Therapeutic effects of boronate ester cross-linked injectable hydrogels for the treatment of hepatocellular carcinoma,Biomaterials Science

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Therapeutic effects of boronate ester cross-linked injectable hydrogels for the treatment of hepatocellular carcinoma
Biomaterials Science ( IF 5.8 ) Pub Date : 2021-09-09 , DOI: 10.1039/d1bm00881a
Jae Min Jung ₁ , Seong Han Kim ₁ , V H Giang Phan ₂ , Thavasyappan Thambi ₁ , Doo Sung Lee ₁

Affiliation

Hepatocellular carcinoma is the most common malignancy with a high incidence rate and is the leading cause of cancer-related deaths. Herein, we developed a thermo-responsive hydrogel comprising poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-b-poly(ε-caprolactone-co-lactide (PCLA) that exhibits acidity-accelerated delivery of the tumor-targeting glucuronic acid-bearing doxorubicin (DOX-pH-GA) conjugate into tumor tissues. The PCLA copolymer was post-modified with boronic acid (BA-PCLA) to covalently cross-link with the pH-responsive DOX-pH-GA conjugate. The BA-PCLA copolymer effectively coordinated with the DOX-pH-GA conjugate through the boronate ester formation and showed a lower critical gelation temperature. The DOX conjugated via boronate ester exhibited a sustained release in vitro. Subcutaneous administration of PCLA copolymers formed in situ gels in the subcutaneous layers of Sprague-Dawley rats and degraded after 6 weeks. Similarly, BA-PCLA copolymers coordinated with DOX-pH-GA formed a stable in situ gel in vivo. In vivo imaging studies demonstrated that DOX-pH-GA was released in a sustained manner. The anti-tumor activity of the DOX releasing injectable hydrogel was examined using a HepG2 liver cancer xenograft model. The in vivo antitumor effect demonstrated that the DOX releasing hydrogel depot remarkably suppresses the tumor growth. These results demonstrate that the pH-responsive DOX releasing thermo-responsive hydrogel depot has great potential for application in localized anticancer therapy.

中文翻译：

硼酸酯交联可注射水凝胶治疗肝细胞癌的疗效

肝细胞癌是最常见的恶性肿瘤，发病率高，是癌症相关死亡的主要原因。在本文中，我们开发了一种热响应水凝胶包括聚（ε-己内酯共-丙交酯） - b -聚（乙二醇） - b -聚（ε-己内酯共聚-丙交酯 (PCLA) 表现出酸度加速将靶向肿瘤的带有葡萄糖醛酸的多柔比星 (DOX-pH-GA) 偶联物递送到肿瘤组织中。PCLA 共聚物用硼酸 (BA-PCLA) 进行后改性，以与 pH 响应性 DOX-pH-GA 偶联物共价交联。BA-PCLA 共聚物通过硼酸酯的形成与 DOX-pH-GA 共轭物有效协调，并显示出较低的临界凝胶温度。通过硼酸酯偶联的 DOX在体外表现出持续释放。PCLA 共聚物的皮下给药在 Sprague-Dawley 大鼠的皮下层中形成原位凝胶，并在 6 周后降解。类似地，BA-PCLA 共聚物与 DOX-pH-GA 协调形成稳定的体内原位凝胶。体内成像研究表明 DOX-pH-GA 以持续的方式释放。使用 HepG2 肝癌异种移植模型检查释放 DOX 的可注射水凝胶的抗肿瘤活性。的体内抗肿瘤效果表明，DOX释放水凝胶贮库显着地抑制了肿瘤的生长。这些结果表明，pH 响应性 DOX 释放热响应性水凝胶储库在局部抗癌治疗中具有巨大的应用潜力。

更新日期：2021-10-06

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