Pub Date : 2024-09-07DOI: 10.3390/pharmaceutics16091187
Noèlia Loza-Rodríguez, Aina Millán-Sánchez, Mireia Mallandrich, Ana Cristina Calpena, Olga López
This study explores the incorporation of 10% 3-O-ethyl L-ascorbic acid (ETVC), a derivative of vitamin C, into two lipid gel systems: a hydrogel (HG) consisting exclusively of lipids and water and a bigel (BG) combining the hydrogel with an oleogel made from olive oil and beeswax. We investigated the ETVC release profiles from both materials using synthetic membranes and measured their permeation through porcine skin in vitro. Additionally, the interaction of these lipid gel systems with the stratum corneum (SC) was determined. Results from the release study indicate that the BG exhibited slower ETVC release compared to the HG. The permeation experiments showed that the presence of lipids in the formulations enhanced ETVC retention in the skin. The HG delivered a higher amount to the SC, while the BG achieved greater retention in the epidermis. This difference is attributed to the different lipophilic nature of each material. The structural analysis of SC lipids revealed that the organization of surface lipids remained unaltered by the application of the gels. Finally, an in vitro efficacy test in porcine skin using methylene blue indicated that our ETVC gels exhibited antioxidant activity. These findings provide valuable insights into the potential of lipid-based gels for topical applications.
{"title":"Lipid-Based Gels for Delivery of 3-O-Ethyl L-Ascorbic acid in Topical Applications","authors":"Noèlia Loza-Rodríguez, Aina Millán-Sánchez, Mireia Mallandrich, Ana Cristina Calpena, Olga López","doi":"10.3390/pharmaceutics16091187","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091187","url":null,"abstract":"This study explores the incorporation of 10% 3-O-ethyl L-ascorbic acid (ETVC), a derivative of vitamin C, into two lipid gel systems: a hydrogel (HG) consisting exclusively of lipids and water and a bigel (BG) combining the hydrogel with an oleogel made from olive oil and beeswax. We investigated the ETVC release profiles from both materials using synthetic membranes and measured their permeation through porcine skin in vitro. Additionally, the interaction of these lipid gel systems with the stratum corneum (SC) was determined. Results from the release study indicate that the BG exhibited slower ETVC release compared to the HG. The permeation experiments showed that the presence of lipids in the formulations enhanced ETVC retention in the skin. The HG delivered a higher amount to the SC, while the BG achieved greater retention in the epidermis. This difference is attributed to the different lipophilic nature of each material. The structural analysis of SC lipids revealed that the organization of surface lipids remained unaltered by the application of the gels. Finally, an in vitro efficacy test in porcine skin using methylene blue indicated that our ETVC gels exhibited antioxidant activity. These findings provide valuable insights into the potential of lipid-based gels for topical applications.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.3390/pharmaceutics16091186
Klervi Golhen, Michael Buettcher, Jörg Huwyler, John van den Anker, Verena Gotta, Kim Dao, Laura E. Rothuizen, Kevin Kobylinski, Marc Pfister
The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h−1 (CV 19%) for CHILD-IVITAB vs. 1.56 h−1 (CV 43%) for STROMECTOL®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.
{"title":"Pharmacometrics to Evaluate Dosing of the Patient-Friendly Ivermectin CHILD-IVITAB in Children ≥ 15 kg and <15 kg","authors":"Klervi Golhen, Michael Buettcher, Jörg Huwyler, John van den Anker, Verena Gotta, Kim Dao, Laura E. Rothuizen, Kevin Kobylinski, Marc Pfister","doi":"10.3390/pharmaceutics16091186","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091186","url":null,"abstract":"The antiparasitic drug ivermectin is approved for persons > 15 kg in the US and EU. A pharmacometric (PMX) population model with clinical PK data was developed (i) to characterize the effect of the patient-friendly ivermectin formulation CHILD-IVITAB on the absorption process and (ii) to evaluate dosing for studies in children < 15 kg. Simulations were performed to identify dosing with CHILD-IVITAB associated with similar exposure coverage in children ≥ 15 kg and < 15 kg as observed in adults receiving the reference formulation STROMECTOL®. A total of 448 ivermectin concentrations were available from 16 healthy adults. The absorption rate constant was 2.41 h−1 (CV 19%) for CHILD-IVITAB vs. 1.56 h−1 (CV 43%) for STROMECTOL®. Simulations indicated that 250 µg/kg of CHILD-IVITAB is associated with exposure coverage in children < 15 kg consistent with that observed in children ≥ 15 kg and adults receiving 200 µg/kg of STROMECTOL®. Performed analysis confirmed that CHILD-IVITAB is associated with faster and more controlled absorption than STROMECTOL®. Simulations indicate that 250 µg/kg of CHILD-IVITAB achieves equivalent ivermectin exposure coverage in children < 15 kg as seen in children ≥ 15 kg and adults.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.3390/pharmaceutics16091181
Ryunosuke Hoshi, Kristyna A. Gorospe, Hagar I. Labouta, Taha Azad, Warren L. Lee, Kelsie L. Thu
The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.
