Synthesis and in vivo antitumor efficacy of PEGylated poly(l-lysine) dendrimer-camptothecin conjugates.
Synthesis and in vivo antitumor efficacy of PEGylated poly(l-lysine) dendrimer-camptothecin conjugates.
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DOI：
10.1021/mp9001206
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发表时间：
2009-09
影响因子：
4.9
通讯作者：
Szoka FC
中科院分区：
文献类型：
--
作者：
Fox ME;Guillaudeu S;Fréchet JM;Jerger K;Macaraeg N;Szoka FC
喜树碱（CPT）的聚合物缀合物一直被寻求作为用CPT及其衍生物治疗癌症中存在的困难的解决方案。CPT与聚合物的共价连接可以提高溶解度，增加血液循环时间，增强肿瘤摄取，并显著提高药物的疗效。在这份报告中，我们描述了一种新的聚合物共轭CPT使用核心功能化，对称聚乙二醇化聚（L-赖氨酸）（PLL）树枝状大分子。PEG化树枝状聚合物由用天冬氨酸官能化的赖氨酸树枝状聚合物组成，其用作聚（乙二醇）（PEG）和CPT的连接位点。最终的缀合物具有40 kDa的分子量，并且负载有4-6重量%的CPT。与游离CPT相比，聚合物结合的CPT显示出具有30.9 ± 8.8小时的长血液循环半衰期和4.2 ± 2.3%注射剂量/g组织的肿瘤摄取，其中游离CPT在30分钟后在血液中保留小于1%，并且具有0.29 ± 0.04%注射剂量/g组织的肿瘤蓄积。与未治疗或伊立替康治疗相比，PEG化PLL-CPT在鼠（C26）和人结肠癌（HT-29）肿瘤模型中显示出上级疗效。在C26肿瘤模型中，对于用单次注射PEG化PLL-CPT治疗的所有小鼠，治疗导致显著延长的存活（P < 0.05）。在HT-29肿瘤模型中，多次注射低剂量的所有小鼠均存活至研究结束，其中8只小鼠中有3只存活无肿瘤。
Polymer conjugates of camptothecin (CPT) have been pursued as a solution to the difficulties present in treating cancers with CPT and its derivatives. Covalent attachment of CPT to a polymer can improve solubility, increase blood circulation time, enhance tumor uptake, and significantly improve efficacy of the drug. In this report, we describe a novel polymer conjugate of CPT using a core-functionalized, symmetrically PEGylated poly(L-lysine) (PLL) dendrimer. The PEGylated dendrimer consisted of a lysine dendrimer functionalized with aspartic acid, which was used as an attachment site for poly(ethylene glycol) (PEG) and CPT. The final conjugate had a molecular weight of 40 kDa and was loaded with 4-6 wt% CPT. Polymer-bound CPT was shown to have a long blood circulation half-life of 30.9 ± 8.8 h and a tumor uptake of 4.2 ± 2.3% of the injected dose/g tissue, compared to free CPT in which less than 1% was retained in the blood after 30 min and had a tumor accumulation of 0.29 ± 0.04% of the injected dose/g tissue. The PEGylated PLL-CPT showed superior efficacy in murine (C26) and human colon carcinoma (HT-29) tumor models when compared with no treatment or treatment with irinotecan. In the C26 tumor model, treatment resulted in significantly prolonged survival (P < 0.05) for all mice treated with a single injection of PEGylated PLL-CPT. In the HT-29 tumor model, all mice treated with multiple injections of a low dose survived to the end of the study, with three mice of eight surviving tumor-free.
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影响因子：
11.5
作者：
Homsi, Jade;Simon, George R.;Daud, Adil I.
通讯作者：
Daud, Adil I.
影响因子：
11.2
作者：
Kukowska-Latallo, JF;Candido, KA;Baker, JR
通讯作者：
Baker, JR
影响因子：
4.7
作者：
Lee, CC;Yoshida, M;Szoka, FC
通讯作者：
Szoka, FC
影响因子：
10.8
作者：
Caiolfa, VR;Zamai, M;Suarato, A
通讯作者：
Suarato, A
影响因子：
5.8
作者：
JENSEN, E;BUNDGAARD, H
通讯作者：
BUNDGAARD, H