Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy.
Transfer of PAMAM dendrimers across human placenta: prospects of its use as drug carrier during pregnancy.
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DOI：
10.1016/j.jconrel.2010.11.023
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发表时间：
2011-03-30
期刊：
影响因子：
--
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Menjoge AR;Rinderknecht AL;Navath RS;Faridnia M;Kim CJ;Romero R;Miller RK;Kannan RM
树枝状大分子作为纳米载体在药物和显像剂的靶向传递方面具有巨大的潜力。本研究的目的是评价PAMAM树状大分子在体外经胎盘的转运、动力学和生物分布，并与安替比林(一种可自由扩散的分子)进行比较。这项研究的目的是确定树枝状大分子作为药物载体是否可以用于设计有选择性地治疗母亲或胎儿的药物输送系统。用高效液相色谱双紫外检测仪和荧光检测器(检测灵敏度分别为10 ng/m L和100 ng/m L)测定了荧光标记的PAMAM树状大分子(16 KDa)和安替比林(188 KDa)从母体到胎儿的胎盘转运。母体灌流液(Tmax=15min)中树枝状大分子-Alexa(DA)的cmax是胎儿灌流液的18倍，且在5.5h内从未与母体灌流液达到平衡(n=4)。DA在5.5h内经胎盘转运显著，为2.2 6±0.12μg/mL，平均经胎盘转运为母体总浓度的0.84±0.11%，母胎比为0.073%±0.0 2。经DA灌流的胎盘的生化和生理分析表明，在整个灌流过程中功能正常。免疫荧光组织化学显示，DA在灌流胎盘中的分布稀疏，主要分布于绒毛间隙和绒毛分支外缘。在合体滋养细胞的胞核、胞浆和绒毛核心内有少量DA内化和定位，但绒毛毛细血管内大多缺乏DA。总而言之，PAMAM树枝状大分子在灌流的人胎盘上表现出从母体侧到胎儿侧的低转移率，这与其他对大分子如免疫球蛋白的研究类似。这些总体发现表明，与较小的药物分子相比，结合在聚合物上的药物，即树枝状大分子，在通过人体胎盘转移方面将受到限制，这表明了选择性地将治疗药物输送给孕妇而不会显著转移到胎儿的新方法，特别是因为树枝状大分子在血液中的半衰期相对较短。
Dendrimers offer significant potential as nanocarriers for targeted delivery of drugs and imaging agents. The objectives of this study were to evaluate the transplacental transport, kinetics and biodistribution of PAMAM dendrimers ex-vivo across the human placenta in comparison with antipyrine, a freely diffusible molecule, using dually perfused re-circulating term human placental lobules. The purpose of this study is to determine if dendrimers as drug carriers can be used to design drug delivery systems directed at selectively treating either the mother or the fetus. The transplacental transfers of fluorescently (Alexa 488) tagged PAMAM dendrimer (16 kDa) and antipyrine (188 Da) from maternal to fetal circulation were measured using HPLC/dual UV and fluorescent detector (sensitivity of 10 ng / mL for dendrimer and 100 ng /mL for antipyrine respectively). Cmax for the dendrimer-Alexa (DA) in maternal perfusate (Tmax = 15min) was 18 times higher than in the fetal perfusate and never equilibrated with the maternal perfusate during 5.5 hours of perfusion (n=4). DA exhibited a significant but low transplacental transport of ~2.26 ± 0.12 μg / mL during 5.5 hours, where the mean transplacental transfer was 0.84 ±0.11 % of the total maternal concentration and the feto-maternal ratio as percent was 0.073% ± 0.02. The biochemical and physiological analysis of the placentae perfused with DA demonstrated normal function throughout the perfusion. The immunofluorescence histochemistry confirmed that the biodistribution of DA in perfused placenta was sparsely dispersed, and when noted was principally seen in the inter-villous spaces and outer rim of the villous branches. In a few cases, DA was found internalized and localized in nuclei and cytoplasm of syncytiotrophoblast and inside the villous core; however, DA was mostly absent from the villous capillaries. In conclusion, the PAMAM dendrimers exhibited a low rate of transfer from maternal to the fetal side across the perfused human placenta, which is similar to other investigations of large macromolecules, eg., IgG. These overall findings suggest that entry of drugs conjugated to polymers, i.e., dendrimers, would be limited in their transfer across the human placenta when compared to smaller drug molecules alone, suggesting novel methods for selectively delivering therapeutics to the pregnant woman without significant transfer to the fetus, especially since the half life of the dendrimer in blood is relatively short.
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影响因子：
5.8
作者：
Bajoria, R;Ryder, TA;Fisk, NM
通讯作者：
Fisk, NM
影响因子：
14
作者：
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6.1
作者：
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通讯作者：
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3.8
作者：
Miller, RK;Mace, K;Treacy, G
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