Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model.
Dendrimer-doxorubicin conjugates exhibit improved anticancer activity and reduce doxorubicin-induced cardiotoxicity in a murine hepatocellular carcinoma model.
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树枝状甲状腺素蛋白偶联物表现出改善的抗癌活性，并在鼠肝细胞癌模型中降低阿霉素诱导的心脏毒性。
DOI：
10.1371/journal.pone.0181944
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Greve JM
中科院分区：
文献类型：
--
作者：
Kuruvilla SP;Tiruchinapally G;Crouch AC;ElSayed MEH;Greve JM
肝细胞癌（HCC）是全球每年癌症相关死亡的第二大原因。最常见的治疗形式，肝动脉输注（HAI），涉及直接注射阿霉素（DOX）到肝动脉。它受到有限的治疗效果和严重毒性（例如心脏毒性）发生的困扰。我们的目标是通过将药物负载到第5代（G5）聚（酰胺基胺）（PAMAM）树枝状聚合物上来提高经由HAI递送的DOX的治疗指数，所述树枝状聚合物经由N-乙酰半乳糖胺（NAcGal）配体靶向肝癌细胞。DOX通过两种不同的酶敏感性连接L3或L4连接到G5分子的表面，以实现肝癌细胞内的可控药物释放。我们先前报道了分别由NAcGal靶向与L3-或L4-DOX键的组合产生的P1和P2颗粒，并且显示出与游离DOX相当的可控DOX释放和对肝癌细胞的毒性。在这项研究中，我们证明，虽然肿瘤内递送游离DOX（1 mg/kg）到荷HCC的nod scid gamma（NSG）小鼠中，与盐水组相比，在30天内实现了2.5倍的肿瘤生长抑制，但以相同DOX剂量递送的P1和P2颗粒分别实现了5.1和4.4倍的抑制。与游离DOX的作用相反，颗粒与人诱导多能干细胞衍生的心肌细胞（hiPSC CM）的孵育显示对单层活力、凋亡诱导或CM电生理学没有作用。此外，磁共振成像显示，P1和P2处理的小鼠在腹膜内给予1 mg/kg DOX 21天后保持心脏功能，与相同剂量的游离DOX组不同，证实P1/P2可以避免DOX诱导的心脏毒性。总之，这些结果突出了P1/P2颗粒改善DOX的治疗指数并为临床HCC治疗提供替代疗法的能力。
Hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer-related deaths every year globally. The most common form of treatment, hepatic arterial infusion (HAI), involves the direct injection of doxorubicin (DOX) into the hepatic artery. It is plagued with limited therapeutic efficacy and the occurrence of severe toxicities (e.g. cardiotoxicity). We aim to improve the therapeutic index of DOX delivered via HAI by loading the drug onto generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers targeted to hepatic cancer cells via N-acetylgalactosamine (NAcGal) ligands. DOX is attached to the surface of G5 molecules via two different enzyme-sensitive linkages, L3 or L4, to achieve controllable drug release inside hepatic cancer cells. We previously reported on P1 and P2 particles that resulted from the combination of NAcGal-targeting with L3- or L4-DOX linkages, respectively, and showed controllable DOX release and toxicity towards hepatic cancer cells comparable to free DOX. In this study, we demonstrate that while the intratumoral delivery of free DOX (1 mg/kg) into HCC-bearing nod scid gamma (NSG) mice achieves a 2.5-fold inhibition of tumor growth compared to the saline group over 30 days, P1 and P2 particles delivered at the same DOX dosage achieve a 5.1- and 4.4-fold inhibition, respectively. Incubation of the particles with human induced pluripotent stem cell derived cardiomyocytes (hiPSC CMs) showed no effect on monolayer viability, apoptosis induction, or CM electrophysiology, contrary to the effect of free DOX. Moreover, magnetic resonance imaging revealed that P1- and P2-treated mice maintained cardiac function after intraperitoneal administration of DOX at 1 mg/kg for 21 days, unlike the free DOX group at an equivalent dosage, confirming that P1/P2 can avoid DOX-induced cardiotoxicity. Taken together, these results highlight the ability of P1/P2 particles to improve the therapeutic index of DOX and offer a replacement therapy for clinical HCC treatment.
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影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
Farokhzad OC
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