John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, 02138, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, 02115, USA.
Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Biomaterials. 2022 Jan;280:121302. doi: 10.1016/j.biomaterials.2021.121302. Epub 2021 Nov 30.
Monotherapy with a single chemotherapeutic regimen has met with significant hurdles in terms of clinical efficacy. The complexity of cancer accentuates the need for an alternative approach with a combination of two or more therapeutic regimens to win the battle. However, it is still a challenge to develop a successful combination of drugs with high efficiency and low toxicity to control cancer growth. While gemcitabine monotherapy remains a choice of standard treatment for advanced breast cancer, the approach has not prolonged the median survival time of metastatic breast cancer patients. Here, we report a hyaluronic acid (HA)-based drug combination of gemcitabine (GEM) with imiquimod (IMQ) to stimulate immune cells for anticancer activity. Treatment of the drug combination (IMQ-HA-GEM) showed enhanced anticancer activity against 4T1 breast tumor cells in vitro. Our study with a microfluidics-based 3D, compartmentalized cancer model showed that infiltration of THP-1 monocytes occurred particularly at the site of cancer cells treated with IMQ-HA-GEM. Moreover, IMQ-HA-GEM significantly suppressed the volume of 4T1 breast tumor of mice in vivo. Flow cytometry study displayed a significantly higher activation of CD11b immune cells in the blood of mice treated with IMQ-HA-GEM, whereas immunohistochemistry study revealed greater prevalence of CD68 tumor-associated macrophages in the tumor. Histological examination of isolated tumors of mice treated with IMQ-HA-GEM further confirmed the efficacy of drug combination on cancer cells. This study supports the conclusion that imiquimod potentiates the effect of gemcitabine by activating immune cells to suppress tumors in the form of combination nanoparticles.
单一化疗方案的单药治疗在临床疗效方面遇到了重大障碍。癌症的复杂性强调了需要采用两种或多种治疗方案联合的替代方法来赢得这场战斗。然而，开发一种高效低毒的成功药物组合来控制癌症生长仍然是一个挑战。虽然吉西他滨单药治疗仍然是晚期乳腺癌标准治疗的选择，但这种方法并没有延长转移性乳腺癌患者的中位生存时间。在这里，我们报告了一种基于透明质酸（HA）的吉西他滨（GEM）与咪喹莫特（IMQ）药物组合，以刺激免疫细胞发挥抗癌活性。该药物组合（IMQ-HA-GEM）的治疗显示出增强的抗癌活性，可体外抑制 4T1 乳腺癌细胞。我们使用基于微流控的 3D 、分区癌症模型的研究表明，THP-1 单核细胞特别浸润在用 IMQ-HA-GEM 处理的癌细胞部位。此外，IMQ-HA-GEM 显著抑制了体内 4T1 乳腺癌小鼠肿瘤的体积。流式细胞术研究显示，用 IMQ-HA-GEM 治疗的小鼠血液中 CD11b 免疫细胞的激活显著增加，而免疫组织化学研究显示肿瘤中 CD68 肿瘤相关巨噬细胞的流行程度更高。用 IMQ-HA-GEM 治疗的小鼠分离肿瘤的组织学检查进一步证实了药物组合对癌细胞的疗效。这项研究支持这样的结论，即咪喹莫特通过激活免疫细胞来抑制肿瘤，从而增强吉西他滨的效果，这种作用是以组合纳米颗粒的形式实现的。
