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Biodegradable PEG-poly(ω-pentadecalactone-co-p-dioxanone) nanoparticles for enhanced and sustained drug delivery to treat brain tumors.
Biomaterials ( IF 12.8 ) Pub Date : 2018-06-18 , DOI: 10.1016/j.biomaterials.2018.06.024
Evan M Chen 1 , Amanda R Quijano 1 , Young-Eun Seo 1 , Christopher Jackson 2 , Alexander D Josowitz 1 , Seth Noorbakhsh 2 , Andrea Merlettini 3 , Ranjini K Sundaram 2 , Maria Letizia Focarete 3 , Zhaozhong Jiang 4 , Ranjit S Bindra 2 , W Mark Saltzman 1
Affiliation  

Intracranial delivery of therapeutic agents is limited by penetration beyond the blood-brain barrier (BBB) and rapid metabolism of the drugs that are delivered. Convection-enhanced delivery (CED) of drug-loaded nanoparticles (NPs) provides for local administration, control of distribution, and sustained drug release. While some investigators have shown that repeated CED procedures are possible, longer periods of sustained release could eliminate the need for repeated infusions, which would enhance safety and translatability of the approach. Here, we demonstrate that nanoparticles formed from poly(ethylene glycol)-poly(ω-pentadecalactone-co-p-dioxanone) block copolymers [PEG-poly(PDL-co-DO)] are highly efficient nanocarriers that provide long-term release: small nanoparticles (less than 100 nm in diameter) continuously released a radiosensitizer (VE822) over a period of several weeks in vitro, provided widespread intracranial drug distribution during CED, and yielded significant drug retention within the brain for over 1 week. One advantage of PEG-poly(PDL-co-DO) nanoparticles is that hydrophobicity can be tuned by adjusting the ratio of hydrophobic PDL to hydrophilic DO monomers, thus making it possible to achieve a wide range of drug release rates and drug distribution profiles. When administered by CED to rats with intracranial RG2 tumors, and combined with a 5-day course of fractionated radiation therapy, VE822-loaded PEG-poly(PDL-co-DO) NPs significantly prolonged survival when compared to free VE822. Thus, PEG-poly(PDL-co-DO) NPs represent a new type of versatile nanocarrier system with potential for sustained intracranial delivery of therapeutic agents to treat brain tumors.

中文翻译:


可生物降解的 PEG-聚(ω-十五内酯-共-对二氧环己酮)纳米颗粒,用于增强和持续药物输送以治疗脑肿瘤。



治疗剂的颅内递送受到血脑屏障(BBB)之外的渗透和所递送药物的快速代谢的限制。载药纳米颗粒 (NP) 的对流增强递送 (CED) 可实现局部给药、分布控制和持续药物释放。虽然一些研究人员表明重复的 CED 程序是可能的,但更长的持续释放时间可以消除重复输注的需要,这将提高该方法的安全性和可转化性。在这里,我们证明由聚(乙二醇)-聚(ω-十五内酯-共-对二氧环己酮)嵌段共聚物[PEG-聚(PDL-共-DO)]形成的纳米颗粒是提供长期释放的高效纳米载体:小纳米粒子(直径小于 100 nm)在体外几周内持续释放放射增敏剂 (VE822),在 CED 期间提供广泛的颅内药物分布,并在大脑内产生显着的药物保留超过 1 周。 PEG-聚(PDL-co-DO)纳米颗粒的优点之一是可以通过调节疏水性PDL与亲水性DO单体的比例来调节疏水性,从而可以实现广泛的药物释放速率和药物分布曲线。当通过 CED 给予患有颅内 RG2 肿瘤的大鼠并结合 5 天疗程的分段放射治疗时,与游离 VE822 相比,负载 VE822 的 PEG-聚(PDL-co-DO) NP 显着延长了生存期。因此,PEG-聚(PDL-co-DO) NPs代表了一种新型的多功能纳米载体系统,具有持续颅内递送治疗剂以治疗脑肿瘤的潜力。
更新日期:2018-06-19
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