Phosphatidylcholine-derived carriers facilitate brain tumor delivery and enhance glioblastoma therapy

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release Pub Date : 2025-07-03 DOI:10.1016/j.jconrel.2025.113999

Jiang Yu , Zewei Tu , Jiali Fan , Kunjian Lei , Zhouqi Meng , Binfan Chen , Zefeng Wang , William Escobar , Jiangbing Zhou

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Abstract

Glioblastoma (GBM) is the most common primary brain cancer without effective treatment. The ineffective treatment of GBM can be partially attributed to the existence of the blood-brain barrier (BBB). Lipids, which constitute over half the weight of the brain and play a vital role in brain tumor biology, can be transported to the brain in the form of lysophosphatidylcholines (LPCs) via specific LPC transporters at the BBB. We hypothesize that LPC analogs could be used as carriers for drug delivery to tumors in the brain. To test this hypothesis, we synthesized and screened a collection of LPC analogs, among which LPC analog 3 (A3), featuring a glycerophosphorylcholine (GPC) headgroup and a 15‑carbon tail, exhibited a marked ability to penetrate brain tumors. We characterized A3 as a carrier for drug delivery to brain tumors by using Doxorubicin (Dox) as the therapeutic payload and found that the A3-Dox conjugate with a cathepsin B-cleavable linker has a great ability to accumulate in brain tumors, leading to effective treatment of GBM without inducing significant cytotoxicity. Our study suggests a novel approach to improving the treatment of GBM by enhancing the delivery of therapeutic agents to the brain using A3 as a carrier.

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磷脂酰胆碱衍生载体促进脑肿瘤的递送和增强胶质母细胞瘤的治疗

胶质母细胞瘤（GBM）是最常见的原发性脑癌，没有有效的治疗。GBM治疗无效的部分原因是血脑屏障（BBB）的存在。脂质占大脑重量的一半以上，在脑肿瘤生物学中起着至关重要的作用，它可以通过血脑屏障上特定的LPC转运体以溶血磷脂酰胆碱（LPC）的形式运输到大脑。我们假设LPC类似物可以作为脑内肿瘤药物递送的载体。为了验证这一假设，我们合成并筛选了一系列LPC类似物，其中LPC类似物3 （A3）具有甘油磷酸胆碱（GPC）头基团和15碳尾，表现出明显的穿透脑肿瘤的能力。我们以阿霉素（Doxorubicin, Dox）作为治疗有效载荷，表征了A3作为脑肿瘤药物递送的载体，并发现A3-Dox结合组织蛋白酶b可切割连接物在脑肿瘤中具有很强的蓄积能力，从而有效治疗GBM而不诱导显著的细胞毒性。我们的研究提出了一种新的方法，通过使用A3作为载体增强治疗剂向大脑的传递来改善GBM的治疗。

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来源期刊

Journal of Controlled Release 医学-化学综合

CiteScore

18.50

自引率

5.60%

发文量

700

审稿时长

39 days

期刊介绍： The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.