Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan, Taiwan.
Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
Int J Nanomedicine. 2023 Jul 28;18:4253-4274. doi: 10.2147/IJN.S412932. eCollection 2023.
Cancer multidrug resistance (MDR) is an important factor that severely affects the chemotherapeutic efficacy. Among various methods to bypass MDR, usage of cytokines, such as tumor necrosis factor alpha (TNFα) is attractive, which exerts antitumor effects of immunotherapeutic response and apoptotic/proinflammatory pathways. Nevertheless, the challenges remain how to implement targeted delivery of TNFα to reduce toxicity and manifest the involved signaling mechanism that subdues MDR.
We synthesized a multifunctional nanosytem, in which TNFα covalently bound to doxorubicin (Dox)-loaded pH-responsive mesoporous silica nanoparticles (MSN) through bi-functional polyethylene glycol (TNFα-PEG-MSN-Hydrazone-Dox) as a robust design to overcome MDR.
The salient features of this nanoplatform are: 1) by judicious tailoring of TNFα concentration conjugated on MSN, we observed it could lead to a contrary effect of either proliferation or suppression of tumor growth; 2) the MSN-TNFα at higher concentration serves multiple functions, besides tumor targeting and inducer of apoptosis through extrinsic pathway, it inhibits the expression level of p-glycoprotein (P-gp), a cell membrane protein that functions as a drug efflux pump; 3) the enormous surface area of MSN provides for TNFα functionalization, and the nanochannels accommodate chemotherapeutics, Dox; 4) targeted intracellular release of Dox through the pH-dependent cleavage of hydrazone bonds induces apoptosis by the specific intrinsic pathway; and 5) TNFα-PEG-MSN-Hydrazone-Dox (MSN-Dox-TNFα) could infiltrate deep into the 3D spheroid tumor model through disintegration of tight junction proteins. When administered intratumorally in a Dox-resistant mouse tumor model, MSN-Dox-TNFα exhibited a synergistic therapeutic effect through the collective performances of TNFα and Dox.
We hereby develop and demonstrate a multifunctional MSN-Dox-TNFα system with concentration-tailored TNFα that can abrogate the drug resistance mechanism, and significantly inhibit the tumor growth through both intrinsic and extrinsic apoptosis pathways, thus making it a highly potential nanomedicine translated in the treatment of MDR tumors.
癌症多药耐药（MDR）是严重影响化疗疗效的重要因素。在克服 MDR 的各种方法中，使用细胞因子（如肿瘤坏死因子-α（TNFα））很有吸引力，因为它具有免疫治疗反应和凋亡/炎症途径的抗肿瘤作用。然而，如何实现 TNFα 的靶向递送来降低毒性并表现出涉及抑制 MDR 的相关信号机制仍然是一个挑战。
我们合成了一种多功能纳米系统，其中 TNFα 通过双功能聚乙二醇（TNFα-PEG-MSN-腙-Dox）共价结合到载多柔比星（Dox）的 pH 响应介孔硅纳米颗粒（MSN）上，作为克服 MDR 的强大设计。
该纳米平台的突出特点是：1）通过精心调整 MSN 上结合的 TNFα 浓度，我们观察到它可能导致肿瘤生长的增殖或抑制的相反效果；2）较高浓度的 MSN-TNFα 除了通过外在途径靶向肿瘤和诱导细胞凋亡外，还具有抑制细胞膜蛋白 P-糖蛋白（P-gp）表达水平的多种功能，P-gp 作为药物外排泵起作用；3）MSN 的巨大表面积为 TNFα 的功能化提供了条件，纳米通道容纳了化疗药物多柔比星；4）通过腙键的 pH 依赖性裂解靶向细胞内释放多柔比星，通过特定的内在途径诱导细胞凋亡；5）TNFα-PEG-MSN-腙-Dox（MSN-Dox-TNFα）可以通过破坏紧密连接蛋白渗透到 3D 球体肿瘤模型的深处。在多柔比星耐药的小鼠肿瘤模型中瘤内给药时，MSN-Dox-TNFα 通过 TNFα 和多柔比星的协同作用表现出协同治疗效果。
我们开发并展示了一种具有浓度可调 TNFα 的多功能 MSN-Dox-TNFα 系统，该系统可以消除耐药机制，并通过内在和外在凋亡途径显著抑制肿瘤生长，因此它是一种很有潜力的纳米药物，可以转化为治疗 MDR 肿瘤的方法。
