Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity.
Nanoparticle delivery of chemosensitizers improve chemotherapy efficacy without incurring additional toxicity.
复制标题
DOI：
10.1039/c4nr07102f
复制
发表时间：
2015-02-14
期刊：
影响因子：
6.7
通讯作者：
Wang AZ
中科院分区：
文献类型：
--
作者：
Caster JM;Sethi M;Kowalczyk S;Wang E;Tian X;Nabeel Hyder S;Wagner KT;Zhang YA;Kapadia C;Man Au K;Wang AZ
化疗增敏剂可以提高化疗的治疗指数，克服化疗耐药。化学增敏剂的成功翻译取决于能够优先将化学增敏剂递送至肿瘤同时避免正常组织的策略的发展。我们假设化学增敏剂的纳米颗粒（NP）制剂可以改善它们向肿瘤的递送，这反过来可以改善它们的治疗指数。为了证明这种方法的原理，我们设计了两种化学增敏剂的NP制剂，PI3激酶抑制剂渥曼菌素（Wtmn）和PARP抑制剂奥拉帕尼。分别使用肺癌细胞和乳腺癌细胞评估NP Wtmn和NP奥拉帕尼作为化学增敏剂。我们发现Wtmn在所有测试的肺癌细胞系中是有效的化疗增敏剂，与单独药物相比，减少肿瘤细胞生长20%至60%。NP制剂在体外没有降低其功效。奥拉帕尼作为游离药物或在NP制剂中显示出不太一致的化学增敏作用。使用肺癌小鼠模型进一步评估NP Wtmn作为化疗增敏剂。我们发现，NP Wtmn是一种有效的化疗增敏剂，并且比游离Wtmn更有效，当与依托泊苷一起给药时，与游离Wtmn相比，显示出肿瘤生长减少32%。重要的是，NP Wtmn能够使多药耐药H69AR细胞对依托泊苷敏感。此外，NP Wtmn和依托泊苷化疗的组合没有显著增加毒性。本研究证明了使用化疗增敏药物的NP制剂提高化疗治疗指数的原理。
Chemosensitizers can improve the therapeutic index of chemotherapy and overcome treatment resistance. Successful translation of chemosensitizers depends on the development of strategies that can preferentially deliver chemosensitizers to tumors while avoiding normal tissue. We hypothesized that nanoparticle (NP) formulation of chemosensitizers can improve their delivery to tumors which can in turn improve their therapeutic index. To demonstrate the proof of principle of this approach, we engineered NP formulations of two chemosensitizers, the PI3-kindase inhibitor wortmanin (Wtmn) and the PARP inhibitor olaparib. NP Wtmn and NP olaparib were evaluated as chemosensitizers using lung cancer cells and breast cancer cells respectively. We found Wtmn to be an efficient chemosensitizer in all tested lung-cancer cell lines reducing tumor cell growth between 20 and 60% compared to drug alone. NP formulation did not decrease its efficacy in vitro. Olaparib showed less consistent chemosensitization as a free drug or in NP formulation. NP Wtmn was further evaluated as a chemosensitizer using mouse models of lung cancer. We found that NP Wtmn is an effective chemosensitizer and more effective than free Wtmn showing a 32% reduction in tumor growth compared to free Wtmn when given with etoposide. Importantly, NP Wtmn was able to sensitize the multi-drug resistant H69AR cells to etoposide. Additionally, the combination of NP Wtmn and etoposide chemotherapy did not significantly increase toxicity. The present study demonstrates the proof of principle of using NP formulation of chemosensitizing drugs to improve the therapeutic index of chemotherapy.
登录
查看更多内容
DOI：
10.1073/pnas.1120508109
发表时间：
2012-05-22
影响因子：
11.1
作者：
Karve, Shrirang;Werner, Michael E.;Wang, Andrew Z.
通讯作者：
Wang, Andrew Z.
影响因子：
4.7
作者：
Shah GM;Robu M;Purohit NK;Rajawat J;Tentori L;Graziani G
通讯作者：
Graziani G
影响因子：
7.3
作者：
Menear, Keith A.;Adcock, Claire;Martin, Niall M. B.
通讯作者：
Martin, Niall M. B.
影响因子：
78.8
作者：
Jain, Rakesh K.;Stylianopoulos, Triantafyllos
通讯作者：
Stylianopoulos, Triantafyllos
DOI：
10.1158/1078-0432.ccr-09-2434
发表时间：
2010-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Evers B;Schut E;van der Burg E;Braumuller TM;Egan DA;Holstege H;Edser P;Adams DJ;Wade-Martins R;Bouwman P;Jonkers J
通讯作者：
Jonkers J