Transport and biodistribution of dendrimers across human fetal membranes: implications for intravaginal administration of dendrimer-drug conjugates.
Transport and biodistribution of dendrimers across human fetal membranes: implications for intravaginal administration of dendrimer-drug conjugates.
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DOI：
10.1016/j.biomaterials.2010.02.075
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发表时间：
2010-06
期刊：
影响因子：
14
通讯作者：
Kannan, Rangaramanujam M.
中科院分区：
文献类型：
--
作者：
Menjoge, Anupa R.;Navath, Raghavendra S.;Asad, Abbas;Kannan, Sujatha;Kim, Chong J.;Romero, Roberto;Kannan, Rangaramanujam M.
关键词：
树枝状聚合物是一种有前途的局部抗菌剂，并作为靶向纳米级药物递送载体。局部阴道内抗菌药物被规定用于治疗孕妇的上行生殖器感染。胎膜将羊膜外空间和胎儿分开。该研究的目的是确定树枝状聚合物是否可以选择性地用于孕妇的局部阴道内应用，而不会穿过膜进入胎儿。在本研究中，运输和渗透性的PAMAM（聚（酰胺胺））树枝状聚合物，通过人胎膜（使用并排扩散室），其生物分布（使用免疫荧光）进行了体外评价。使用荧光素（FITC）（一种已建立的经胎盘标记物（阳性对照，大小约400 Da））和荧光团标记的G4-PAMAM树枝状聚合物（约16 kDa）评价穿过人胎膜（从母体侧）的转运。合成了荧光团标记的G4-PAMAM树枝状大分子，并使用1H NMR、MALDI TOF-MS和HPLC分析进行了表征。测量穿过完整的胎膜（绒毛膜羊膜）以及分离的绒毛膜和羊膜层的转移。在5小时的时间内，树枝状聚合物穿过所有三种膜的转运小于<3%，而FITC的转运相对较快，穿过羊膜的转运高达49%。FITC对绒毛膜羊膜的渗透性（7.9 × 10-7 cm 2/s）是树枝状聚合物的7倍（5.8 × 10-8 cm 2/s）。生物分布表明，树枝状聚合物主要存在于蜕膜基质细胞和绒毛膜滋养层细胞（在2.5至4小时）的间隙空间，令人惊讶的是，在较小程度上内化在滋养层细胞的细胞核和基质细胞的细胞核和细胞质。被动扩散和细胞旁运输似乎是树枝状聚合物运输的主要途径。总体研究结果进一步表明，当通过阴道内途径局部给药时，与树枝状聚合物缀合的药物的进入将被限制穿过人胎膜，这表明了选择性地将治疗剂递送至母亲而不影响胎儿的新方法。
Dendrimers are emerging as promising topical antimicrobial agents, and as targeted nanoscale drug delivery vehicles. Topical intravaginal antimicrobial agents are prescribed to treat the ascending genital infections in pregnant women. The fetal membranes separate the extra-amniotic space and fetus. The purpose of the study is to determine if the dendrimers can be selectively used for local intravaginal application to pregnant women without crossing the membranes into the fetus. In the present study, the transport and permeability of PAMAM (poly(amidoamine)) dendrimers, across human fetal membrane (using a side-by-side diffusion chamber), and its biodistribution (using immunofluorescence) are evaluated ex-vivo. Transport across human fetal membranes (from the maternal side) was evaluated using Fluorescein (FITC), an established transplacental marker (positive control, size~ 400 Da) and fluorophore-tagged G4-PAMAM dendrimers (~ 16 kDa). The fluorophore-tagged G4-PAMAM dendrimers were synthesized and characterized using 1H NMR, MALDI TOF-MS and HPLC analysis. Transfer was measured across the intact fetal membrane (chorioamnion), and the separated chorion and amnion layers. Over a five hour period, the dendrimer transport across all the three membranes was less than < 3 %, whereas the transport of FITC was relatively fast with as much as 49% transport across the amnion. The permeability of FITC (7.9 × 10-7 cm2/s) through the chorioamnion was 7-fold higher than that of the dendrimer (5.8 × 10-8 cm2/s). The biodistribution showed that the dendrimers were largely present in interstitial spaces in the decidual stromal cells and the chorionic trophoblast cells (in 2.5 to 4 h) and surprisingly, to a smaller extent internalized in nuclei of trophoblast cells and nuclei and cytoplasm of stromal cells. Passive diffusion and paracellular transport appear to be the major route for dendrimer transport. The overall findings further suggest that entry of drugs conjugated to dendrimers would be restricted across the human fetal membranes when administered topically by intravaginal route, suggesting new ways of selectively delivering therapeutics to the mother without affecting the fetus.
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