Cationic Poly-L-lysine Dendrimer Complexes Doxorubicin and Delays Tumor Growth in Vitro and in Vivo
Cationic Poly-L-lysine Dendrimer Complexes Doxorubicin and Delays Tumor Growth in Vitro and in Vivo
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DOI：
10.1021/nn305860k
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发表时间：
2013-03-01
期刊：
影响因子：
17.1
通讯作者：
Kostarelos, Kostas
中科院分区：
文献类型：
--
作者：
Al-Jamal, Khuloud T.;Al-Jamal, Wafa' T.;Kostarelos, Kostas
在这项研究中，我们报告的化疗药物阿霉素（DOX）与新的第六代阳离子聚-L-赖氨酸树枝状聚合物（DM）（MW 8149 kDa），我们以前报道表现出全身抗血管生成活性在荷瘤小鼠的络合。通过荧光偏振测量、质子核磁共振光谱和分子建模证实DOX DM络合。与游离DOX相比，DOX DM（以1：10摩尔比）向前列腺3D多细胞肿瘤球体（MTS）中的渗透增强通过共聚焦激光扫描显微镜证实。此外，如生长延迟曲线所示，与游离药物相比，DOX DM复合物在DU 145 MTS系统中实现了显著更高的细胞毒性。与未处理的MTS或用游离DOX处理的MTS相比，用与DM复合的低DOX浓度（1 μ M）孵育MTS导致MTS生长的显著延迟。在荷瘤小鼠的Calu-6肺癌异种移植模型中也实现了DOX DM复合物保留，如通过活体整体动物荧光成像所示。在B16 F10肿瘤跳动小鼠中的治疗实验已经显示当与DM复合时DOX的增强的治疗功效。这项研究表明，阳离子聚-L-赖氨酸DM分子研究，除了他们的全身性抗血管生成的属性，复杂的化疗药物，如DOX和改善其积累和细胞毒性MTS和实体瘤在体内。这种方法为设计抗血管生成/抗癌组合疗法提供了新的能力。
We report in this study the complexation of the chemotherapeutic drug doxorubicin (DOX) with the novel sixth-generation cationic poly-L-lysine dendrimer (DM) (MW 8149 kDa), which we previously reported to exhibit systemic antiangiogenic activity In tumor-bearing mice. DOX DM complexation was confirmed by florescence polarization measurement, proton nuclear magnetic resonance spectroscopy, and molecular modeling. Enhanced penetration of DOX DM (at 1:10 molar ratio), compared to the free DOX, into prostate 3D multicellular tumor spheroids (MTS) was confirmed by confocal laser scanning microscopy. Furthermore, DOX DM complexes achieved a significantly higher cytotoxicity in DU145 MTS system compared to the free drug, as shown by growth delay curves. Incubation of MTS with low DOX concentration (1 mu M) complexed with DM led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX DM complex retention was also achieved In a Calu-6 lung cancer xenograft model In tumor-bearing mice, as shown by live whole animal fluorescence imaging. Therapeutic experiments in B16F10 tumor beating mice have shown enhanced therapeutic efficacy of DOX when complexed to DM. This study suggests that the cationic poly-L-lysine DM molecules studied here could, in addition to their systemic antiangiogenic property, complex chemotherapeutic drugs such as DOX and Improve their accumulation and cytotoxicity into MTS and solid tumors in vivo. Such an approach offers new capabilities for the design of combinatory antiangiogenic/anticancer therapeutics.