程序性死亡-1/程序性死亡配体 1（PD-1/PD-L1）免疫检查点是一种抑制途径，因其调节分化群 8（CD8）+ T 细胞介导的免疫反应而最为人熟知。PD-L1 与 CD8+ T 细胞上表达的 PD-1 相互接触，激活下游信号通路，最终导致 T 细胞衰竭和/或凋亡。从生理学角度讲，这些免疫抑制效应的存在是为了防止自身免疫，但癌细胞却利用这一途径，通过过量表达 PD-L1 来促进免疫逃逸。静脉注射的免疫检查点抑制剂（ICIs）可阻断 PD-1/PD-L1 之间的相互作用，在逆转 T 细胞衰竭和促进各种恶性肿瘤的消退方面取得了巨大成功。然而，这些 ICIs 会因肿瘤外毒性而导致免疫相关不良事件（irAEs），从而限制了其治疗潜力。因此，人们一直在努力探索其他递送策略，以增强 PD-1/PD-L1 ICIs 的肿瘤定向递送并减少 irAEs。在此，我们将简要介绍 PD-1/PD-L1 靶向癌症免疫疗法及相关的 irAEs。然后，我们详细回顾了替代给药方法，包括局部区域（LDD）给药、溶瘤病毒（OV）给药、纳米颗粒（NP）给药以及超声和微泡（USMB）给药，这些方法目前正在研究如何增强肿瘤特异性给药以最大限度地减少肿瘤外毒性效应。最后，我们将对与这些给药方法相关的主要挑战以及缓解这些挑战的潜在策略进行评述。
{"title":"Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer","authors":"Ryunosuke Hoshi, Kristyna A. Gorospe, Hagar I. Labouta, Taha Azad, Warren L. Lee, Kelsie L. Thu","doi":"10.3390/pharmaceutics16091181","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091181","url":null,"abstract":"The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8)+ T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8+ T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape. Intravenously (IV) administered immune checkpoint inhibitors (ICIs) that block the interaction between PD-1/PD-L1 have achieved great success in reversing T cell exhaustion and promoting tumor regression in various malignancies. However, these ICIs can cause immune-related adverse events (irAEs) due to off-tumor toxicities which limits their therapeutic potential. Therefore, considerable effort has been channeled into exploring alternative delivery strategies that enhance tumor-directed delivery of PD-1/PD-L1 ICIs and reduce irAEs. Here, we briefly describe PD-1/PD-L1-targeted cancer immunotherapy and associated irAEs. We then provide a detailed review of alternative delivery approaches, including locoregional (LDD)-, oncolytic virus (OV)-, nanoparticle (NP)-, and ultrasound and microbubble (USMB)-mediated delivery that are currently under investigation for enhancing tumor-specific delivery to minimize toxic off-tumor effects. We conclude with a commentary on key challenges associated with these delivery methods and potential strategies to mitigate them.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.3390/pharmaceutics16091184
Hong Lu, Zheng Cai, Ping Hu
In the realm of modern therapeutics, the development of polymeric delivery vehicles has revolutionized drug administration, offering a sophisticated approach to controlled and sustained drug release [...]
{"title":"Recent Advances in Polymeric Delivery Vehicles for Controlled and Sustained Drug Release","authors":"Hong Lu, Zheng Cai, Ping Hu","doi":"10.3390/pharmaceutics16091184","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091184","url":null,"abstract":"In the realm of modern therapeutics, the development of polymeric delivery vehicles has revolutionized drug administration, offering a sophisticated approach to controlled and sustained drug release [...]","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3390/pharmaceutics16091176
Nilima Rajpal Kundnani, Mihaela Codrina Levai, Mihaela-Diana Popa, Claudia Borza, Mihai Iacob, Alexandra Laura Mederle, Alexandru Blidisel
Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Discussion: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Conclusions: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients’ quality of life.
