glutathione and H2O2, leading to the tumor-specific release of Mn2+ and lidocaine. The Mn2+-mediated Fenton-like reaction promotes the accumulation of reactive oxygen species, and the resulting oxidative stress, combined with glutathione depletion, exacerbates redox imbalance. Simultaneously, the released lidocaine downregulates nerve growth factor and neuronatin. The reduction in nerve growth factor significantly inhibits nerve fiber formation and infiltration in tumor tissue, while the decrease in neuronatin reduces intracellular Ca2+, which helps prevent metastasis. Overall, this strategy highlights the potential of nanoparticle-based tumor innervation disruptors in antineoplastic therapy.
{"title":"Nanoparticle-mediated synergistic disruption of tumor innervation and redox homeostasis for potent antineoplastic therapy","authors":"Jie He , Xingli Zhang , Haiyan Xing , Jiangwei Tan , Lei Zhang , Zhigang Xu , Yuejun Kang , Peng Xue","doi":"10.1016/j.jconrel.2024.10.039","DOIUrl":"10.1016/j.jconrel.2024.10.039","url":null,"abstract":"<div><div>Innervation is closely linked to several biological processes that promote tumor growth, making it an increasingly promising therapeutic target. In this study, biomimetic hollow MnO<sub>2</sub> nanocarriers camouflaged with tumor cell membranes (HMLC) are developed to encapsulate lidocaine, an innervation inhibitor, for effective antineoplastic therapy. This approach aims to suppress nerve fiber growth and induce intracellular redox imbalance. Benefiting from the tumor-homing effect, HMLC accumulates in cancerous tissue during circulation and is endocytosed by tumor cells through homologous membrane fusion. Once inside the cells, MnO<sub>2</sub> can be degraded by the overproduced glutathione and H<sub>2</sub>O<sub>2</sub>, leading to the tumor-specific release of Mn<sup>2+</sup> and lidocaine. The Mn<sup>2+</sup>-mediated Fenton-like reaction promotes the accumulation of reactive oxygen species, and the resulting oxidative stress, combined with glutathione depletion, exacerbates redox imbalance. Simultaneously, the released lidocaine downregulates nerve growth factor and neuronatin. The reduction in nerve growth factor significantly inhibits nerve fiber formation and infiltration in tumor tissue, while the decrease in neuronatin reduces intracellular Ca<sup>2+</sup>, which helps prevent metastasis. Overall, this strategy highlights the potential of nanoparticle-based tumor innervation disruptors in antineoplastic therapy.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 457-469"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142486847","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 : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.023
Ambre Dauba , Claire Spitzlei , Kathlyne Jayne B. Bautista , Laurène Jourdain , Erwan Selingue , Kelly E. VanTreeck , Jacob A. Mattern , Caroline Denis , Malika Ouldali , Ana-Andreea Arteni , Charles Truillet , Benoit Larrat , James Tsuruta , Phillip G. Durham , Virginie Papadopoulou , Paul A. Dayton , Nicolas Tsapis , Anthony Novell
Low-boiling point perfluorocarbon nanodroplets (NDs) are valued as effective sonosensitive agents, encapsulating a liquid perfluorocarbon that would instantaneously vaporize at body temperature without the NDs shell. Those NDs have been explored for both therapeutic and diagnostic purposes. Here, phospholipid-shelled nanodroplets containing octafluoropropane (C3F8) or decafluorobutane (C4F10) formed by condensation of microbubbles were thoroughly characterized before blood-brain (BBB) permeabilization. Transmission electron microscopy (TEM) and cryo-TEM were employed to confirm droplet formation while providing high-resolution insights into the droplet surface and lipid arrangement assessed from electron density observation after condensation. The vaporization threshold of NDs was determined with a high-speed camera, and the frequency signal emitted by the freshly vaporized bubbles was analyzed using cavitation detection. C3F8 NDs exhibited vaporization at 0.3 MPa (f0 = 1.5 MHz, 50 cycles), and emitted signals at 2 f0 and 1.5 f0 from 0.45 MPa onwards (f0 = 1.5 MHz, 50 cycles), while broadband noise was measured starting from 0.55 MPa. NDs with the higher boiling point C4F10 vaporized at 1.15 MPa and emitted signals at 2 f0 from 0.65 MPa and 1.5 f0 from 0.9 MPa, while broadband noise was detected starting from 0.95 MPa. Both ND formulations were used to permeabilize the BBB in healthy mice using tailored ultrasound sequences, allowing for the identification of optimal applications for each NDs type. C3F8 NDs proved suitable and safe for permeabilizing a large area, potentially the entire brain, at low acoustic pressure. Meanwhile, C4F10 droplets facilitated very localized (400 μm isotropic) permeabilization at higher pressure. This study prompts a closer examination of the structural rearrangements occurring during the condensation of microbubbles into NDs and highlights the potential to tailor solutions for different brain pathologies by choosing the composition of the NDs and adjusting the ultrasound sequence.
