Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy.
Tumor-Penetrating Nanoparticles for Enhanced Anticancer Activity of Combined Photodynamic and Hypoxia-Activated Therapy.
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DOI：
10.1021/acsnano.6b08731
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发表时间：
2017-02-28
期刊：
影响因子：
17.1
通讯作者：
Oupický D
中科院分区：
文献类型：
--
作者：
Wang Y;Xie Y;Li J;Peng ZH;Sheinin Y;Zhou J;Oupický D
肿瘤渗透性差是纳米粒子在抗癌治疗中使用的主要挑战。此外，无法到达远离血管的缺氧肿瘤细胞导致抗肿瘤治疗药物暴露不足，并导致化疗耐药性的发展和转移的增加。在本研究中，我们开发了 iRGD 修饰的纳米颗粒，用于同时向肿瘤递送光敏剂吲哚菁绿 (ICG) 和缺氧激活的前药替拉扎明 (TPZ)。负载 ICG 和 TPZ 的 iRGD 修饰纳米颗粒在体外 3D 肿瘤球体和体内原位乳腺肿瘤中的渗透性均显着提高。 ICG 介导的光动力疗法在近红外激光照射下诱导缺氧，从而激活共同传递的 TPZ 的抗肿瘤活性，从而发挥协同细胞杀伤作用。体内研究表明，纳米颗粒可以在 4T1 原位肿瘤中有效地递送药物组合。 iRGD修饰的组合纳米颗粒有效抑制原发性肿瘤的生长和转移，且副作用最小。结果还表明，与含有单独药物的纳米颗粒混合物相比，在单一纳米颗粒制剂中共同递送 ICG 和 TPZ 具有抗癌益处。该研究证明了肿瘤穿透纳米颗粒与缺氧激活药物治疗相结合的好处，并建立了 PDT 和缺氧激活化疗的递送平台。
Poor tumor penetration is a major challenge for the use of nanoparticles in anticancer therapy. Moreover, the inability to reach hypoxic tumor cells which are distant from blood vessels results in inadequate exposure to antitumor therapeutics and contributes to development of chemoresistance and increased metastasis. In the present study, we developed iRGD-modified nanoparticles for simultaneous tumor delivery of a photosensitizer indocyanine green (ICG) and hypoxia-activated prodrug tirapazamine (TPZ). The iRGD-modified nanoparticles loaded with ICG and TPZ showed significantly improved penetration in both 3D tumor spheroids in vitro and orthotopic breast tumors in vivo. ICG-mediated photodynamic therapy upon irradiation with a near-IR laser induced hypoxia, which activated antitumor activity of the co-delivered TPZ for synergistic cell-killing effect. In vivo studies demonstrated that the nanoparticles could efficiently deliver the drug combination in 4T1 orthotopic tumors. Primary tumor growth and metastasis were effectively inhibited by the iRGD-modified combination nanoparticles with minimal side effects. The results also showed the anticancer benefits of co-delivering ICG and TPZ in single nanoparticle formulation in contrast to a mixture of nanoparticles containing individual drugs. The study demonstrates the benefits of combining tumor-penetrating nanoparticles with hypoxia-activated drug treatment and establishes a delivery platform for PDT and hypoxia-activated chemotherapy.