Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia.
Synergistic enhancement of cancer therapy using a combination of heat shock protein targeted HPMA copolymer-drug conjugates and gold nanorod induced hyperthermia.
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DOI：
10.1016/j.jconrel.2013.04.006
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发表时间：
2013-08-28
期刊：
影响因子：
--
通讯作者：
Ghandehari H
中科院分区：
文献类型：
--
作者：
Larson N;Gormley A;Frazier N;Ghandehari H
在纳米医学领域，选择性递送到癌细胞是一个共同的目标，其中经常采用主动靶向策略来增加肿瘤积聚。在这项研究中，肿瘤热疗被用来作为一种手段，以增加热休克蛋白（HSP）靶向N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-药物缀合物的主动递送。热疗后，诱导表达细胞表面热休克蛋白（HSP）葡萄糖调节蛋白78 kDa（GRP 78）用于靶向药物治疗。合成并表征了带有抗癌剂氨基己基格尔德霉素（AHGDM）、多西他赛（DOC）或顺铂和GRP 78靶向肽WDLAWMFRLPVG的缀合物。评价了与人前列腺癌DU 145细胞表面上表达的热休克蛋白GRP 78的细胞表面结合。HSP靶向的AHGDM和DOC缀合物表现出与天然靶向肽相当的活性结合。然后在体外评估它们与中度高温（43°C，30分钟）组合协同诱导细胞毒性的能力。HSP靶向DOC缀合物对DU 145细胞表现出高效力，IC 50为2.4 nM。HSP靶向AHGDM和DOC缀合物与热疗组合显示协同效应，组合指数值分别为0.65和0.45。基于这些结果，选择HSP靶向DOC缀合物用于体内评价。在DU 145荷瘤小鼠中，通过金纳米棒介导的等离子体光热疗法诱导的肿瘤高热的单次治疗和以10 mg/kg静脉内施用HSP靶向的HPMA共聚物-多西他赛导致维持肿瘤消退30天的时间。这些结果表明肿瘤热疗增加HSP靶向大分子化疗药物的递送的潜力。
In the field of nanomedicine, selective delivery to cancer cells is a common goal, where active targeting strategies are often employed to increase tumor accumulation. In this study, tumor hyperthermia was utilized as a means to increase the active delivery of heat shock protein (HSP) targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates. Following hyperthermia, induced expression of cell surface heat shock protein (HSP) glucose regulated protein 78 kDa (GRP78) was utilized for targeted drug therapy. Conjugates bearing the anticancer agents aminohexylgeldanamycin (AHGDM), docetaxel (DOC), or cisplatin and the GRP78 targeting peptide WDLAWMFRLPVG were synthesized and characterized. Binding to cell surface expressed heat shock protein GRP78 on the surface of human prostate cancer DU145 cells was evaluated. HSP targeted AHGDM and DOC conjugates demonstrated active binding comparable to native targeting peptide. They were then assessed in vitro for the ability to synergistically induce cytotoxicity in combination with moderate hyperthermia (43°C, 30 min.). HSP targeted DOC conjugates exhibited high potency against DU145 cells with an IC50 of 2.4 nM. HSP targeted AHGDM and DOC conjugates demonstrated synergistic effects in combination with hyperthermia with combination index values of 0.65 and 0.45 respectively. Based on these results, HSP targeted DOC conjugates were selected for in vivo evaluation. In DU145 tumor bearing mice, a single treatment of tumor hyperthermia, induced via gold nanorod mediated plasmonic photothermal therapy, and intravenous administration of HSP targeted HPMA copolymer-docetaxel at 10 mg/kg resulted in maintained tumor regression for a period of 30 days. These results demonstrate the potential for tumor hyperthermia to increase the delivery of HSP targeted macromolecular chemotherapeutics.
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DOI：
10.1002/apmc.1978.050700110
发表时间：
1978-01-01
期刊：
ANGEWANDTE MAKROMOLEKULARE CHEMIE
影响因子：
--
作者：
STROHALM, J;KOPECEK, J
通讯作者：
KOPECEK, J
影响因子：
4.9
作者：
Borgman MP;Aras O;Geyser-Stoops S;Sausville EA;Ghandehari H
通讯作者：
Ghandehari H
DOI：
10.1016/j.jconrel.2012.04.014
发表时间：
2012-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Denison TA;Bae YH
通讯作者：
Bae YH
影响因子：
17.4
作者：
Gormley AJ;Larson N;Sadekar S;Robinson R;Ray A;Ghandehari H
通讯作者：
Ghandehari H
影响因子：
5.8
作者：
Hopper-Borge EA;Nasto RE;Ratushny V;Weiner LM;Golemis EA;Astsaturov I
通讯作者：
Astsaturov I