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Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.
Biomaterials Science ( IF 6.6 ) Pub Date : 2020-06-04 , DOI: 10.1039/d0bm00338g
Zongren Zhao 1 , Jiawei Shen 2 , Long Zhang 1 , Lansheng Wang 1 , Haoyue Xu 1 , Yuhan Han 1 , Jun Jia 1 , Yang Lu 1 , Rutong Yu 3 , Hongmei Liu 3
Affiliation  

Glioma is the most aggressive primary malignant brain tumor. The eradication of the gliomas by performing neurosurgery has not been successful due to the diffuse nature of malignant gliomas. Temozolomide (TMZ) is the first-line agent in treating gliomas after surgery, and its therapeutic efficacy is limited mainly due to the high activity levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in glioma cells. Herein, we used an injectable matrix metalloproteinase (MMP) enzyme responsive hydrogel that loaded TMZ and O6-benzylamine (BG) (MGMT inhibitor) for eradicating residual TMZ-resistant gliomas after surgery. The hydrogels exhibited three features: (1) TMZ and BG could be encapsulated within the hydrophobic lamellae of the hydrogel to form Tm (TMZ + BG) hydrogels; (2) The hydrogels could release TMZ and BG in response to the high concentration of MMP enzymes after glioma surgery; (3) The hydrogels could increase local TMZ concentration and reduce side effects of BG. In vivo, the Tm (TMZ + BG) hydrogels inhibited the MGMT expression and sensitized TMZ-resistant glioma cells to TMZ. Moreover, the Tm (TMZ + BG) hydrogels effectively reduced the recurrence of TMZ-resistant glioma after surgery and significantly enhanced the efficiency of TMZ to inhibit glioma growth. Together, these data suggest that an MMP-responsive hydrogel is a promising localized drug delivery method to inhibit TMZ-resistant glioma recurrence after surgery.

中文翻译:

术后可注射的酶促反应水凝胶可逆转替莫唑胺耐药性并减少神经胶质瘤手术后的局部复发。

胶质瘤是最具侵略性的原发性恶性脑肿瘤。由于恶性神经胶质瘤的扩散性质,通过神经外科手术根除神经胶质瘤尚未成功。替莫唑胺(TMZ)是手术后治疗神经胶质瘤的一线药物,其治疗效果受到限制,主要是因为神经胶质瘤细胞中DNA修复蛋白O 6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)的活性较高。在本文中,我们使用了载有TMZ和O 6的可注射基质金属蛋白酶(MMP)响应性水凝胶-苄胺(BG)(MGMT抑制剂)用于根除术后残留的耐TMZ的神经胶质瘤。该水凝胶表现出三个特征:(1)TMZ和BG可以被包封在水凝胶的疏水薄片中以形成Tm(TMZ + BG)水凝胶;(2)胶质瘤术后高浓度的MMP酶引起水凝胶释放TMZ和BG;(3)水凝胶可增加局部TMZ浓度并减少BG的副作用。体内Tm(TMZ + BG)水凝胶可抑制MGMT表达,并使对TMZ耐药的神经胶质瘤细胞对TMZ敏感。此外,Tm(TMZ + BG)水凝胶可有效减少术后对TMZ耐药的神经胶质瘤的复发,并显着提高TMZ抑制神经胶质瘤生长的效率。总之,这些数据表明,MMP反应性水凝胶是一种有希望的局部药物递送方法,可抑制术后对TMZ耐药的神经胶质瘤的复发。
更新日期:2020-06-04
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