Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin.
Poly(amido amine) dendrimers as absorption enhancers for oral delivery of camptothecin.
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DOI：
10.1016/j.ijpharm.2013.07.071
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发表时间：
2013-11-01
影响因子：
5.8
通讯作者：
Ghandehari, H.
中科院分区：
文献类型：
--
作者：
Sadekar, S.;Thiagarajan, G.;Bartlett, K.;Hubbard, D.;Ray, A.;McGill, L. D.;Ghandehari, H.
关键词：
口服喜树碱具有治疗优势，但受到生物利用度低和胃肠道毒性的限制。聚酰胺-胺（PAMAM）树枝状大分子作为肠渗透促进剂、药物增溶剂和药物载体在体外和原位口服给药方面显示出了良好的前景。已经有非常有限的研究在体内评价PAMAM树枝状聚合物用于口服药物递送。在本研究中，在CD-1小鼠中配制喜树碱（5 mg/kg），并与阳离子胺封端的PAMAM树状聚合物4.0代（G4.0）（100和300 mg/kg）和阴离子羧酸盐封端的PAMAM 3.5代（G3.5）（300和1000 mg/kg）共递送。在制剂中，喜树碱与G4.0的结合程度高于G3.5，这归因于G4.0表面上的静电相互作用。PAMAM G4.0和G3.5都增加了喜树碱在模拟胃液中的溶解，并且当在2小时递送时，使喜树碱的口服吸收增加2-3倍。PAMAM G4.0和G3.5没有增加甘露醇转运，表明喜树碱的口服吸收不是由于紧密连接调节。给药后4小时胃肠道（GIT）小肠段上皮层的组织学观察结果支持在评价剂量的PAMAM树枝状聚合物下无毒性证据。这项研究表明，阳离子（G.4）和阴离子（G3.5）PAMAM树枝状聚合物是有效的，在提高喜树碱的口服吸收。结果表明，药物包合在PAMAM内部控制溶解在模拟胃液和肠液中，并增加口服生物利用度。
Oral delivery of camptothecin has a treatment advantage but is limited by low bioavailability and gastrointestinal toxicity. Poly(amido amine) or PAMAM dendrimers have shown promise as intestinal penetration enhancers, drug solubilizers and drug carriers for oral delivery in vitro and in situ. There have been very limited studies in vivo to evaluate PAMAM dendrimers for oral drug delivery. In this study, camptothecin (5 mg/kg) was formulated and co-delivered with cationic, amine-terminated PAMAM dendrimer generation 4.0 (G4.0) (100 and 300 mg/kg) and anionic, carboxylate-terminated PAMAM generation 3.5 (G3.5) (300 and 1000 mg/kg) in CD-1 mice. Camptothecin associated to a higher extent with G4.0 than G3.5 in the formulation, attributed to an electrostatic interaction on the surface of G4.0. Both PAMAM G4.0 and G3.5 increased camptothecin solubilization in simulated gastric fluid and caused a 2-3 fold increase in oral absorption of camptothecin when delivered at 2 hours. PAMAM G4.0 and G3.5 did not increase mannitol transport suggesting that the oral absorption of camptothecin was not due to tight junction modulation. Histologic observations of the epithelial layer of small intestinal segments of the gastrointestinal tract (GIT) at 4 hours post dosing supported no evidence of toxicity at the evaluated doses of PAMAM dendrimers. This study demonstrates that both cationic (G.4) and anionic (G3.5) PAMAM dendrimers were effective in enhancing the oral absorption of camptothecin. Results suggest that drug inclusion in PAMAM interior controlled solubilization in simulated gastric and intestinal fluids, and increased oral bioavailability.
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影响因子：
10.8
作者：
El-Sayed, M;Ginski, M;Ghandehari, H
通讯作者：
Ghandehari, H
影响因子：
10.8
作者：
Chauhan, AS;Sridevi, S;Diwan, PV
通讯作者：
Diwan, PV
影响因子：
2.7
作者：
Aisner, Joseph
通讯作者：
Aisner, Joseph
影响因子：
1.7
作者：
El-Sayed, M;Ginski, M;Ghandehari, H
通讯作者：
Ghandehari, H
DOI：
10.1016/s1461-5347(00)00268-6
发表时间：
2000-06-01
期刊：
Pharmaceutical science & technology today
影响因子：
--
作者：
Emerson
通讯作者：
Emerson