导言系统性红斑狼疮（SLE）是一种多发性自身免疫性疾病，其特点是存在大量自身抗体，尤其是针对核抗原的自身抗体。系统性红斑狼疮的发病机制涉及遗传、环境和激素因素。病程包括发作和缓解，涉及多个器官。最近的治疗进展（包括生物制剂）改善了治疗和预后，但新型疗法的长期影响仍有待确定。系统性红斑狼疮的生物制剂利妥昔单抗（Rituximab）是最早的以B细胞为导向的生物制剂，它能结合CD20并消耗CD20+B细胞，从而使一些系统性红斑狼疮患者的病情得到缓解。贝利木单抗是一种B细胞活化因子（BAFF）抑制剂，最近新增了狼疮肾炎的适应症。CALIBRATE和BLISS-BELIEVE研究调查了这些药物与传统疗法的组合，结果显示了不同的疗效。Ocrelizumab和obinutuzumab是以CD20为导向的新型系统性红斑狼疮疗法，它们与ofatumumab和veltuzumab一起使用也很有前景。最新的试验强调了它们的疗效和安全性。针对I型干扰素受体的阿尼单抗已在TULIP 1/2试验中进行了评估。正在进行的 TULIP LTE 试验证明了安非鲁单抗的长期安全性和有效性。此外，IRIS III 期试验正在探索用阿尼夫单抗治疗狼疮肾炎，结果显示肾脏反应良好。Tocilizumab和secukinumab正在接受系统性红斑狼疮的评估，结果喜忧参半。一些针对C5补体蛋白的生物制剂，以及免疫调节剂和免疫治疗药物也在研究中，它们对系统性红斑狼疮有潜在的益处。讨论：治疗系统性红斑狼疮的生物制剂以特定的免疫成分为靶点，旨在改善疾病控制并减少传统疗法的副作用。然而，由于纳入标准和试验设计等因素，试验结果各不相同。结论：生物技术的进步使系统性红斑狼疮的靶向生物疗法成为可能，从而减少疾病活动并改善患者的生活质量。
{"title":"Biologics in Systemic Lupus Erythematosus: Recent Evolutions and Benefits","authors":"Nilima Rajpal Kundnani, Mihaela Codrina Levai, Mihaela-Diana Popa, Claudia Borza, Mihai Iacob, Alexandra Laura Mederle, Alexandru Blidisel","doi":"10.3390/pharmaceutics16091176","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091176","url":null,"abstract":"Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Discussion: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Conclusions: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients’ quality of life.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216010","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Using an endogenous carrier is the best method to address the biocompatibility of carriers in the drug delivery field. Herein, we prepared a glutathione-responsive paclitaxel prodrug micelle based on an endogenous molecule of L-glutathione oxidized (GSSG) for cancer therapy using one-pot synthesis. The carboxyl groups in L-glutathione oxidized were reacted with the hydroxyl group in paclitaxel (PTX) using the catalysts dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Then, the amino-polyethylene glycol monomethyl ether (mPEG-NH2) was conjugated with GSSG to prepare PTX-GSSG-PEG. The structure of PTX-GSSG-PEG was characterized using infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). The drug release kinetics of PTX within PTX-GSSG-PEG were quantified using ultraviolet spectroscopy (UV-Vis). The size of the PTX-GSSG-PEG micelles was 83 nm, as evaluated using dynamic light scattering (DLS), and their particle size remained stable in a pH 7.4 PBS for 7 days. Moreover, the micelles could responsively degrade and release PTX in a reduced glutathione environment. The drug loading of PTX in PTX-GSSG-PEG was 13%, as determined using NMR. Furthermore, the cumulative drug release rate of PTX from the micelles reached 72.1% in a reduced glutathione environment of 5 mg/mL at 120 h. Cell viability experiments demonstrated that the PTX-GSSG-PEG micelles could induce the apoptosis of MCF-7 cells. Additionally, cell uptake showed that the micelles could distribute to the cell nuclei within 7 h. To sum up, with this glutathione-responsive paclitaxel prodrug micelle based on the endogenous molecule GSSG, it may be possible to develop novel nanomedicines in the future.
