Wang Zhuoran, Guo Jianwen, Sun Jiawei, Liang Ping, Wei Yan, Deng Xuliang, Gao Weiping
Department of Biomedical Engineering School of Medicine Tsinghua University Beijing 100084 P. R. China.
Department of Neurosurgery Beijing Tsinghua Changgung Hospital School of Clinical Medicine Tsinghua University Beijing 102218 P. R. China.
Adv Sci (Weinh). 2019 Jun 14;6(16):1900586. doi: 10.1002/advs.201900586. eCollection 2019 Aug 21.
Protein-polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature-responsive and matrix metalloproteinase (MMP)-cleavable conjugate of interferon alpha (IFNα) and elastin-like polypeptide (ELP) is reported with spatiotemporally programmed two-step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1-month zero-order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease-cleavable protein-polymer conjugates with spatiotemporally programmed two-step release kinetics for tumor treatment.
与天然蛋白质相比，蛋白质-聚合物偶联物显示出改善的药代动力学，但生物活性和肿瘤穿透性降低，导致抗肿瘤疗效有限。为了解决这一困境，本文报道了一种对体温有响应且可被基质金属蛋白酶（MMP）切割的干扰素α（IFNα）与弹性蛋白样多肽（ELP）的偶联物的基因工程，其具有用于肿瘤治疗的时空编程两步释放动力学。值得注意的是，该偶联物皮下注射后可发生相分离形成储存库，导致1个月的零级释放动力学。此外，它可以被肿瘤中过表达的MMP选择性切割，从而从ELP中释放IFNα，进而恢复IFNα的生物活性。因此，在两种黑色素瘤和卵巢肿瘤小鼠模型中，与游离IFNα相比，它表现出显著增强的肿瘤积累、肿瘤穿透性和抗肿瘤疗效。这些发现可能为肿瘤治疗提供一种具有时空编程两步释放动力学的热响应性和蛋白酶可切割蛋白质-聚合物偶联物的智能技术。
