Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders.
Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders.
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DOI：
10.1371/journal.pone.0156452
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Tosi G
中科院分区：
文献类型：
--
作者：
Salvalaio M;Rigon L;Belletti D;D'Avanzo F;Pederzoli F;Ruozi B;Marin O;Vandelli MA;Forni F;Scarpa M;Tomanin R;Tosi G
溶酶体储存障碍(LSD)是一组代谢综合征，每一种都是由于一种溶酶体酶的缺陷引起的。许多LSD影响到大多数器官系统，总体上约75%的患者出现神经损害。酶替代疗法虽然确定了一些全身性的临床改善，但由于酶无法通过血脑屏障(BBB)，对中枢神经系统疾病无效。为了通过血脑屏障传递治疗酶，我们在LSD的两种小鼠模型-粘多糖病I和II(MPS I和MPS II)中检测了可生物降解和生物相容的PLGA纳米颗粒(NPs)。用7-氨基酸糖肽(G7)修饰PLGA-NPs，但证明能够将低分子(MW)分子带过啮齿类动物的血脑屏障。我们首次专门研究了G7-NPs转移具有高相对分子质量的模型药物(FITC-白蛋白)的能力，与LSD脑部治疗所需的酶相当。在野生型小鼠和MPS I和II基因敲除小鼠模型上进行的活体实验，还包括一整套对照注射，以获得对程序效率的广泛初步看法。结果清楚地表明，在所有注射的小鼠中，白蛋白有效地穿过了血脑屏障，这是NPs将高分子量分子运送到大脑的能力的基础。这些结果鼓励用酶负载的G7-NPs进行成功的实验，将足够数量的药物输送到LSD上的大脑区域，在那里对病理表型产生纠正作用。
Lysosomal Storage Disorders (LSDs) are a group of metabolic syndromes, each one due to the deficit of one lysosomal enzyme. Many LSDs affect most of the organ systems and overall about 75% of the patients present neurological impairment. Enzyme Replacement Therapy, although determining some systemic clinical improvements, is ineffective on the CNS disease, due to enzymes' inability to cross the blood-brain barrier (BBB). With the aim to deliver the therapeutic enzymes across the BBB, we here assayed biodegradable and biocompatible PLGA-nanoparticles (NPs) in two murine models for LSDs, Mucopolysaccharidosis type I and II (MPS I and MPS II). PLGA-NPs were modified with a 7-aminoacid glycopeptide (g7), yet demonstrated to be able to deliver low molecular weight (MW) molecules across the BBB in rodents. We specifically investigated, for the first time, the g7-NPs ability to transfer a model drug (FITC-albumin) with a high MW, comparable to the enzymes to be delivered for LSDs brain therapy. In vivo experiments, conducted on wild-type mice and knockout mouse models for MPS I and II, also included a whole series of control injections to obtain a broad preliminary view of the procedure efficiency. Results clearly showed efficient BBB crossing of albumin in all injected mice, underlying the ability of NPs to deliver high MW molecules to the brain. These results encourage successful experiments with enzyme-loaded g7-NPs to deliver sufficient amounts of the drug to the brain district on LSDs, where exerting a corrective effect on the pathological phenotype.