Division of Radiation Oncology, Mayo Clinic and Foundation, 200 First Street, Rochester, MN 55905, USA.
Department of Cell and Molecular Biology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Molecules. 2022 May 24;27(11):3371. doi: 10.3390/molecules27113371.
The anticancer agent doxorubicin(dox) has been widely used in the treatment of a variety of hematological malignancies and solid tumors. Despite doxorubicin's efficiency in killing tumor cells, severe damage to healthy tissues, along with cardiotoxicity, limits its clinical use. To overcome these adverse side effects, improve patient safety, and enhance therapeutic efficacy, we have designed a thermally responsive biopolymer doxorubicin carrier that can be specifically targeted to tumor tissue by locally applying mild hyperthermia (41 °C). The developed drug vehicle is composed of the following: a cell penetrating peptide (SynB1) to promote tumor and cellular uptake; thermally responsive Elastin-like polypeptide (ELP); and the (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH) containing a pH-sensitive hydrazone linker that releases doxorubicin in the acidic tumor environment. We used the in vivo imaging system, IVIS, to determine biodistribution of doxorubicin-delivered ELP in MDA-MB-231 xenografts in nude mice. Tumor bearing mice were treated with a single IV injection of 10 mg/kg doxorubicin equivalent dose with free doxorubicin, thermally responsive SynB1 ELP 1-DOXO, and a thermally nonresponsive control biopolymer, SynB1 ELP 2-DOXO. Following a 2 h treatment with hyperthermia, tumors showed a 2-fold higher uptake when treated with SynB1 ELP 1-DOXO compared to free doxorubicin. Accumulation of the thermally non-responsive control SynB1 ELP2 -DOXO was comparable to free doxorubicin, indicating that an increase in dox accumulation with ELP is due to aggregation in response to thermal targeting. Higher levels of SynB1 ELP1-DOXO and SynB1 ELP2 -DOXO with respect to free doxorubicin were observed in kidneys. Fluorescence intensity from hearts of animals treated with SynB1 ELP1-DOXO show a 5-fold decrease in accumulation of doxorubicin than the same dose of free doxorubicin. SynB1-ELP1-DOXO biopolymers demonstrated a 6-fold increase in tumor/heart ratio in comparison to free doxorubicin, indicating preferential accumulation of the drug in tumors. These results demonstrate that thermally targeted polymers are a promising therapy to enhance tumor targeting and uptake of anticancer drugs and to minimize free drug toxicity in healthy tissues, representing a great potential for clinical application.
阿霉素（dox）是一种抗癌药物，已广泛用于治疗各种血液系统恶性肿瘤和实体肿瘤。尽管阿霉素在杀死肿瘤细胞方面具有高效性，但它对健康组织的严重损害以及心脏毒性限制了其临床应用。为了克服这些不良反应，提高患者安全性并增强治疗效果，我们设计了一种热敏生物聚合物阿霉素载体，通过局部应用温和的热疗（41°C）可以特异性靶向肿瘤组织。所开发的药物载体由以下组成：细胞穿透肽（SynB1）以促进肿瘤和细胞摄取；热敏弹性蛋白样多肽（ELP）；以及阿霉素的（6-马来酰亚胺基己酰基）腙衍生物（DOXO-EMCH），其中包含在酸性肿瘤环境中释放阿霉素的 pH 敏感腙接头。我们使用体内成像系统（IVIS）确定了阿霉素递送的 ELP 在裸鼠 MDA-MB-231 异种移植物中的生物分布。荷瘤小鼠接受单次静脉注射 10mg/kg 阿霉素等效剂量的游离阿霉素、热敏 SynB1 ELP 1-DOXO 和热敏非响应性对照生物聚合物 SynB1 ELP 2-DOXO。在接受 2 小时热疗治疗后，与游离阿霉素相比，用 SynB1 ELP 1-DOXO 处理的肿瘤摄取量增加了 2 倍。热敏非响应性对照 SynB1 ELP2-DOXO 的积累与游离阿霉素相当，表明 ELP 中阿霉素积累的增加是由于热靶向引起的聚集。与游离阿霉素相比，在肾脏中观察到更高水平的 SynB1 ELP1-DOXO 和 SynB1 ELP2-DOXO。用 SynB1 ELP1-DOXO 处理的动物心脏的荧光强度显示阿霉素的积累比相同剂量的游离阿霉素减少了 5 倍。与游离阿霉素相比，SynB1-ELP1-DOXO 生物聚合物的肿瘤/心脏比值增加了 6 倍，表明药物在肿瘤中的优先积累。这些结果表明，热敏靶向聚合物是一种有前途的治疗方法，可增强肿瘤靶向和抗癌药物的摄取，并最大限度地减少健康组织中游离药物的毒性，为临床应用提供了巨大潜力。
