Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation.
Activated Microglia Targeting Dendrimer-Minocycline Conjugate as Therapeutics for Neuroinflammation.
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DOI：
10.1021/acs.bioconjchem.7b00569
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发表时间：
2017-11-15
影响因子：
4.7
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Sharma R;Kim SY;Sharma A;Zhang Z;Kambhampati SP;Kannan S;Kannan RM
脑相关疾病已超过癌症和心血管疾病，成为全球发病率和死亡率的主要原因。缺乏有效的治疗方法和相对干燥的中枢神经系统（CNS）药物管道构成了巨大的挑战。当前临床批准的药物的上级靶向递送可能提供显著的潜力。米诺环素由于其穿透血脑屏障（BBB）的能力和效力而显示出用于治疗神经系统疾病的前景。尽管其在临床和临床前模型中具有潜力，但影响积极治疗反应所需的高剂量已导致副作用。将米诺环素靶向递送至脑中的损伤部位和损伤细胞可以是非常有益的。全身给药的羟基聚（酰胺基胺）（PAMAM）第6代（G6）树枝状聚合物具有较长的血液循环时间，并已被证明可以穿过受损的BBB。我们成功地制备了羟基-G6 PAMAM树状大分子-9-氨基-米诺环素偶联物（D-mino），并对其体外疗效和体内靶向能力进行了表征。米诺环素是一种具有挑战性的药物进行化学转化，由于其固有的不稳定性。我们使用了一个高效和温和的铜催化的叠氮化物-炔点击反应（CuAAC）沿着与微波能量的组合，以共轭9-氨基米诺环素（米诺）的树枝状聚合物表面通过酶响应键。在脂多糖激活的鼠小胶质细胞中进一步评价D-mino的抗炎和抗氧化活性。由于其快速摄取，D-mino缀合物增强了药物的细胞内利用度，抑制了炎性细胞因子肿瘤坏死因子α（TNF-α）的产生，并通过抑制一氧化氮的产生减少了氧化应激，所有这些均显著优于游离药物。在出生后第1天，将标记的树枝状聚合物缀合物（Cy 5-D-mino）系统地施用（静脉内，55 mg/kg）给具有临床相关脑瘫表型的兔试剂盒。体内成像研究表明，Cy 5-D-mino穿过受损的血脑屏障，并与激活的小胶质细胞共定位在脑室周围白色物质区域，包括胼胝体和侧脑室角，具有积极的治疗结果的重要意义。当与PAMAM树枝状聚合物固有的神经炎症靶向能力相结合时，D-mino的增强功效可能为靶向药物递送治疗神经系统疾病提供新的机会。
Brain-related disorders have outmatched cancer and cardiovascular diseases worldwide as the leading cause of morbidity and mortality. The lack of effective therapies and the relatively dry central nervous system (CNS) drug pipeline pose formidable challenge. Superior, targeted delivery of current clinically approved drugs may offer significant potential. Minocycline has shown promise for the treatment of neurological diseases owing to its ability to penetrate the blood–brain barrier (BBB) and potency. Despite its potential in the clinic and in preclinical models, the high doses needed to affect a positive therapeutic response have led to side effects. Targeted delivery of minocycline to the injured site and injured cells in the brain can be highly beneficial. Systemically administered hydroxyl poly(amidoamine) (PAMAM) generation-6 (G6) dendrimers have a longer blood circulation time and have been shown to cross the impaired BBB. We have successfully prepared and characterized the in vitro efficacy and in vivo targeting ability of hydroxyl-G6 PAMAM dendrimer–9-amino-minocycline conjugate (D-mino). Minocycline is a challenging drug to carry out chemical transformations due to its inherent instability. We used a combination of a highly efficient and mild copper catalyzed azide–alkyne click reaction (CuAAC) along with microwave energy to conjugate 9-amino-minocycline (mino) to the dendrimer surface via enzyme responsive linkages. D-mino was further evaluated for anti-inflammatory and antioxidant activity in lipopolysaccharides-activated murine microglial cells. D-mino conjugates enhanced the intracellular availability of the drug due to their rapid uptake, suppressed inflammatory cytokine tumor necrosis factor α (TNF-α) production, and reduced oxidative stress by suppressing nitric oxide production, all significantly better than the free drug. Fluorescently labeled dendrimer conjugate (Cy5–D-mino) was systematically administered (intravenous, 55 mg/kg) on postnatal day 1 to rabbit kits with a clinically relevant phenotype of cerebral palsy. The in vivo imaging study indicates that Cy5–D-mino crossed the impaired blood–brain barrier and co-localized with activated microglia at the periventricular white matter areas, including the corpus callosum and the angle of the lateral ventricle, with significant implications for positive therapeutic outcomes. The enhanced efficacy of D-mino, when combined with the inherent neuroinflammation-targeting capability of the PAMAM dendrimers, may provide new opportunities for targeted drug delivery to treat neurological disorders.
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影响因子：
3.4
作者：
Kovesdi E;Kamnaksh A;Wingo D;Ahmed F;Grunberg NE;Long JB;Kasper CE;Agoston DV
通讯作者：
Agoston DV
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：
4.4
作者：
Kambhampati, Siva P.;Clunies-Ross, Alexander J. M.;Lutty, Gerard
通讯作者：
Lutty, Gerard
影响因子：
4.9
作者：
Neibert, Kevin;Gosein, Varin;Kakkar, Ashok
通讯作者：
Kakkar, Ashok