Center for Nanomedicine and Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, United States.
Nano Lett. 2022 Jan 12;22(1):111-118. doi: 10.1021/acs.nanolett.1c03293. Epub 2021 Dec 28.
Current clinical applications of protein therapy are largely limited to systemically accessible targets in vascular or extracellular areas. Major obstacles to the widespread application of protein therapeutics in cancer treatment include low membrane permeability and endosomal entrapment. Herein, we report a multistage nanoparticle (NP) strategy for systemic and cytosolic protein delivery to tumor cells, by encapsulating a protein conjugate, tetra-guanidinium (TG)-modified saporin, into tumor microenvironment (TME) pH-responsive polymeric NPs. Upon reaching the tumor site after systemic circulation, the polymeric NPs respond rapidly to the acidic tumor microenvironment and release the TG-saporin conjugates, which penetrate the tumor tissue and enter into tumor cells via TG-mediated cytosolic transportation. The TG-saproin NPs showed potent inhibition of lung cancer cell growth in vitro and in vivo. We expect that this multistage NP delivery strategy with long blood circulation, deep tumor penetration, and efficient cytosolic transport may be applicable to various therapeutic proteins for effective cancer treatment.
目前蛋白质疗法的临床应用主要局限于血管或细胞外区域中可全身接触的靶点。蛋白质疗法在癌症治疗中的广泛应用面临的主要障碍包括低膜通透性和内涵体捕获。在此，我们报告了一种多阶段纳米颗粒（NP）策略，用于将蛋白质缀合物，四胍基（TG）修饰的丝裂原蛋白递送至肿瘤细胞，方法是将其包裹在肿瘤微环境（TME）pH 响应性聚合物 NP 中。在系统循环后到达肿瘤部位后，聚合物 NP 会迅速响应酸性肿瘤微环境并释放 TG-丝裂原蛋白缀合物，该缀合物穿透肿瘤组织并通过 TG 介导的细胞质运输进入肿瘤细胞。TG-丝氨酸 NP 在体外和体内均显示出对肺癌细胞生长的强烈抑制作用。我们期望这种具有长血液循环、深肿瘤穿透和高效细胞质转运的多阶段 NP 递药策略可适用于各种治疗性蛋白质，以实现有效的癌症治疗。