{"title":"Low-boiling-point perfluorocarbon nanodroplets for adaptable ultrasound-induced blood-brain barrier opening","authors":"Ambre Dauba , Claire Spitzlei , Kathlyne Jayne B. Bautista , Laurène Jourdain , Erwan Selingue , Kelly E. VanTreeck , Jacob A. Mattern , Caroline Denis , Malika Ouldali , Ana-Andreea Arteni , Charles Truillet , Benoit Larrat , James Tsuruta , Phillip G. Durham , Virginie Papadopoulou , Paul A. Dayton , Nicolas Tsapis , Anthony Novell","doi":"10.1016/j.jconrel.2024.10.023","DOIUrl":"10.1016/j.jconrel.2024.10.023","url":null,"abstract":"<div><div>Low-boiling point perfluorocarbon nanodroplets (NDs) are valued as effective sonosensitive agents, encapsulating a liquid perfluorocarbon that would instantaneously vaporize at body temperature without the NDs shell. Those NDs have been explored for both therapeutic and diagnostic purposes. Here, phospholipid-shelled nanodroplets containing octafluoropropane (C<sub>3</sub>F<sub>8</sub>) or decafluorobutane (C<sub>4</sub>F<sub>10</sub>) formed by condensation of microbubbles were thoroughly characterized before blood-brain (BBB) permeabilization. Transmission electron microscopy (TEM) and cryo-TEM were employed to confirm droplet formation while providing high-resolution insights into the droplet surface and lipid arrangement assessed from electron density observation after condensation. The vaporization threshold of NDs was determined with a high-speed camera, and the frequency signal emitted by the freshly vaporized bubbles was analyzed using cavitation detection. C<sub>3</sub>F<sub>8</sub> NDs exhibited vaporization at 0.3 MPa (<em>f</em><sub><em>0</em></sub> = 1.5 MHz, 50 cycles), and emitted signals at 2 <em>f</em><sub><em>0</em></sub> and 1.5 <em>f</em><sub><em>0</em></sub> from 0.45 MPa onwards (<em>f</em><sub><em>0</em></sub> = 1.5 MHz, 50 cycles), while broadband noise was measured starting from 0.55 MPa. NDs with the higher boiling point C<sub>4</sub>F<sub>10</sub> vaporized at 1.15 MPa and emitted signals at 2 <em>f</em><sub><em>0</em></sub> from 0.65 MPa and 1.5 <em>f</em><sub><em>0</em></sub> from 0.9 MPa, while broadband noise was detected starting from 0.95 MPa. Both ND formulations were used to permeabilize the BBB in healthy mice using tailored ultrasound sequences, allowing for the identification of optimal applications for each NDs type. C<sub>3</sub>F<sub>8</sub> NDs proved suitable and safe for permeabilizing a large area, potentially the entire brain, at low acoustic pressure. Meanwhile, C<sub>4</sub>F<sub>10</sub> droplets facilitated very localized (400 μm isotropic) permeabilization at higher pressure. This study prompts a closer examination of the structural rearrangements occurring during the condensation of microbubbles into NDs and highlights the potential to tailor solutions for different brain pathologies by choosing the composition of the NDs and adjusting the ultrasound sequence.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 441-456"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.030
Guodong Ren , Xuewei Wang , Zhaobo Yang , Xiaowan Li , Yingyu Ma , Liang Zhou , Lili Yan , Sufang Ma , Lihong Li , Lixia Guo , Boye Zhang , Haipeng Diao , Haojiang Wang , Bin Wang , Li Lu , Chengwu Zhang , Wen Liu
Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths, and its treatment poses significant challenges. In recent years, photodynamic, photothermal, and chemodynamic therapies have emerged as alternative strategies for tumor intervention. However, limitations such as poor tumor targeting, insufficient microenvironment responsiveness, and unclear mechanisms hinder their application. In this study, we found that hypoxia-inducible factor 1 alpha (HIF-1α) was highly expressed in clinical EC samples, which contributed to tumor malignancy and metastasis. We developed a carbon dots (CDs)-based tumor microenvironment (TME)-responsive nanoplatform, CDs-MnO2-Au-Cet (CMAC), designed for multimodal imaging-guided precision therapy in EC. Both in vitro and in vivo experiments demonstrated that CMAC effectively targeted and imaged EC cells and tissues. CMAC significantly inhibited tumor growth by inducing apoptosis and reducing lung metastasis. Mechanistically, CMAC administration led to a substantial downregulation of HIF-1α and its downstream targets, GLUT1 and MMP9. In summary, we presented a novel nanoplatform for imaging-guided synergistic therapy in EC, which demonstrated excellent anti-tumor growth and metastasis capabilities, along with favorable biocompatibility. This study laid the groundwork for developing innovative theranostic strategies for EC.
