Systemic dendrimer-drug nanomedicines for long-term treatment of mild-moderate cerebral palsy in a rabbit model.
Systemic dendrimer-drug nanomedicines for long-term treatment of mild-moderate cerebral palsy in a rabbit model.
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全身性树枝状聚合物-药物纳米药物长期治疗兔模型中的轻中度脑瘫。
DOI：
10.1186/s12974-020-01984-1
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发表时间：
2020-10-25
影响因子：
9.3
通讯作者：
Kannan S
中科院分区：
文献类型：
--
作者：
Zhang Z;Lin YA;Kim SY;Su L;Liu J;Kannan RM;Kannan S
小胶质细胞介导的神经炎症在包括脑性瘫痪(CP)在内的围产期/新生儿脑损伤的发病机制中起核心作用。减轻神经炎症的治疗方法可能提供一种有效的策略来减缓疾病的进展和挽救正常的大脑发育。基于我们先前的结果，即第四代羟基聚酰胺胺(PAMAM)树枝状大分子可以将药物特异性地输送到体循环中激活的胶质细胞，我们评估了一种第六代(G6)羟基端基PAMAM树枝状大分子的持续疗效，该树状分子显示出更长的血液循环时间和更多的脑积聚。N-乙酰-L-半胱氨酸(NAC)是一种抗氧化剂和抗炎剂，具有较高的血浆蛋白结合力和较差的脑渗透性，被偶联到G6-PAMAM树枝状大分子-NAC(G6D-NAC)上。小胶质细胞靶向的G6D-NAC结合物在临床相关的CP兔模型中进行了疗效评估，该模型具有轻度/中度CP表型，可提供未经处理的CP试剂盒更长的生存期，从而能够评估超过15天的持续疗效。G6D-NAC被偶联，并进行了表征。对BV-2小胶质细胞进行细胞毒性和抗炎实验。在兔CP模型上评价G6D-NAC的疗效。CP试剂盒于出生后第1天(PND1)随机分为5组，分别静脉注射PBS、G6D-NAC(2或5 mg/kg)、NAC(2或5 mg/kg)。在出生后第5天(PND5)和第15天(PND15)评估神经行为测试、小胶质细胞形态和神经炎症。单剂全身“长循环”G6D-NAC可显著穿透受损的血脑屏障(BBB)，将NAC特异性地输送到激活的小胶质细胞，并显著减少皮质和小脑白质区域小胶质细胞介导的神经炎症。此外，G6D-NAC处理显著提高了新生兔的存活率，至少在出生后15天(PND15)将运动功能挽救到接近健康的对照水平，而用游离NAC处理的CP试剂盒在PND9之前死亡。在新生儿脑损伤中，靶向激活的小胶质细胞给予治疗药物可以改善损伤后的促炎性小胶质细胞反应，提高存活率，并改善可持续的神经预后。对G6D-NAC激活的小胶质细胞进行适当的操作可以显著影响损伤，而不是炎症。
Neuroinflammation mediated by microglia plays a central role in the pathogenesis of perinatal/neonatal brain injury, including cerebral palsy (CP). Therapeutics mitigating neuroinflammation potentially provide an effective strategy to slow the disease progression and rescue normal brain development. Building on our prior results which showed that a generation-4 hydroxyl poly(amidoamine) (PAMAM) dendrimer could deliver drugs specifically to activated glia from systemic circulation, we evaluated the sustained efficacy of a generation-6 (G6) hydroxyl-terminated PAMAM dendrimer that showed a longer blood circulation time and increased brain accumulation. N-acetyl-l-cysteine (NAC), an antioxidant and anti-inflammatory agent that has high plasma protein binding properties and poor brain penetration, was conjugated to G6-PAMAM dendrimer-NAC (G6D-NAC). The efficacy of microglia-targeted G6D-NAC conjugate was evaluated in a clinically relevant rabbit model of CP, with a mild/moderate CP phenotype to provide a longer survival of untreated CP kits, enabling the assessment of sustained efficacy over 15 days of life. G6D-NAC was conjugated and characterized. Cytotoxicity and anti-inflammatory assays were performed in BV-2 microglial cells. The efficacy of G6D-NAC was evaluated in a rabbit model of CP. CP kits were randomly divided into 5 groups on postnatal day 1 (PND1) and received an intravenous injection of a single dose of PBS, or G6D-NAC (2 or 5 mg/kg), or NAC (2 or 5 mg/kg). Neurobehavioral tests, microglia morphology, and neuroinflammation were evaluated at postnatal day 5 (PND5) and day 15 (PND15). A single dose of systemic ‘long circulating’ G6D-NAC showed a significant penetration across the impaired blood-brain-barrier (BBB), delivered NAC specifically to activated microglia, and significantly reduced microglia-mediated neuroinflammation in both the cortex and cerebellum white matter areas. Moreover, G6D-NAC treatment significantly improved neonatal rabbit survival rate and rescued motor function to nearly healthy control levels at least up to 15 days after birth (PND15), while CP kits treated with free NAC died before PND9. Targeted delivery of therapeutics to activated microglia in neonatal brain injury can ameliorate pro-inflammatory microglial responses to injury, promote survival rate, and improve neurological outcomes that can be sustained for a long period. Appropriate manipulation of activated microglia enabled by G6D-NAC can impact the injury significantly beyond inflammation.
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DOI：
10.1016/j.jconrel.2015.07.009
发表时间：
2015-09-28
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Nance E;Porambo M;Zhang F;Mishra MK;Buelow M;Getzenberg R;Johnston M;Kannan RM;Fatemi A;Kannan S
通讯作者：
Kannan S
影响因子：
17.1
作者：
Mishra, Manoj K.;Beaty, Claude A.;Lesniak, Wojciech G.;Kambhampati, Siva R.;Zhang, Fan;Wilson, Mary A.;Blue, Mary E.;Troncoso, Juan C.;Kannan, Sujatha;Johnston, Michael V.;Baumgartner, William A.;Kannan, Rangaramanujam M.
通讯作者：
Kannan, Rangaramanujam M.
影响因子：
9.8
作者：
Buhimschi, IA;Buhimschi, CS;Weiner, CP
通讯作者：
Weiner, CP
影响因子：
3.7
作者：
Harada, D;Naito, S;Otagiri, M
通讯作者：
Otagiri, M
影响因子：
17.1
作者：
Kannan S;Dai H;Navath RS;Balakrishnan B;Jyoti A;Janisse J;Romero R;Kannan RM
通讯作者：
Kannan RM