{"title":"Preparation of Glutathione-Responsive Paclitaxel Prodrug Based on Endogenous Molecule of L-Glutathione Oxidized for Cancer Therapy","authors":"Xiao Duan, Qiang Wang, Yue Wang, Xinping Liu, Manman Lu, Zhifang Li, Xuelian Jiang, Jingquan Ji","doi":"10.3390/pharmaceutics16091178","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091178","url":null,"abstract":"Using an endogenous carrier is the best method to address the biocompatibility of carriers in the drug delivery field. Herein, we prepared a glutathione-responsive paclitaxel prodrug micelle based on an endogenous molecule of L-glutathione oxidized (GSSG) for cancer therapy using one-pot synthesis. The carboxyl groups in L-glutathione oxidized were reacted with the hydroxyl group in paclitaxel (PTX) using the catalysts dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP). Then, the amino-polyethylene glycol monomethyl ether (mPEG-NH2) was conjugated with GSSG to prepare PTX-GSSG-PEG. The structure of PTX-GSSG-PEG was characterized using infrared spectroscopy (FT-IR), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS). The drug release kinetics of PTX within PTX-GSSG-PEG were quantified using ultraviolet spectroscopy (UV-Vis). The size of the PTX-GSSG-PEG micelles was 83 nm, as evaluated using dynamic light scattering (DLS), and their particle size remained stable in a pH 7.4 PBS for 7 days. Moreover, the micelles could responsively degrade and release PTX in a reduced glutathione environment. The drug loading of PTX in PTX-GSSG-PEG was 13%, as determined using NMR. Furthermore, the cumulative drug release rate of PTX from the micelles reached 72.1% in a reduced glutathione environment of 5 mg/mL at 120 h. Cell viability experiments demonstrated that the PTX-GSSG-PEG micelles could induce the apoptosis of MCF-7 cells. Additionally, cell uptake showed that the micelles could distribute to the cell nuclei within 7 h. To sum up, with this glutathione-responsive paclitaxel prodrug micelle based on the endogenous molecule GSSG, it may be possible to develop novel nanomedicines in the future.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3390/pharmaceutics16091177
José Athayde Vasconcelos Morais, Pedro H. A. Barros, Marcelo de Macedo Brigido, Clara Luna Marina, Anamelia Bocca, André de Lima e Silva Mariano, Paulo E. N. de Souza, Karen L. R. Paiva, Marina Mesquita Simões, Sonia Nair Bao, Luana C. Camargo, João P. Figueiró Longo, Amanda Alencar Cabral Morais, Ricardo B. de Azevedo, Marcio J. P. Fonseca, Luis A. Muehlmann
Melanoma, the most aggressive form of skin cancer, presents a major clinical challenge due to its tendency to metastasize and recalcitrance to traditional therapies. Despite advances in surgery, chemotherapy, and radiotherapy, the outlook for advanced melanoma remains bleak, reinforcing the urgent need for more effective treatments. Photodynamic therapy (PDT) has emerged as a promising alternative, leading to targeted tumor destruction with minimal harm to surrounding tissues. In this study, the direct and abscopal antitumor effects of PDT in a bilateral murine melanoma model were evaluated. Although only one of the two tumors was treated, effects were observed in both. Our findings revealed significant changes in systemic inflammation and alterations in CD4+ and CD8+ T cell populations in treated groups, as evidenced by blood analyses and flow cytometry. High-throughput RNA sequencing (RNA-Seq) further unveiled shifts in gene expression profiles in both treated and untreated tumors. This research sheds light on the novel antitumor and abscopal effects of nanoemulsion of aluminum chloride phthalocyanine (AlPcNE)-mediated PDT in melanoma, highlighting the potential of different PDT protocols to modulate immune responses and to achieve more effective and targeted cancer treatments.
