Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.
Tri-partite complex for axonal transport drug delivery achieves pharmacological effect.
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DOI：
10.1186/1471-2202-11-8
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发表时间：
2010-01-20
期刊：
影响因子：
2.4
通讯作者：
Lever AM
中科院分区：
文献类型：
--
作者：
Filler AG;Whiteside GT;Bacon M;Frederickson M;Howe FA;Rabinowitz MD;Sokoloff AJ;Deacon TW;Abell C;Munglani R;Griffiths JR;Bell BA;Lever AM
将药剂靶向递送到选定的CNS（中枢神经系统）神经元群体中是一个极其引人注目的目标。目前，全身方法通常用于输送止痛药、治疗皮节感染的抗病毒药物、抗痉挛药和神经保护剂。对不参与病理学的CNS部分的全身性副作用或不期望的作用限制了许多类别的药物的功效并限制了其临床实用性。从外周的轴突运输提供了一种可能的选择性途径，但通过这种神经内途径实现靶向递送的药物设计进展甚微。为了实现这一目标，我们开发了一种三重分子构建概念，包括轴突转运促进剂分子、聚合物连接体和大量与连接体缀合的药物分子，然后试图评估其神经生物学和药理学行为。我们开发了化学合成方法组装这些三方复合物使用各种轴突运输促进剂，包括神经生长因子，麦胚凝集素，和合成的促进剂来自噬菌体展示工作。实现了每个复合物装载多达100个药物分子。使用缀合方法，其允许药物在运输后以活性形式在细胞体内释放。肌内和皮内注射被证明是有效的，可将有效剂量引入选定的CNS神经元群体。加巴喷丁在缩爪潜伏期模型中的药理学功效显示，当使用三重载体通过轴突运输递送药物时，相对于加巴喷丁的全身给药，半衰期增加10倍，必要剂量减少300倍。选择CNS神经元亚群的特异性靶向用于通过轴突运输的药物递送具有很大的前景。这里显示的数据提供了一个基本的框架，神经内药理学的这三方复杂。在此证明的高效的药物递送验证了使用轴突运输用于靶向药物递送的基本可行性。
Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery.
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影响因子：
2.9
作者：
COLIN, W;DONOFF, RB;FOOTE, WE
通讯作者：
FOOTE, WE
影响因子：
4.8
作者：
Bohnert, S;Schiavo, G
通讯作者：
Schiavo, G
DOI：
10.1073/pnas.74.1.34
发表时间：
1977-01-01
影响因子：
11.1
作者：
BARCHI, RL;BONILLA, E;WONG, M
通讯作者：
WONG, M
影响因子：
7.4
作者：
BENNETT, GJ;XIE, YK
通讯作者：
XIE, YK
影响因子：
4.9
作者：
BIRON, KK;ELION, GB
通讯作者：
ELION, GB