{"title":"TME-responsive nanoplatform for multimodal imaging-guided synergistic precision therapy of esophageal cancer via inhibiting HIF-1α signal pathway","authors":"Guodong Ren , Xuewei Wang , Zhaobo Yang , Xiaowan Li , Yingyu Ma , Liang Zhou , Lili Yan , Sufang Ma , Lihong Li , Lixia Guo , Boye Zhang , Haipeng Diao , Haojiang Wang , Bin Wang , Li Lu , Chengwu Zhang , Wen Liu","doi":"10.1016/j.jconrel.2024.10.030","DOIUrl":"10.1016/j.jconrel.2024.10.030","url":null,"abstract":"<div><div>Esophageal cancer (EC) is the sixth leading cause of cancer-related deaths, and its treatment poses significant challenges. In recent years, photodynamic, photothermal, and chemodynamic therapies have emerged as alternative strategies for tumor intervention. However, limitations such as poor tumor targeting, insufficient microenvironment responsiveness, and unclear mechanisms hinder their application. In this study, we found that hypoxia-inducible factor 1 alpha (HIF-1α) was highly expressed in clinical EC samples, which contributed to tumor malignancy and metastasis. We developed a carbon dots (CDs)-based tumor microenvironment (TME)-responsive nanoplatform, CDs-MnO<sub>2</sub>-Au-Cet (CMAC), designed for multimodal imaging-guided precision therapy in EC. Both <em>in vitro</em> and <em>in vivo</em> experiments demonstrated that CMAC effectively targeted and imaged EC cells and tissues. CMAC significantly inhibited tumor growth by inducing apoptosis and reducing lung metastasis. Mechanistically, CMAC administration led to a substantial downregulation of HIF-1α and its downstream targets, GLUT1 and MMP9. In summary, we presented a novel nanoplatform for imaging-guided synergistic therapy in EC, which demonstrated excellent anti-tumor growth and metastasis capabilities, along with favorable biocompatibility. This study laid the groundwork for developing innovative theranostic strategies for EC.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 518-529"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451414","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 : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.040
Yanjiao Ding , Zhiqiang Hou , Mingming Wang , Lei Xu , Haibo Wang
Hearing loss is a prevalent disability worldwide. Dexamethasone (Dex) is commonly used to treat hearing loss, administered either systemically or locally. However, targeted delivery of Dex to the inner ear remains challenging, which limits its therapeutic efficacy. This study aimed to develop new methods to improve Dex delivery to the inner ear and enhance its treatment effect. Mastoid, intraperitoneal, and intratympanic delivery routes for Dex were investigated in guinea pig cochlea. Liquid chromatography-mass spectrometry and immunohistochemistry were employed to compare the distribution of Dex in the perilymph and tissue uptake. Poly (lactic-co-glycolic acid) nanoparticles loaded with Dex (PLGA-NPs-Dex) were prepared, and their transport mechanism across the round window membrane (RWM) was explored. Among the three delivery routes, mastoid administration produced the highest Dex concentration in the perilymph. Compared to the control, PLGA-NPs-Dex provided significantly enhanced protection against lipopolysaccharide- and noise-induced hearing damage following mastoid administration. Mastoid delivery provides an accessible route for drug delivery to the inner ear and nanoparticle-based systems via this route represent a viable strategy for treating inner ear diseases. This approach caused less damage to the inner ear, making it a promising option for clinical use in treating hearing loss.
