Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate.
Indium-based and iodine-based labeling of HPMA copolymer-epirubicin conjugates: Impact of structure on the in vivo fate.
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DOI：
10.1016/j.jconrel.2016.06.004
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发表时间：
2016-08-10
期刊：
影响因子：
--
通讯作者：
Kopeček J
中科院分区：
文献类型：
--
作者：
Zhang L;Zhang R;Yang J;Wang J;Kopeček J
最近，我们开发了第二代主链可降解的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-药物缀合物，其在聚合物主链和侧链中都含有酶促可裂解序列（GFLG）。该设计允许使用分子量高于肾阈值的聚合物载体而不损害其生物相容性，从而导致治疗功效的显著改善。例如，第二代HPMA共聚物-表阿霉素（EPI）缀合物（2 P-EPI）在治疗携带卵巢癌的小鼠中显示出完全的肿瘤消退。为了更好地了解该系统的体内命运，我们开发了一种双标记策略，以同时研究聚合物载体和药物EPI的药代动力学和生物分布。首先，我们合成了两种不同类型的双放射性标记缀合物，包括1）111 In-2 P-EPI-125 I（聚合物载体2 P用111 In放射性标记，药物EPI用125 I放射性标记）和2）125 I-2 P-EPI-111 In（聚合物载体2 P用125 I放射性标记，药物EPI用111 In放射性标记）。然后，我们比较了这两个双标记的缀合物在荷A2780人卵巢癌的雌性裸鼠体内的药代动力学和生物分布。聚合物载体和有效载荷之间的血液循环无显著差异;载体（111 In-2 P和125 I-2 P）在肿瘤和主要器官（肾脏除外）中显示出相似的放射性保留。然而，与111 In标记的有效负载EPI相比，125 I标记的EPI在静脉内施用缀合物后48 h和144 h在正常器官和肿瘤中显示出较低的放射性。这可能是由于对酶-底物复合物形成的空间位阻导致的不同药物释放速率，如溶酶体酶（Tritosomes）的裂解实验所示。EPI（DTPA）111 In的释放速率比EPI（Tyr）125 I慢。这也可能是由于文献报道的体内卡他汀和随后的碘损失。然而，两种放射性核素的肿瘤-组织摄取比是相当的，表明药物标记策略不影响HPMA共聚物缀合物的肿瘤靶向能力。
Recently, we developed 2nd generation backbone degradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates which contain enzymatically cleavable sequences (GFLG) in both polymeric backbone and side-chains. This design allows using polymeric carriers with molecular weights above renal threshold without impairing their biocompatibility, thereby leading to significant improvement in therapeutic efficacy. For example, 2nd generation HPMA copolymer-epirubicin (EPI) conjugates (2P-EPI) demonstrated complete tumor regression in the treatment of mice bearing ovarian carcinoma. To obtain a better understanding of the in vivo fate of this system, we developed a dual-labeling strategy to simultaneously investigate the pharmacokinetics and biodistribution of the polymer carrier and drug EPI. First, we synthesized two different types of dual-radiolabeled conjugates, including 1) 111In-2P-EPI-125I (polymeric carrier 2P was radiolabeled with 111In and drug EPI with 125I), and 2) 125I-2P-EPI-111In (polymeric carrier 2P was radiolabeled with 125I and drug EPI with 111In). Then, we compared the pharmacokinetics and biodistribution of these two dual-labeled conjugates in female nude mice bearing A2780 human ovarian carcinoma. There was no significant difference in the blood circulation between polymeric carrier and payload; the carriers (111In-2P and 125I-2P) showed similar retention of radioactivity in both tumor and major organs except kidney. However, compared to 111In-labeled payload EPI, 125I-labeled EPI showed lower radioactivity in normal organs and tumor at 48 h and 144 h after intravenous administration of conjugates. This may be due to different drug release rates resulting from steric hindrance to the formation of enzyme-substrate complex as indicated by cleavage experiments with lysosomal enzymes (Tritosomes). A slower release rate of EPI(DTPA)111In than EPI(Tyr)125I was observed. It may be also due to in vivo catabolism and subsequent iodine loss as literature reported. Nevertheless, tumor-to-tissue uptake ratios of both radionuclides were comparable, indicating that drug-labeling strategy does not affect the tumor targeting ability of HPMA copolymer conjugates.
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影响因子：
17.1
作者：
Kunjachan S;Gremse F;Theek B;Koczera P;Pola R;Pechar M;Etrych T;Ulbrich K;Storm G;Kiessling F;Lammers T
通讯作者：
Lammers T
影响因子：
10.8
作者：
Julyan, PJ;Seymour, LW;Kerr, DJ
通讯作者：
Kerr, DJ
影响因子：
5.5
作者：
Luo K;Yang J;Kopečková P;Kopeček J
通讯作者：
Kopeček J
DOI：
10.1073/pnas.1003919107
发表时间：
2010-10-19
影响因子：
11.1
作者：
Ding, Hui;Inoue, Satoshi;Ljubimova, Julia Y.
通讯作者：
Ljubimova, Julia Y.
影响因子：
3
作者：
Araujo, Renata L.;Carvalho, Denise P.
通讯作者：
Carvalho, Denise P.