{"title":"Direct and Abscopal Antitumor Responses Elicited by AlPcNE-Mediated Photodynamic Therapy in a Murine Melanoma Model","authors":"José Athayde Vasconcelos Morais, Pedro H. A. Barros, Marcelo de Macedo Brigido, Clara Luna Marina, Anamelia Bocca, André de Lima e Silva Mariano, Paulo E. N. de Souza, Karen L. R. Paiva, Marina Mesquita Simões, Sonia Nair Bao, Luana C. Camargo, João P. Figueiró Longo, Amanda Alencar Cabral Morais, Ricardo B. de Azevedo, Marcio J. P. Fonseca, Luis A. Muehlmann","doi":"10.3390/pharmaceutics16091177","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091177","url":null,"abstract":"Melanoma, the most aggressive form of skin cancer, presents a major clinical challenge due to its tendency to metastasize and recalcitrance to traditional therapies. Despite advances in surgery, chemotherapy, and radiotherapy, the outlook for advanced melanoma remains bleak, reinforcing the urgent need for more effective treatments. Photodynamic therapy (PDT) has emerged as a promising alternative, leading to targeted tumor destruction with minimal harm to surrounding tissues. In this study, the direct and abscopal antitumor effects of PDT in a bilateral murine melanoma model were evaluated. Although only one of the two tumors was treated, effects were observed in both. Our findings revealed significant changes in systemic inflammation and alterations in CD4+ and CD8+ T cell populations in treated groups, as evidenced by blood analyses and flow cytometry. High-throughput RNA sequencing (RNA-Seq) further unveiled shifts in gene expression profiles in both treated and untreated tumors. This research sheds light on the novel antitumor and abscopal effects of nanoemulsion of aluminum chloride phthalocyanine (AlPcNE)-mediated PDT in melanoma, highlighting the potential of different PDT protocols to modulate immune responses and to achieve more effective and targeted cancer treatments.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3390/pharmaceutics16091180
Laura Ben Olivo, Pricilla de Oliveira Henz, Sophia Wermann, Bruna Bernar Dias, Gabriel Osorio Porto, Amanda Valle Pinhatti, Manoela Domingues Martins, Lauro José Gregianin, Teresa Dalla Costa, Bibiana Verlindo de Araújo
Methotrexate (MTX), which presents high inter-individual variability, is part of the Brazilian Osteosarcoma Treatment Group (BOTG) protocol. This work aimed to develop a MTX population pharmacokinetic model (POPPK) for Brazilian children with osteosarcoma (OS) following the BOTG protocol to guide rescue therapy and avoid toxicity. The model was developed in NONMEM 7.4 (Icon®) using retrospective sparse data from MTX therapeutic drug monitoring of children attending a southern Brazilian public reference hospital. Data were described by a two-compartment model using 216 MTX cycles from 32 patients (5–18 y.o.) with OS who received 12 g/m2 dose/cycle. To explain inter-individual and inter-occasion variability in clearance and peripheral volume, covariates from demographic and biochemical data were evaluated. Serum creatinine was a significant covariate of MTX clearance (14.8 L/h), and the body surface area (BSA) was significant for central compartment volume (82.5 L). Inter-compartmental clearance and volume of peripheral compartment were 0.178 L/h and 5.72 L, respectively. The model adequately describes MTX exposure in Brazilian children with OS. Successful simulations were performed to predict MTX concentrations in pediatric patients above five years old with acute kidney injury and anticipate rescue therapy adjustments.
{"title":"Anticipating Leucovorin Rescue Therapy in Patients with Osteosarcoma through Methotrexate Population Pharmacokinetic Model","authors":"Laura Ben Olivo, Pricilla de Oliveira Henz, Sophia Wermann, Bruna Bernar Dias, Gabriel Osorio Porto, Amanda Valle Pinhatti, Manoela Domingues Martins, Lauro José Gregianin, Teresa Dalla Costa, Bibiana Verlindo de Araújo","doi":"10.3390/pharmaceutics16091180","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091180","url":null,"abstract":"Methotrexate (MTX), which presents high inter-individual variability, is part of the Brazilian Osteosarcoma Treatment Group (BOTG) protocol. This work aimed to develop a MTX population pharmacokinetic model (POPPK) for Brazilian children with osteosarcoma (OS) following the BOTG protocol to guide rescue therapy and avoid toxicity. The model was developed in NONMEM 7.4 (Icon®) using retrospective sparse data from MTX therapeutic drug monitoring of children attending a southern Brazilian public reference hospital. Data were described by a two-compartment model using 216 MTX cycles from 32 patients (5–18 y.o.) with OS who received 12 g/m2 dose/cycle. To explain inter-individual and inter-occasion variability in clearance and peripheral volume, covariates from demographic and biochemical data were evaluated. Serum creatinine was a significant covariate of MTX clearance (14.8 L/h), and the body surface area (BSA) was significant for central compartment volume (82.5 L). Inter-compartmental clearance and volume of peripheral compartment were 0.178 L/h and 5.72 L, respectively. The model adequately describes MTX exposure in Brazilian children with OS. Successful simulations were performed to predict MTX concentrations in pediatric patients above five years old with acute kidney injury and anticipate rescue therapy adjustments.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3390/pharmaceutics16091179
Angel Pulido-Capiz, Brenda Chimal-Vega, Luis Pablo Avila-Barrientos, Alondra Campos-Valenzuela, Raúl Díaz-Molina, Raquel Muñiz-Salazar, Octavio Galindo-Hernández, Victor García-González
Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7Var E; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7Var E. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7Var E cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy.
