Institute of Nuclear Chemistry, Johannes Gutenberg University, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany.
Institute of Organic Chemistry, Johannes Gutenberg University, Duesbergweg 10-14, 55128 Mainz, Germany.
Nucl Med Biol. 2018 Mar;58:59-66. doi: 10.1016/j.nucmedbio.2017.12.002. Epub 2017 Dec 16.
For the evaluation of macromolecular drug delivery systems suitable pre-clinical monitoring of potential nanocarrier systems is needed. In this regard, both short-term as well as long-term in vivo tracking is crucial to understand structure-property relationships of polymer carrier systems and their resulting pharmacokinetic profile. Based on former studies revealing favorable in vivo characteristics for F-labeled random (ran) copolymers consisting of N-(2-hydroxypropyl)methacrylamide (HPMA) and lauryl methacrylate (LMA) - including prolonged plasma half-life as well as enhanced tumor accumulation - the presented work focuses on their long-term investigation in the living organism.
In this respect, four different HPMA-based polymers (homopolymers as well as random copolymers with LMA as hydrophobic segment) were synthesized and subsequent radioactive labeling was accomplished via the longer-lived radioisotope I. In vivo results, concentrating on the pharmacokinetics of a high molecular weight HPMA-ran-LMA copolymer, were obtained by means of biodistribution and metabolism studies in the Walker 256 mammary carcinoma model over a time-span of up to three days. Besides, a direct comparison with the F-radiolabeled polymer was drawn. To consider physico-chemical differences between the differently labeled polymer (F or I) on the critical micelle concentration (CMC) and the size of the polymeric micelles, those properties were determined using the F- or I-functionalized polymer. Special emphasis was laid on the time-dependent correlation between blood circulation properties and corresponding tumor accumulation, particularly regarding the enhanced permeability and retention (EPR) effect.
Studies revealed, at first, differences in the short time (2h) body distribution, despite the very similar properties (molecular structure, CMC and size of the micellar aggregates) of the non-radioactive F- and I-functionalized polymers. Long-term investigations with the I-labeled polymer demonstrated that, despite a polymer clearance from the blood within 72h, there was still an increase in tumor uptake observed over time. Regarding the stability of the I-label, ex vivo biodistribution experiments, considering the uptake in the thyroid, indicated low metabolism rates.
The observed in vivo characteristics strongly underline the EPR effect. The findings illustrate the need to combine information of different labeling approaches and in vivo evaluation techniques to generate an overall pharmacokinetic picture of potential nanocarriers in the pre-clinical setting.
The in vivo behavior of the investigated HPMA-ran-LMA copolymer demonstrates great potential in terms of an effective accumulation in the tumor.
为了评估适合临床前监测的大分子药物传递系统，需要对潜在的纳米载体系统进行短期和长期的体内跟踪。这对于了解聚合物载体系统的结构-性质关系及其药代动力学特征至关重要。基于以前的研究表明，由 N-(2-羟丙基)甲基丙烯酰胺 (HPMA) 和月桂甲基丙烯酸酯 (LMA) 组成的 F 标记的无规 (ran) 共聚物具有良好的体内特性，包括延长的血浆半衰期和增强的肿瘤积累，本研究重点研究了它们在活体内的长期情况。
为此，合成了四种不同的基于 HPMA 的聚合物（均聚物以及作为疏水性部分的 LMA 无规共聚物），并通过半衰期更长的放射性同位素 I 进行放射性标记。通过在 Walker 256 乳腺癌模型中进行生物分布和代谢研究，获得了高分子量 HPMA-ran-LMA 共聚物的体内结果，时间跨度长达三天。此外，还与 F 放射性标记的聚合物进行了直接比较。为了考虑不同标记聚合物（F 或 I）在临界胶束浓度 (CMC) 和聚合物胶束尺寸上的理化差异，使用 F 或 I 功能化聚合物确定了这些性质。特别强调了血液循环特性与相应肿瘤积累之间的时间相关性，特别是关于增强的通透性和保留 (EPR) 效应。
研究首先揭示了在非常相似的性质（分子结构、CMC 和胶束聚集体的大小）的非放射性 F 和 I 功能化聚合物中，在短时间（2h）体内分布上存在差异。用 I 标记的聚合物进行的长期研究表明，尽管聚合物在 72h 内从血液中清除，但仍观察到肿瘤摄取随时间增加。关于 I 标记的稳定性，考虑到甲状腺摄取的离体生物分布实验表明代谢率较低。
观察到的体内特征强烈强调了 EPR 效应。这些发现表明，需要结合不同标记方法和体内评估技术的信息，以生成潜在纳米载体在临床前环境中的整体药代动力学图像。
所研究的 HPMA-ran-LMA 共聚物的体内行为表明，在肿瘤中的有效积累方面具有很大的潜力。
