通过基于 HPMA 共聚物的具有 pH 值敏感性的纳米疗法同时递送 STAT3 抑制剂和多柔比星,实现对肿瘤的化疗增敏

IF 4.2 2区 医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Nanomedicine : nanotechnology, biology, and medicine Pub Date : 2023-12-27 DOI:10.1016/j.nano.2023.102730
M. Kovář PhD , V. Šubr PhD , K. Běhalová MSc , M. Studenovský PhD , D. Starenko MSc , J. Kovářová PhD , P. Procházková PhD , T. Etrych PhD, DSc , L. Kostka PhD
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摘要

我们合成了三种新型 STAT3 抑制剂(S3iD1-S3iD3),它们具有氧化庚酸残基,可通过 pH 敏感的腙键与 HPMA 共聚物载体连接。我们合成了含有多柔比星(Dox)和 STAT3 抑制剂的 HPMA 共聚物共轭物,以评估多柔比星和 STAT3 抑制剂联合递送到肿瘤中的抗癌效果。S3iD1-3 及其共聚物结合的对应物(P-S3iD1-P-S3iD3)在五种小鼠和人类癌细胞系中显示出相当高的体外细胞抑制活性,IC50 分别为 ~0.6-7.9 μM 和 0.7-10.9 μM。S3iD2 和 S3iD3 被证实能抑制 STAT3 信号通路。HPMA共聚物结合Dox(P-Dox)和P-S3iD3以可忽略不计的毒性剂量组合在B16F10黑色素瘤小鼠中显示出显著的抗肿瘤活性,15只小鼠中有2只完全治愈。而单用 P-Dox 的治疗活性明显较低,没有完全治愈的小鼠。因此,含有 STAT3 抑制剂的聚合物共轭物可用于化疗难治性肿瘤的化疗增敏。
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Chemosensitization of tumors via simultaneous delivery of STAT3 inhibitor and doxorubicin through HPMA copolymer-based nanotherapeutics with pH-sensitive activation

We synthesized three novel STAT3 inhibitors (S3iD1-S3iD3) possessing oxoheptanoic residue enabling linkage to HPMA copolymer carrier via a pH-sensitive hydrazone bond. HPMA copolymer conjugates bearing doxorubicin (Dox) and our STAT3 inhibitors were synthesized to evaluate the anticancer effect of Dox and STAT3 inhibitor co-delivery into tumors. S3iD1–3 and their copolymer-bound counterparts (P-S3iD1-P-S3iD3) showed considerable in vitro cytostatic activities in five mouse and human cancer cell lines with IC50 ~0.6–7.9 μM and 0.7–10.9 μM, respectively. S3iD2 and S3iD3 were confirmed to inhibit the STAT3 signaling pathway. The combination of HPMA copolymer-bound Dox (P-Dox) and P-S3iD3 at the dosage showing negligible toxicity demonstrated significant antitumor activity in B16F10 melanoma-bearing mice and completely cured 2 out of 15 mice. P-Dox alone had a significantly lower therapeutic activity with no completely cured mice. Thus, polymer conjugates bearing STAT3 inhibitors may be used for the chemosensitization of chemorefractory tumors.

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来源期刊
CiteScore
11.10
自引率
0.00%
发文量
133
审稿时长
42 days
期刊介绍: The mission of Nanomedicine: Nanotechnology, Biology, and Medicine (Nanomedicine: NBM) is to promote the emerging interdisciplinary field of nanomedicine. Nanomedicine: NBM is an international, peer-reviewed journal presenting novel, significant, and interdisciplinary theoretical and experimental results related to nanoscience and nanotechnology in the life and health sciences. Content includes basic, translational, and clinical research addressing diagnosis, treatment, monitoring, prediction, and prevention of diseases.
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