Zhang Libo, Ren Zhen, Lü Jinhui, Mo Xinhai, Lin Jie, Li Ya, Ma Wenjing, Liu Pengfei, Shen Yajing, Zhao Qian, Qian Lu, Cheng Xiaoxin, Yu Zuoren, Zhang Bo
Department of Ultrasound Medicine, Shanghai East Hospital, Nanjing Medical University, 150 Jimo Road, Shanghai, China.
Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Cell Death Discov. 2023 Aug 15;9(1):298. doi: 10.1038/s41420-023-01594-9.
Nanomaterials have been well demonstrated to have the potential to be used for tumor cell-targeted drug delivery. Targeted inhibition of miR-221 was proved to promote the sensitivity of triple genitive breast cancer (TNBC) cells to chemo-drugs. In order to improve the chemotherapeutic effect in TNBC, herein, we developed a novel kind of nanoparticles shelled with PLGA and loaded with perfluoropentane (PFP), paclitaxel (PTX), and anti-miR-221 inhibitor, which was named PANP. Ultrasound-triggered vaporization of PFP in PANPs was utilized for real-time imaging track of the nanoparticles in vivo. In addition, macrophages were applied for the internalization of PANPs to form RAW-PANP with strong chemotaxis to accumulate around cancer cells. Nanoparticles with different contents did not cause M2 polarization compared with the control group but caused polarization toward M1. We compared the inherent tumor-homing behavior of macrophages containing different contents with that of normal macrophages and no significant abnormalities were observed. After injection into the tumor-burden mice, RAW-PANPs showed enrichment within tumor tissues. Upon the ultrasound cavitation-triggered burst, PTX was released in the tumor. Meanwhile, the release of anti-miR-221 improved the sensitivity of tumor cells to PTX. As a result, RAW-PANPs showed high efficiency in suppressing TNBC cell proliferation in vitro and inhibiting tumor growth and progression in vivo. The treatments did not induce liver, heart, or kidney injury. In conclusion, the current study not only developed a macrophage-carried, ultrasound-triggered, cancer cell-targeted chemotherapeutic system, but also demonstrated a miRNA-based technique to promote drug sensitivity of cancer cells, which holds strong potential to treat patients with TNBC, especially for those suffering drug-resistance. The innovation of this study is to use macrophages to deliver nanoparticles to the tumors and then use ultrasound locally to burst the nanoparticles to release the miRNA and PTX.
纳米材料已被充分证明有潜力用于肿瘤细胞靶向给药。靶向抑制miR-221被证明可提高三阴性乳腺癌（TNBC）细胞对化疗药物的敏感性。为了提高TNBC的化疗效果，在此，我们开发了一种新型纳米颗粒，其外壳为聚乳酸-羟基乙酸共聚物（PLGA），负载全氟戊烷（PFP）、紫杉醇（PTX）和抗miR-221抑制剂，命名为PANP。利用超声触发PANP中PFP的汽化实现纳米颗粒在体内的实时成像追踪。此外，巨噬细胞用于内化PANP以形成对癌细胞具有强趋化性并在其周围聚集的RAW-PANP。与对照组相比，不同含量的纳米颗粒未引起M2极化，但引起向M1极化。我们比较了含有不同含量的巨噬细胞与正常巨噬细胞的固有肿瘤归巢行为，未观察到明显异常。注射到荷瘤小鼠体内后，RAW-PANPs在肿瘤组织中富集。在超声空化触发的爆裂作用下，PTX在肿瘤中释放。同时，抗miR-221的释放提高了肿瘤细胞对PTX的敏感性。结果，RAW-PANPs在体外高效抑制TNBC细胞增殖，在体内抑制肿瘤生长和进展。这些治疗未诱导肝、心或肾损伤。总之，当前研究不仅开发了一种巨噬细胞携带、超声触发、癌细胞靶向的化疗系统，还证明了一种基于miRNA的促进癌细胞药物敏感性的技术，这对治疗TNBC患者，尤其是那些耐药患者具有强大潜力。本研究的创新之处在于利用巨噬细胞将纳米颗粒递送至肿瘤，然后利用局部超声使纳米颗粒爆裂以释放miRNA和PTX。