约80%的乳腺癌（BC）病例雌激素受体阳性（ER+），对激素治疗敏感；他莫昔芬是一种原药，其主要浆液活性代谢产物是4-羟基他莫昔芬（4-OH Tam）和内昔芬。尽管他莫昔芬治疗有效，但也会产生抗药性。真核起始因子-4A复合物（eIF4A）活性的增加会导致肿瘤细胞对他莫昔芬产生抗药性。在这项工作中，我们开发了一种对 4-OH Tam 和内昔芬具有抗性的细胞变体，称为 MCF-7Var E；然后，这项研究的目的是通过加入天然化合物 auraptene 来逆转这种变体对他莫昔芬代谢物的获得性抗性。他莫昔芬衍生物和痩素的联合治疗成功地使具有化疗耐药性的 MCF-7Var E 变得敏感。将 4-OH Tam 和内昔芬与呋喃妥因联合处理，发现了一种新的化疗抗性破坏焦点。使用auraptene分子和他莫昔芬衍生代谢物可以产生协同作用，诱导MCF-7Var E细胞和ERα亲本细胞产生敏感性，而在三阴性乳腺癌细胞（TNBC）中却观察不到这种作用。我们的研究结果表明，在耐药的ER+乳腺癌模型中，痩素和他莫昔芬代谢物具有协同作用，这可能是实现药理策略的第一步。
{"title":"Auraptene Boosts the Efficacy of the Tamoxifen Metabolites Endoxifen and 4-OH-Tamoxifen in a Chemoresistant ER+ Breast Cancer Model","authors":"Angel Pulido-Capiz, Brenda Chimal-Vega, Luis Pablo Avila-Barrientos, Alondra Campos-Valenzuela, Raúl Díaz-Molina, Raquel Muñiz-Salazar, Octavio Galindo-Hernández, Victor García-González","doi":"10.3390/pharmaceutics16091179","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091179","url":null,"abstract":"Approximately 80% of breast cancer (BC) cases are estrogen receptor positive (ER+) and sensitive to hormone treatment; Tamoxifen is a prodrug, and its main plasmatic active metabolites are 4-hydroxytamoxifen (4-OH Tam) and endoxifen. Despite the effectiveness of tamoxifen therapy, resistance can be developed. An increment in eukaryotic initiation factor-4A complex (eIF4A) activity can result in tamoxifen-resistant tumor cells. For this work, we developed a cell variant resistant to 4-OH Tam and endoxifen, denominated MCF-7Var E; then, the aim of this research was to reverse the acquired resistance of this variant to tamoxifen metabolites by incorporating the natural compound auraptene. Combination treatments of tamoxifen derivatives and auraptene successfully sensitized the chemoresistant MCF-7Var E. Our data suggest a dual regulation of eIF4A and ER by auraptene. Joint treatments of 4-OH Tam and endoxifen with auraptene identified a novel focus for chemoresistance disruption. Synergy was observed using the auraptene molecule and tamoxifen-derived metabolites, which induced a sensitization in MCF-7Var E cells and ERα parental cells that was not observed in triple-negative breast cancer cells (TNBC). Our results suggest a synergistic effect between auraptene and tamoxifen metabolites in a resistant ER+ breast cancer model, which could represent the first step to achieving a pharmacologic strategy.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142216013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-06DOI: 10.3390/pharmaceutics16091175
Adina Bianca Boșca, Elena Dinte, Carmen Mihaela Mihu, Alina Elena Pârvu, Carmen Stanca Melincovici, Alina Simona Șovrea, Mariana Mărginean, Anne-Marie Constantin, Anida-Maria Băbțan, Alexandrina Muntean, Aranka Ilea
Periodontitis is a chronic inflammation caused by periodontopathogenic bacteria in the dental biofilm, and also involves the inflammatory-immune response of the host. Polymorphonuclear neutrophils (PMNs) play essential roles in bacterial clearance by multiple mechanisms, including the formation of neutrophil extracellular traps (NETs) that retain and destroy pathogens. During PD progression, the interaction between PMNs, NETs, and bacteria leads to an exaggerated immune response and a prolonged inflammatory state. As a lesion matures, PMNs accumulate in the periodontal tissues and die via NETosis, ultimately resulting in tissue injury. A better understanding of the role of NETs, the associated molecules, and the pathogenic pathways of NET formation in periodontitis, could provide markers of NETosis as reliable diagnostic and prognostic tools. Moreover, an assessment of NET biomarker levels in biofluids, particularly in saliva or gingival crevicular fluid, could be useful for monitoring periodontitis progression and treatment efficacy. Preventing excessive NET accumulation in periodontal tissues, by both controlling NETs’ formation and their appropriate removal, could be a key for further development of more efficient therapeutic approaches. In periodontal therapy, local drug delivery (LDD) systems are more targeted, enhancing the bioavailability of active pharmacological agents in the periodontal pocket and surrounding tissues for prolonged time to ensure an optimal therapeutic outcome.