{"title":"Mastoid approach for local drug delivery to the inner ear for treating hearing loss","authors":"Yanjiao Ding , Zhiqiang Hou , Mingming Wang , Lei Xu , Haibo Wang","doi":"10.1016/j.jconrel.2024.10.040","DOIUrl":"10.1016/j.jconrel.2024.10.040","url":null,"abstract":"<div><div>Hearing loss is a prevalent disability worldwide. Dexamethasone (Dex) is commonly used to treat hearing loss, administered either systemically or locally. However, targeted delivery of Dex to the inner ear remains challenging, which limits its therapeutic efficacy. This study aimed to develop new methods to improve Dex delivery to the inner ear and enhance its treatment effect. Mastoid, intraperitoneal, and intratympanic delivery routes for Dex were investigated in guinea pig cochlea. Liquid chromatography-mass spectrometry and immunohistochemistry were employed to compare the distribution of Dex in the perilymph and tissue uptake. Poly (lactic-<em>co</em>-glycolic acid) nanoparticles loaded with Dex (PLGA-NPs-Dex) were prepared, and their transport mechanism across the round window membrane (RWM) was explored. Among the three delivery routes, mastoid administration produced the highest Dex concentration in the perilymph. Compared to the control, PLGA-NPs-Dex provided significantly enhanced protection against lipopolysaccharide- and noise-induced hearing damage following mastoid administration. Mastoid delivery provides an accessible route for drug delivery to the inner ear and nanoparticle-based systems via this route represent a viable strategy for treating inner ear diseases. This approach caused less damage to the inner ear, making it a promising option for clinical use in treating hearing loss.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 488-501"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487564","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 : 2024-10-23DOI: 10.1016/j.jconrel.2024.10.007
Richa Vartak, Ketan Patel
With 60 % of non-small cell lung cancer (NSCLC) expressing epidermal growth factor receptor (EGFR), it has been explored as an important therapeutic target for lung tumors. However, even the well-established EGFR inhibitors tend to promptly develop resistance over time. Moreover, strategies that could impede resistance development and be advantageous for both EGFR-Tyrosine kinase inhibitor (TKI)-sensitive and mutant NSCLC patients are constrained. Based on the critical relationship between EGFR, c-MYC, and Kirsten rat sarcoma virus (K-Ras), simultaneous degradation of EGFR and Bromodomain-containing protein 4 (BRD4) using “Proteolysis Targeting Chimeras (PROTACs)” could be a promising approach. PROTACs are emerging class of oncoprotein degraders but very challanging to deliver in vivo. Compared to individual IC50s, strong synergism was observed at 1:1 ratio of BPRO and EPRO in NSCLC cell lines with diverse mutation. Significant inhibition of cell growth with higher cellular apoptosis was observed in 2D and 3D-based cell assays in nanomolar concentrations. EGFR activation assay revealed 47.60 % EGFR non-expressing cells confirming EGFR-degrading potential of EPRO. A lung cancer specific nanoliposomal formulation of EGFR and BRD4-degrading PROTACs (EPRO and BPRO) was prepared and characetrized. Successful encapsulation of the two highly lipophilic molecules was achieved in EGFR-targeting nanoliposomal carriers (T-BEPRO) using a modified hydration technique. T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.
{"title":"Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice","authors":"Richa Vartak, Ketan Patel","doi":"10.1016/j.jconrel.2024.10.007","DOIUrl":"10.1016/j.jconrel.2024.10.007","url":null,"abstract":"<div><div>With 60 % of non-small cell lung cancer (NSCLC) expressing epidermal growth factor receptor (EGFR), it has been explored as an important therapeutic target for lung tumors. However, even the well-established EGFR inhibitors tend to promptly develop resistance over time. Moreover, strategies that could impede resistance development and be advantageous for both EGFR-Tyrosine kinase inhibitor (TKI)-sensitive and mutant NSCLC patients are constrained. Based on the critical relationship between EGFR, c-MYC, and Kirsten rat sarcoma virus (K-Ras), simultaneous degradation of EGFR and Bromodomain-containing protein 4 (BRD4) using “Proteolysis Targeting Chimeras (PROTACs)” could be a promising approach. PROTACs are emerging class of oncoprotein degraders but very challanging to deliver in vivo. Compared to individual IC50s, strong synergism was observed at 1:1 ratio of BPRO and EPRO in NSCLC cell lines with diverse mutation. Significant inhibition of cell growth with higher cellular apoptosis was observed in 2D and 3D-based cell assays in nanomolar concentrations. EGFR activation assay revealed 47.60 % EGFR non-expressing cells confirming EGFR-degrading potential of EPRO. A lung cancer specific nanoliposomal formulation of EGFR and BRD4-degrading PROTACs (EPRO and BPRO) was prepared and characetrized. Successful encapsulation of the two highly lipophilic molecules was achieved in EGFR-targeting nanoliposomal carriers (T-BEPRO) using a modified hydration technique. T-BEPRO revealed a particle size of 109.22 ± 0.266 nm with enhanced cellular uptake and activity. Remarkably, parenterally delivered T-BEPRO in tumor-bearing mice showed a substantially higher % tumor growth inhibition (TGI) of 77.6 % with long-lasting tumor inhibitory potential as opposed to individual drugs.</div></div>","PeriodicalId":15450,"journal":{"name":"Journal of Controlled Release","volume":"376 ","pages":"Pages 502-517"},"PeriodicalIF":10.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443725","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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