A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma.
A sulfur dioxide polymer prodrug showing combined effect with doxorubicin in combating subcutaneous and metastatic melanoma.
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一种二氧化硫聚合物前药，与多柔比星在对抗皮下和转移性黑色素瘤方面表现出联合作用
DOI：
10.1016/j.bioactmat.2020.10.027
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发表时间：
2021-05
影响因子：
18.9
通讯作者：
Xiao C
中科院分区：
文献类型：
--
作者：
An L;Zhang P;Shen W;Yi X;Yin W;Jiang R;Xiao C
黑色素瘤作为最具侵袭性且对治疗有抵抗性的皮肤恶性肿瘤，约占所有皮肤癌死亡病例的80%。它易于侵入真皮并形成远处转移，这大大降低了患者的生存率。因此，对原位黑色素瘤进行早期治疗或及时阻止转移恶化至关重要。在本研究中，设计了一种二氧化硫（SO₂）聚合物前药，它既是一种细胞内谷胱甘肽（GSH）响应的SO₂发生器，又是阿霉素（DOX）的载体，用于治疗皮下和转移性黑色素瘤。首先，将4 - N -（2,4 - 二硝基苯磺酰基）-亚氨基-1 - 丁酸（DIBA）化学偶联到甲氧基聚乙二醇接枝葡聚糖（mPEG - g - Dex）的侧链上，合成了SO₂的两亲性聚合物前药mPEG - g - Dex（DIBA）。所得的mPEG - g - Dex（DIBA）能够自组装成稳定的胶束纳米粒子，并表现出谷胱甘肽响应的SO₂释放行为。随后，将DOX包封到mPEG - g - Dex（DIBA）胶束的核心中，形成载DOX的纳米粒子（PDDN - DOX）。形成的PDDN - DOX能够被B16F10细胞摄取，并同步将DOX和SO₂释放到肿瘤细胞中。结果，由于SO₂的氧化损伤特性和DOX的毒性作用，PDDN - DOX在B16F10黑色素瘤细胞中发挥了协同抗肿瘤作用。此外，体内实验证实PDDN - DOX在治疗皮下和转移性黑色素瘤方面具有巨大潜力。总之，我们目前的工作表明，基于SO₂的气体疗法与化疗药物的结合为抑制黑色素瘤进展和转移提供了一种新途径。
一种新型的SO₂聚合物前药被制备出来，并用作GSH响应的SO₂发生器和DOX的载体。
载DOX的SO₂聚合物前药纳米粒子（称为PDDN - DOX）能够响应GSH同时释放SO₂和DOX。
PDDN - DOX在B16F10黑色素瘤细胞中显示出协同抗癌作用。
PDDN - DOX在治疗皮下和转移性黑色素瘤方面很有前景。
Melanoma, as the most aggressive and treatment-resistant skin malignancy, is responsible for about 80% of all skin cancer mortalities. Prone to invade into the dermis and form distant metastases significantly reduce the patient survival rate. Therefore, early treatment of the melanoma in situ or timely blocking the deterioration of metastases is critical. In this study, a sulfur dioxide (SO2) polymer prodrug was designed as both an intracellular glutathione (GSH)-responsive SO2 generator and a carrier of doxorubicin (DOX), and used for the treatment of subcutaneous and metastatic melanoma. Firstly, chemical conjugation of 4-N-(2,4-dinitrobenzenesulfonyl)-imino-1-butyric acid (DIBA) onto the side chains of methoxy poly (ethylene glycol) grafted dextran (mPEG-g-Dex) resulted in the synthesis of the amphiphilic polymer prodrug of SO2, mPEG-g-Dex (DIBA). The obtained mPEG-g-Dex (DIBA) could self-assemble into stable micellar nanoparticles and exhibited a glutathione-responsive SO2 release behavior. Subsequently, DOX was encapsulated into the core of mPEG-g-Dex (DIBA) micelles to form DOX-loaded nanoparticles (PDDN-DOX). The formed PDDN-DOX could be internalized by B16F10 cells and synchronously release DOX and SO2 into the tumor cells. As a result, PDDN-DOX exerted synergistic anti-tumor effects in B16F10 melanoma cells because of the oxidative damage properties of SO2 and toxic effects of DOX. Furthermore, in vivo experiments verified that PDDN-DOX had great potential for the treatment of subcutaneous and metastasis melanoma. Collectively, our present work demonstrates that the combination of SO2-based gas therapy and chemotherapeutics offers a new avenue for inhibiting melanoma progression and metastases. A novel SO2 polymer prodrug is prepared and used as both a GSH-responsive SO2 generator and a carrier of DOX. The DOX-loaded SO2 polymer prodrug nanoparticles (termed PDDN-DOX) can simultaneously release SO2 and DOX in response to GSH. The PDDN-DOX demonstrates synergistic anticancer effect in B16F10 melanoma cells. The PDDN-DOX is promising for the treatment of subcutaneous and metastatic melanoma.
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