Development of fluorescent- and radio-traceable T1307-polymeric micelles as biomedical agents for cancer diagnosis: biodistribution on 4T1 tumor-bearing mice

Abstract In recent years, nanocarriers have been studied as promising pharmaceutical tools for controlled drug-delivery, treatment-efficacy follow-up and disease imaging. Among them, X-shaped amphiphilic polymeric micelles (Tetronic®, poloxamines) display great potential due to their biocompatibility and non-toxic effects, among others. In the present work, polymeric micelles based on the T1307 copolymer were initially decorated with a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-fluorophore in order to determinate its in vivo biodistribution on 4T1 tumor-bearing mice. However, unfavorable results with this probe led to two different strategies. On the one hand, the BODIPY-micelle-loaded, L-T1307-BODIPY, and on the other hand, the 99mTc-micelle-radiolabeled, L-T1307- 99m Tc, were analyzed separately in vivo. The results indicated that T1307 accumulates mainly in the stomach, the kidneys, the lungs and the tumor, reaching the maximum organ-accumulation 2 hours after intravenous injection. Additionally, and according to the results obtained for L-T1307- 99m Tc, the capture of the polymeric micelles in organs could be observed up to 24 hours after injection. The results obtained in this work were promising towards the development of new radiotracer agents for breast cancer based on X-shaped polymeric micelles.

摘要：近年来，纳米载体（nanocarriers）作为用于控释给药（controlled drug-delivery）、治疗效果随访（treatment-efficacy follow-up）及疾病成像（disease imaging）的极具潜力的医药工具受到广泛研究。其中，X形两亲性聚合物胶束（X-shaped amphiphilic polymeric micelles，商品名Tetronic®，又称泊洛沙明（poloxamines））因良好的生物相容性与低毒性等优势展现出巨大应用潜力。本研究首先以T1307共聚物为基材制备聚合物胶束，并通过4,4-二氟-4-硼-3a,4a-二氮杂-s-茚满（氟化硼二吡咯，BODIPY）荧光探针对胶束进行修饰，以期探究其在4T1荷瘤小鼠（4T1 tumor-bearing mice）体内的生物分布。然而该探针的实验结果未达预期，因此我们采用两种不同策略开展后续研究：一方面对负载BODIPY的L-T1307-BODIPY胶束进行体内分析，另一方面对经锝-99m（99mTc）放射性标记的L-T1307-99mTc胶束单独开展体内实验。实验结果表明，T1307胶束主要富集于胃、肾、肺与肿瘤组织，于静脉注射（intravenous injection）后2小时达到器官摄取峰值。此外，基于L-T1307-99mTc的实验结果，直至注射后24小时仍可观测到聚合物胶束在各器官内的摄取情况。本研究所得结果为基于X形聚合物胶束的乳腺癌新型放射性示踪剂（radiotracer agents）开发提供了极具前景的实验依据。