牙周炎是由牙齿生物膜中的牙周致病菌引起的慢性炎症，也涉及宿主的炎症免疫反应。多形核中性粒细胞（PMNs）通过多种机制在清除细菌的过程中发挥重要作用，包括形成中性粒细胞胞外捕获器（NETs），以保留和消灭病原体。在帕金森病的发展过程中，PMN、NET 和细菌之间的相互作用会导致免疫反应的加剧和炎症状态的延长。随着病变的成熟，PMNs 在牙周组织中积聚并通过 NETosis 死亡，最终导致组织损伤。如果能更好地了解NET的作用、相关分子以及NET在牙周炎中形成的致病途径，就能将NETosis的标记物作为可靠的诊断和预后工具。此外，评估生物流体（尤其是唾液或牙龈缝液）中的 NET 生物标志物水平有助于监测牙周炎的进展和治疗效果。通过控制 NET 的形成和适当清除，防止 NET 在牙周组织中过度积聚，是进一步开发更有效治疗方法的关键。在牙周治疗中，局部给药系统（LDD）更有针对性，可提高活性药剂在牙周袋和周围组织中长时间的生物利用度，以确保达到最佳治疗效果。
{"title":"Local Drug Delivery Systems as Novel Approach for Controlling NETosis in Periodontitis","authors":"Adina Bianca Boșca, Elena Dinte, Carmen Mihaela Mihu, Alina Elena Pârvu, Carmen Stanca Melincovici, Alina Simona Șovrea, Mariana Mărginean, Anne-Marie Constantin, Anida-Maria Băbțan, Alexandrina Muntean, Aranka Ilea","doi":"10.3390/pharmaceutics16091175","DOIUrl":"https://doi.org/10.3390/pharmaceutics16091175","url":null,"abstract":"Periodontitis is a chronic inflammation caused by periodontopathogenic bacteria in the dental biofilm, and also involves the inflammatory-immune response of the host. Polymorphonuclear neutrophils (PMNs) play essential roles in bacterial clearance by multiple mechanisms, including the formation of neutrophil extracellular traps (NETs) that retain and destroy pathogens. During PD progression, the interaction between PMNs, NETs, and bacteria leads to an exaggerated immune response and a prolonged inflammatory state. As a lesion matures, PMNs accumulate in the periodontal tissues and die via NETosis, ultimately resulting in tissue injury. A better understanding of the role of NETs, the associated molecules, and the pathogenic pathways of NET formation in periodontitis, could provide markers of NETosis as reliable diagnostic and prognostic tools. Moreover, an assessment of NET biomarker levels in biofluids, particularly in saliva or gingival crevicular fluid, could be useful for monitoring periodontitis progression and treatment efficacy. Preventing excessive NET accumulation in periodontal tissues, by both controlling NETs’ formation and their appropriate removal, could be a key for further development of more efficient therapeutic approaches. In periodontal therapy, local drug delivery (LDD) systems are more targeted, enhancing the bioavailability of active pharmacological agents in the periodontal pocket and surrounding tissues for prolonged time to ensure an optimal therapeutic outcome.","PeriodicalId":19894,"journal":{"name":"Pharmaceutics","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142215973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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