Cheng Zhiliang, Thorek Daniel L J, Tsourkas Andrew
Department of Bioengineering, University of Pennsylvania 210 South 33rd Street, 240 Skirkanich Hall, Philadelphia, PA 19104 (USA).
Adv Funct Mater. 2009 Dec 9;19(23):3753-3759. doi: 10.1002/adfm.200901253.
The use of nanovesicles with encapsulated Gd as MR contrast agents has largely been ignored due to the detrimental effects of the slow water exchange rate through the vesicle bilayer on the relaxivity of encapsulated Gd. Here, we describe the facile synthesis of a composite MR contrast platform, consisting of dendrimer conjugates encapsulated in porous polymersomes. These nanoparticles exhibit improved permeability to water flux and a large capacity to store chelated Gd within the aqueous lumen, resulting in enhanced longitudinal relaxivity. The porous polymersomes, ~130 nm in diameter, were produced through the aqueous assembly of the polymers, polyethylene oxide-b-polybutadiene (PBdEO), and polyethylene oxide-b-polycaprolactone (PEOCL). Subsequent hydrolysis of the caprolactone (CL) block resulted in a highly permeable outer membrane. To prevent the leakage of small Gd-chelate through the pores, Gd was conjugated to PAMAM dendrimer via diethylenetriaminepentaacetic acid dianhydride (DTPA dianhydride) prior to encapsulation. As a result of the slower rotational correlation time of Gd-labeled dendrimers, the porous outer membrane of the nanovesicle, and the high Gd payload, these functional nanoparticles were found to exhibit a relaxivity (R1) of 292,109 mM(-1) s(-1) per particle. The polymersomes were also found to exhibit unique pharmacokinetics with a circulation half-life of >3.5 hrs and predominantly renal clearance.
由于通过囊泡双层的水交换速率缓慢对包封的钆弛豫率产生不利影响，使用包封钆的纳米囊泡作为磁共振成像（MR）造影剂在很大程度上被忽视了。在此，我们描述了一种复合MR造影平台的简便合成方法，该平台由封装在多孔聚合物囊泡中的树枝状聚合物缀合物组成。这些纳米颗粒对水通量表现出更高的渗透性，并且在水腔内储存螯合钆的能力很大，从而导致纵向弛豫率增强。直径约130纳米的多孔聚合物囊泡是通过聚合物聚环氧乙烷-b-聚丁二烯（PBdEO）和聚环氧乙烷-b-聚己内酯（PEOCL）的水性组装产生的。己内酯（CL）嵌段的后续水解导致形成高度可渗透的外膜。为了防止小的钆螯合物通过孔隙泄漏，在封装之前，钆通过二乙三胺五乙酸二酐（DTPA二酐）与聚酰胺-胺（PAMAM）树枝状聚合物缀合。由于钆标记的树枝状聚合物的旋转相关时间较慢、纳米囊泡的多孔外膜以及高钆负载量，发现这些功能性纳米颗粒的弛豫率（R1）为每个颗粒292,109 mM⁻¹ s⁻¹。还发现聚合物囊泡表现出独特的药代动力学，循环半衰期大于3.5小时，主要通过肾脏清除。
