Swanson Scott D, Kukowska-Latallo Jolanta F, Patri Anil K, Chen Chunyan, Ge Song, Cao Zhengyi, Kotlyar Alina, East Andrea T, Baker James R
Department of Radiology,The University of Michigan Medical School, The University of Michigan, USA.
Int J Nanomedicine. 2008;3(2):201-10.
A target-specific MRI contrast agent for tumor cells expressing high affinity folate receptor was synthesized using generation five (G5) ofpolyamidoamine (PAMAM) dendrimer. Surface modified dendrimer was functionalized for targeting with folic acid (FA) and the remaining terminal primary amines of the dendrimer were conjugated with the bifunctional NCS-DOTA chelator that forms stable complexes with gadolinium (Gd III). Dendrimer-DOTA conjugates were then complexed with GdCl3 followed by ICP-OES as well as MRI measurement of their longitudinal relaxivity (T1 s(-1) mM(-1)) of water. In xenograft tumors established in immunodeficient (SCID) mice with KB human epithelial cancer cells expressing folate receptor (FAR), the 3D MRI results showed specific and statistically significant signal enhancement in tumors generated with targeted Gd(III)-DOTA-G5-FA compared with signal generated by non-targeted Gd(III)-DOTA-G5 contrast nanoparticle. The targeted dendrimer contrast nanoparticles infiltrated tumor and were retained in tumor cells up to 48 hours post-injection of targeted contrast nanoparticle. The presence of folic acid on the dendrimer resulted in specific delivery of the nanoparticle to tissues and xenograft tumor cells expressing folate receptor in vivo. We present the specificity of the dendrimer nanoparticles for targeted cancer imaging with the prolonged clearance time compared with the current clinically approved gadodiamide (Omniscan) contrast agent. Potential application of this approach may include determination of the folate receptor status of tumors and monitoring of drug therapy.
使用第五代聚酰胺 - 胺（PAMAM）树枝状大分子合成了一种针对表达高亲和力叶酸受体的肿瘤细胞的靶向性磁共振成像（MRI）造影剂。对表面修饰的树枝状大分子用叶酸（FA）进行功能化修饰，使其具有靶向性，并且树枝状大分子剩余的末端伯胺与双功能NCS - DOTA螯合剂共轭，该螯合剂能与钆（Gd III）形成稳定的络合物。然后将树枝状大分子 - DOTA共轭物与GdCl3络合，接着进行电感耦合等离子体发射光谱法（ICP - OES）分析以及对其水的纵向弛豫率（T1 s(-1) mM(-1)）进行MRI测量。在免疫缺陷（SCID）小鼠中建立的异种移植瘤中，接种了表达叶酸受体（FAR）的KB人上皮癌细胞，三维MRI结果显示，与非靶向性Gd(III) - DOTA - G5造影纳米颗粒产生的信号相比，靶向性Gd(III) - DOTA - G5 - FA产生的肿瘤信号有特异性且具有统计学意义的增强。靶向性树枝状大分子造影纳米颗粒在注射靶向造影纳米颗粒后长达48小时都能渗入肿瘤并保留在肿瘤细胞中。树枝状大分子上叶酸的存在导致纳米颗粒在体内特异性地递送至表达叶酸受体的组织和异种移植肿瘤细胞。我们展示了树枝状大分子纳米颗粒在靶向癌症成像方面的特异性，与目前临床批准的钆双胺（欧乃影）造影剂相比，其清除时间延长。这种方法的潜在应用可能包括确定肿瘤的叶酸受体状态以及监测药物治疗。
