Technical University of Denmark, DTU Nanotech, Department of Micro- and Nanotechnology, Center for Nanomedicine and Theranostics, Building 423, 2800 Lyngby, Denmark.
J Control Release. 2012 Jun 10;160(2):254-63. doi: 10.1016/j.jconrel.2011.12.038. Epub 2012 Jan 5.
Targeted therapeutic and diagnostic nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize over-expressed receptors or antigens on tumor cells have potential in the diagnosis and therapy of cancer. Somatostatin receptors (SSTRs) are over-expressed in a variety of cancers, particularly neuroendocrine tumors (NETs) and can be targeted with somatostatin peptide analogs such as octreotate (TATE). In the present study we investigate liposomes that target SSTR in a NET xenograft mouse model (NCI-H727) by use of TATE. TATE was covalently attached to the distal end of DSPE-PEG(2000) on PEGylated liposomes with an encapsulated positron emitter (64)Cu that can be utilized for positron emission tomography (PET) imaging. The biodistribution and pharmacokinetics of the (64)Cu-loaded PEGylated liposomes with and without TATE was investigated and their ability to image NETs was evaluated using PET. Additionally, the liposome accumulation and imaging capability was compared with free radiolabelled TATE peptide administered as (64)Cu-DOTA-TATE. The presence of TATE on the liposomes resulted in a significantly faster initial blood clearance in comparison to control-liposomes without TATE. PEGylated liposomes with or without TATE accumulated at significantly higher quantities in NETs (5.1±0.3 and 5.8±0.2 %ID/g, respectively) than the free peptide (64)Cu-DOTA-TATE (1.4±0.3 %ID/g) 24 h post-injection. Importantly, (64)Cu-loaded PEGylated liposomes with TATE showed significantly higher tumor-to-muscle (T/M) ratio (12.7±1.0) than the control-liposomes without TATE (8.9±0.9) and the (64)Cu-DOTA-TATE free peptide (7.2±0.3). The higher T/M ratio of the PEGylated liposomes with TATE suggests some advantage of active targeting of NETs, although no absolute benefit in tumor accumulation over the non-targeted liposomes was observed. Collectively, these data showed that (64)Cu-loaded PEGylated liposomes with TATE conjugated to the surface could be promising new imaging agents for visualizing tumor tissue and especially NETs using PET.
靶向治疗和诊断的纳米载体通过抗体、肽或其他靶向配体进行功能化，这些配体能够识别肿瘤细胞上过度表达的受体或抗原，在癌症的诊断和治疗方面具有潜力。生长抑素受体 (SSTR) 在多种癌症中过度表达，特别是神经内分泌肿瘤 (NET)，可以用生长抑素类似物如奥曲肽 (TATE) 进行靶向治疗。在本研究中，我们通过使用 TATE 研究了针对 NET 异种移植小鼠模型 (NCI-H727) 中 SSTR 的脂质体。TATE 通过与 PEG 化脂质体上的 DSPE-PEG(2000) 末端的共价键连接，带有包裹的正电子发射体 (64)Cu，可用于正电子发射断层扫描 (PET) 成像。研究了负载 (64)Cu 的 PEG 化脂质体有无 TATE 的生物分布和药代动力学，并使用 PET 评估其对 NET 成像的能力。此外，还比较了游离放射性标记 TATE 肽 (64)Cu-DOTA-TATE 给药的脂质体积累和成像能力。与没有 TATE 的对照脂质体相比，TATE 存在于脂质体上会导致初始血液清除速度明显加快。载有或未载有 TATE 的 PEG 化脂质体在 NET 中积累的数量明显高于游离肽 (64)Cu-DOTA-TATE（分别为 5.1±0.3 和 5.8±0.2 %ID/g）24 小时后注射。重要的是，与未载有 TATE 的对照脂质体 (8.9±0.9) 和游离肽 (64)Cu-DOTA-TATE(7.2±0.3) 相比，载有 TATE 的 (64)Cu 负载 PEG 化脂质体的肿瘤与肌肉 (T/M) 比值明显更高 (12.7±1.0)。TATE 修饰的 PEG 化脂质体的较高 T/M 比表明对 NET 的主动靶向具有一定优势，尽管与非靶向脂质体相比，肿瘤积聚没有绝对优势。总的来说，这些数据表明，表面结合 TATE 的 (64)Cu 负载 PEG 化脂质体可能是使用 PET 可视化肿瘤组织特别是 NET 的有前途的新型成像剂。
