Giofrè Sabrina, Renda Antonio, Sesana Silvia, Formicola Beatrice, Vergani Barbara, Leone Biagio Eugenio, Denti Vanna, Paglia Giuseppe, Groppuso Serena, Romeo Valentina, Muzio Luca, Balboni Andrea, Menegon Andrea, Antoniou Antonia, Amenta Arianna, Passarella Daniele, Seneci Pierfausto, Pellegrino Sara, Re Francesca
Dipartimento di Chimica, Università degli Studi di Milano, 20133 Milan, Italy.
School of Medicine and Surgery, University of Milano-Bicocca, 20854 Vedano al Lambro, Italy.
Pharmaceutics. 2022 Nov 7;14(11):2402. doi: 10.3390/pharmaceutics14112402.
Dual functionalized liposomes were developed to cross the blood−brain barrier (BBB) and to release their cargo in a pathological matrix metalloproteinase (MMP)-rich microenvironment. Liposomes were surface-functionalized with a modified peptide deriving from the receptor-binding domain of apolipoprotein E (mApoE), known to promote cargo delivery to the brain across the BBB in vitro and in vivo; and with an MMP-sensitive moiety for an MMP-triggered drug release. Different MMP-sensitive peptides were functionalized at both ends with hydrophobic stearate tails to yield MMP-sensitive lipopeptides (MSLPs), which were assembled into mApoE liposomes. The resulting bi-functional liposomes (i) displayed a < 180 nm diameter with a negative ζ-potential; (ii) were able to cross an in vitro BBB model with an endothelial permeability of 3 ± 1 × 10−5 cm/min; (iii) when exposed to functional MMP2 or 9, efficiently released an encapsulated fluorescein dye; (iv) showed high biocompatibility when tested in neuronal cultures; and (v) when loaded with glibenclamide, a drug candidate with poor aqueous solubility, reduced the release of proinflammatory cytokines from activated microglial cells.
开发了双功能化脂质体，以跨越血脑屏障（BBB），并在富含病理基质金属蛋白酶（MMP）的微环境中释放其所载药物。脂质体用源自载脂蛋白E受体结合域的修饰肽（mApoE）进行表面功能化，已知该肽在体外和体内均能促进药物通过血脑屏障输送至大脑；还用MMP敏感部分实现MMP触发的药物释放。不同的MMP敏感肽在两端用疏水性硬脂酸酯尾巴进行功能化，以产生MMP敏感脂肽（MSLP），将其组装到mApoE脂质体中。所得的双功能脂质体（i）直径<180 nm，ζ电位为负；（ii）能够穿过体外血脑屏障模型，内皮通透性为3±1×10−5 cm/min；（iii）当暴露于功能性MMP2或MMP9时，能有效释放包封的荧光素染料；（iv）在神经元培养物中测试时显示出高生物相容性；（v）当装载格列本脲（一种水溶性差的候选药物）时，可减少活化小胶质细胞中促炎细胞因子 的释放。
