Local delivery of doxorubicin prodrug via lipid nanocapsule-based hydrogel for the treatment of glioblastoma.

IF 5.7 3区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Drug Delivery and Translational Research Pub Date : 2024-12-01 Epub Date: 2023-10-27 DOI:10.1007/s13346-023-01456-y
Mingchao Wang, Raphaël Bergès, Alessio Malfanti, Véronique Préat, Chiara Bastiancich
{"title":"Local delivery of doxorubicin prodrug via lipid nanocapsule-based hydrogel for the treatment of glioblastoma.","authors":"Mingchao Wang, Raphaël Bergès, Alessio Malfanti, Véronique Préat, Chiara Bastiancich","doi":"10.1007/s13346-023-01456-y","DOIUrl":null,"url":null,"abstract":"<p><p>Glioblastoma (GBM) recurrences appear in most cases around the resection cavity borders and arise from residual GBM cells that cannot be removed by surgery. Here, we propose a novel treatment that combines the advantages of nanomedicine and local drug delivery to target these infiltrating GBM cells. We developed an injectable lipid nanocapsule (LNC)-based formulation loaded with lauroyl-doxorubicin prodrug (DOXC<sub>12</sub>). Firstly, we demonstrated the efficacy of intratumoral administration of DOXC<sub>12</sub> in GL261 GBM-bearing mice, which extended mouse survival. Then, we formulated an injectable hydrogel by mixing the appropriate amount of prodrug with the lipophilic components of LNC. We optimized the hydrogel by incorporating cytidine-C<sub>16</sub> (CytC<sub>16</sub>) to achieve a mechanical stiffness adapted for an application in the brain post-surgery (DOXC<sub>12</sub>-LNC<sup>CL</sup>). DOXC<sub>12</sub>-LNC<sup>CL</sup> exhibited high DOXC<sub>12</sub> encapsulation efficiency (95%) and a size of approximately 60 nm with sustained drug release for over 1 month in vitro. DOXC<sub>12</sub>-LNC<sup>CL</sup> exhibited enhanced cytotoxicity compared to free DOXC<sub>12</sub> (IC<sub>50</sub> of 349 and 86 nM, respectively) on GL261 GBM cells and prevented the growth of GL261 spheroids cultured on organotypic brain slices. In vivo, post-surgical treatment with DOXC<sub>12</sub>-LNC<sup>CL</sup> significantly improved the survival of GL261-bearing mice. The combination of this local treatment with the systemic administration of anti-inflammatory drug ibuprofen further delayed the onset of recurrences. In conclusion, our study presents a promising therapeutic approach for the treatment of GBM. By targeting residual GBM cells and reducing the inflammation post-surgery, we present a new strategy to delay the onset of recurrences in the gap period between surgery and standard of care therapy.</p>","PeriodicalId":11357,"journal":{"name":"Drug Delivery and Translational Research","volume":" ","pages":"3322-3338"},"PeriodicalIF":5.7000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11499358/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Delivery and Translational Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s13346-023-01456-y","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/27 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Glioblastoma (GBM) recurrences appear in most cases around the resection cavity borders and arise from residual GBM cells that cannot be removed by surgery. Here, we propose a novel treatment that combines the advantages of nanomedicine and local drug delivery to target these infiltrating GBM cells. We developed an injectable lipid nanocapsule (LNC)-based formulation loaded with lauroyl-doxorubicin prodrug (DOXC12). Firstly, we demonstrated the efficacy of intratumoral administration of DOXC12 in GL261 GBM-bearing mice, which extended mouse survival. Then, we formulated an injectable hydrogel by mixing the appropriate amount of prodrug with the lipophilic components of LNC. We optimized the hydrogel by incorporating cytidine-C16 (CytC16) to achieve a mechanical stiffness adapted for an application in the brain post-surgery (DOXC12-LNCCL). DOXC12-LNCCL exhibited high DOXC12 encapsulation efficiency (95%) and a size of approximately 60 nm with sustained drug release for over 1 month in vitro. DOXC12-LNCCL exhibited enhanced cytotoxicity compared to free DOXC12 (IC50 of 349 and 86 nM, respectively) on GL261 GBM cells and prevented the growth of GL261 spheroids cultured on organotypic brain slices. In vivo, post-surgical treatment with DOXC12-LNCCL significantly improved the survival of GL261-bearing mice. The combination of this local treatment with the systemic administration of anti-inflammatory drug ibuprofen further delayed the onset of recurrences. In conclusion, our study presents a promising therapeutic approach for the treatment of GBM. By targeting residual GBM cells and reducing the inflammation post-surgery, we present a new strategy to delay the onset of recurrences in the gap period between surgery and standard of care therapy.

Abstract Image

通过基于脂质纳米胶囊的水凝胶局部递送阿霉素前药用于治疗胶质母细胞瘤。
胶质母细胞瘤(GBM)复发大多出现在切除腔边界附近,由无法通过手术切除的残留GBM细胞引起。在这里,我们提出了一种新的治疗方法,该方法结合了纳米药物和局部药物递送的优势,以靶向这些浸润性GBM细胞。我们开发了一种基于注射脂质纳米胶囊(LNC)的制剂,该制剂负载月桂酰阿霉素前药(DOXC12)。首先,我们证明了DOXC12在携带GL261 GBM的小鼠中肿瘤内给药的疗效,这延长了小鼠的生存期。然后,我们通过将适量的前药与LNC的亲脂性成分混合来配制可注射水凝胶。我们通过掺入胞苷-C16(CytC16)来优化水凝胶,以实现适用于手术后大脑应用的机械刚度(DOXC12-LNCCL)。DOXC12-LNCCL表现出高的DOXC12包封效率(95%)和约60nm的尺寸,在体外持续药物释放超过1个月。与游离DOXC12(IC50分别为349和86nM)相比,DOXC12-LNCCL对GL261 GBM细胞表现出增强的细胞毒性,并阻止了在器官型脑切片上培养的GL261球体的生长。在体内,DOXC12-LNCCL的手术后治疗显著提高了携带GL261的小鼠的存活率。这种局部治疗与抗炎药布洛芬的全身给药相结合,进一步延缓了复发的发生。总之,我们的研究为GBM的治疗提供了一种有前景的治疗方法。通过靶向残留的GBM细胞并减少术后炎症,我们提出了一种新的策略,以在手术和标准护理治疗之间的间隙期延迟复发的发生。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Drug Delivery and Translational Research
Drug Delivery and Translational Research MEDICINE, RESEARCH & EXPERIMENTALPHARMACOL-PHARMACOLOGY & PHARMACY
CiteScore
11.70
自引率
1.90%
发文量
160
期刊介绍: The journal provides a unique forum for scientific publication of high-quality research that is exclusively focused on translational aspects of drug delivery. Rationally developed, effective delivery systems can potentially affect clinical outcome in different disease conditions. Research focused on the following areas of translational drug delivery research will be considered for publication in the journal. Designing and developing novel drug delivery systems, with a focus on their application to disease conditions; Preclinical and clinical data related to drug delivery systems; Drug distribution, pharmacokinetics, clearance, with drug delivery systems as compared to traditional dosing to demonstrate beneficial outcomes Short-term and long-term biocompatibility of drug delivery systems, host response; Biomaterials with growth factors for stem-cell differentiation in regenerative medicine and tissue engineering; Image-guided drug therapy, Nanomedicine; Devices for drug delivery and drug/device combination products. In addition to original full-length papers, communications, and reviews, the journal includes editorials, reports of future meetings, research highlights, and announcements pertaining to the activities of the Controlled Release Society.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信