Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity.
Copper-doxorubicin as a nanoparticle cargo retains efficacy with minimal toxicity.
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DOI：
10.1021/mp100245u
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发表时间：
2010-12-06
影响因子：
4.9
通讯作者：
Ferrara KW
中科院分区：
文献类型：
--
作者：
Kheirolomoom A;Mahakian LM;Lai CY;Lindfors HA;Seo JW;Paoli EE;Watson KD;Haynam EM;Ingham ES;Xing L;Cheng RH;Borowsky AD;Cardiff RD;Ferrara KW
为了有效治疗高侵袭性肿瘤，通常需要反复施用化疗药物，并经常导致全身毒性。我们已经在脂质体的核心内创建了铜-阿霉素复合物，并将所得到的颗粒应用于多剂量治疗。24小时血池中铜和阿霉素浓度相似（约为注射剂量的40%），表明复合物循环稳定。高度淬灭的阿霉素荧光在血池中保留了数十小时，只有在脂质体破坏和铜转螯合作用的联合作用下，荧光才会增加。注射后48小时，心脏和皮肤内的阿霉素荧光分别为载硫酸铵阿霉素脂质体观察到的荧光的五分之一和二分之一。每周两次给药6 mg/kg阿霉素28天后，阿霉素铜脂质体未检测到全身毒性（心脏肥厚、体重和脱发），但硫酸铵负载的阿霉素脂质体有明显毒性。然后，我们采用了两种旨在提高疗效的策略，mTOR抑制（雷帕霉素）减缓增殖和治疗性超声增强积累和局部扩散。肿瘤积累约为10% ID/g，并且随着治疗性超声的加入而增强约两倍。治疗28天后，同基因肿瘤恢复到~ (1 mm)3的癌前表型或无法检测到。
Repeated administration of chemotherapeutics is typically required for the effective treatment of highly aggressive tumors and often results in systemic toxicity. We have created a copper-doxorubicin complex within the core of liposomes and applied the resulting particle in multi-dose therapy. Copper and doxorubicin concentrations in the blood pool were similar at 24 hours (~40% of the injected dose) indicating stable circulation of the complex. Highly-quenched doxorubicin fluorescence remained in the blood pool over tens of hours, with fluorescence increasing only with the combination of liposome disruption and copper trans-chelation. At 48 hours after injection, doxorubicin fluorescence within the heart and skin was one-fifth and one-half, respectively, of fluorescence observed with ammonium sulfate-loaded doxorubicin liposomes. After 28 days of twice per week doxorubicin administration of 6 mg/kg, systemic toxicity (cardiac hypertrophy and weight and hair loss) was not detected with the copper-doxorubicin liposomes but was substantial with ammonium sulfate-loaded doxorubicin liposomes. We then incorporated two strategies designed to enhance efficacy, mTOR inhibition (rapamycin) to slow proliferation and therapeutic ultrasound to enhance accumulation and local diffusion. Tumor accumulation was ~10% ID/g and was enhanced approximately two-fold with the addition of therapeutic ultrasound. After the 28-day course of therapy, syngeneic tumors regressed to a pre-malignant phenotype of ~ (1 mm)3 or could not be detected.
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影响因子：
10.8
作者：
Chiu, GNC;Abraham, SA;Bally, MB
通讯作者：
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