Fang Yuan, Yang Weijing, Cheng Liang, Meng Fenghua, Zhang Jian, Zhong Zhiyuan
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
Biomedical Polymers Laboratory, and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China; Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, PR China.
Acta Biomater. 2017 Dec;64:323-333. doi: 10.1016/j.actbio.2017.10.013. Epub 2017 Oct 10.
Liver cancer is a globally leading malignancy that has a poor five-year survival rate of less than 20%. The systemic chemotherapeutics are generally ineffective for liver cancers partly due to fast clearance and low tumor uptake. Here, we report that GE11 peptide functionalized polymersomal doxorubicin (GE11-PS-DOX) effectively targets and inhibits epidermal growth factor receptor (EGFR)-positive SMMC7721 orthotopic human liver tumor xenografts in mice. GE11-PS-DOX with a GE11 surface density of 10% displayed a high drug loading of 15.4 wt%, a small size of 78 nm, and glutathione-triggered release of DOX. MTT assays, flow cytometry and confocal microscopy studies revealed that GE11-PS-DOX mediated obviously more efficient DOX delivery into SMMC7721 cells than the non-targeting PS-DOX and clinically used liposomal doxorubicin (Lipo-DOX) controls. The in vivo studies showed that GE11-PS-DOX had a long circulation time and an extraordinary accumulation in the tumors (13.3 %ID/g). Interestingly, GE11-PS-DOX caused much better treatment of SMMC7721 orthotopic liver tumor-bearing mice as compared to PS-DOX and Lipo-DOX. The mice treated with GE11-PS-DOX (12 mg DOX equiv./kg) exhibited a significantly improved survival rate (median survival time: 130 days versus 70 and 38 days for PS-DOX at 12 mg DOX equiv./kg and Lipo-DOX at 6 mg DOX equiv./kg, respectively) and achieved 50% complete regression. Notably, GE11-PS-DOX induced obviously lower systemic toxicity than Lipo-DOX. EGFR-targeted multifunctional polymersomal doxorubicin with improved efficacy and safety has a high potential for treating human liver cancers.
Liver cancer is one of the top five leading causes of cancer death worldwide. The systemic chemotherapeutics and biotherapeutics generally have a low treatment efficacy for hepatocellular carcinoma partly due to fast clearance and/or low tumor uptake. Nanomedicines based on biodegradable micelle and polymersomes offer a most promising treatment for malignant liver cancers. Their clinical effectiveness remains, however, suboptimal owing to issues like inadequate systemic stability, low tumor accumulation and selectivity, and poor control over drug release. Here we report that GE11 peptide-functionalized, disulfide-crosslinked multifunctional polymersomal doxorubicin (GE11-PS-DOX) can effectively suppress the growth of orthotopic SMMC7721 human liver tumors in nude mice. They showed significantly decreased systemic toxicity and improved mouse survival rate with 3.4-fold longer median survival time as compared to clinically used pegylated liposomal doxorubicin (Lipo-DOX) and achieving 50% complete regression. GE11-PS-DOX, based on PEG-PTMC is biodegradable, nontoxic, and easy to prepare, appears as a safe, robust, versatile and all-function-in-one nanoplatform that has a high potential in targeted chemotherapy of EGFR expressed hepatocellular carcinoma.
肝癌是一种全球主要的恶性肿瘤，其五年生存率不到20%，情况较差。全身化疗药物对肝癌通常无效，部分原因是药物清除快且肿瘤摄取率低。在此，我们报告GE11肽功能化的聚合物囊泡阿霉素（GE11-PS-DOX）能有效靶向并抑制小鼠体内表皮生长因子受体（EGFR）阳性的SMMC7721原位人肝肿瘤异种移植瘤。表面GE11密度为10%的GE11-PS-DOX具有15.4 wt%的高载药量、78 nm的小尺寸以及谷胱甘肽触发的阿霉素释放。MTT试验、流式细胞术和共聚焦显微镜研究表明，与非靶向的PS-DOX和临床使用的脂质体阿霉素（Lipo-DOX）对照相比，GE11-PS-DOX介导的阿霉素向SMMC7721细胞内的递送效率明显更高。体内研究表明，GE11-PS-DOX具有较长的循环时间，在肿瘤中具有非凡的蓄积（13.3 %ID/g）。有趣的是，与PS-DOX和Lipo-DOX相比，GE11-PS-DOX对携带SMMC7721原位肝肿瘤的小鼠治疗效果要好得多。用GE11-PS-DOX（12 mg阿霉素等效物/kg）治疗的小鼠生存率显著提高（中位生存时间：130天，而12 mg阿霉素等效物/kg的PS-DOX和6 mg阿霉素等效物/kg的Lipo-DOX分别为70天和38天），并实现了50%的完全消退。值得注意的是，GE11-PS-DOX诱导的全身毒性明显低于Lipo-DOX。具有更高疗效和安全性的EGFR靶向多功能聚合物囊泡阿霉素在治疗人类肝癌方面具有很高的潜力。
肝癌是全球癌症死亡的五大主要原因之一。全身化疗药物和生物治疗药物对肝细胞癌的治疗效果通常较低，部分原因是清除快和/或肿瘤摄取率低。基于可生物降解胶束和聚合物囊泡的纳米药物为恶性肝癌提供了最有前景的治疗方法。然而，由于全身稳定性不足、肿瘤蓄积和选择性低以及药物释放控制不佳等问题，它们的临床有效性仍然欠佳。在此我们报告，GE11肽功能化、二硫键交联的多功能聚合物囊泡阿霉素（GE11-PS-DOX）能有效抑制裸鼠体内原位SMMC7721人肝肿瘤的生长。与临床使用的聚乙二醇化脂质体阿霉素（Lipo-DOX）相比，它们的全身毒性显著降低，小鼠生存率提高，中位生存时间延长3.4倍，并实现了50%的完全消退。基于聚乙二醇-聚三亚甲基碳酸酯的GE11-PS-DOX可生物降解、无毒且易于制备，似乎是一种安全、强大、通用且集多种功能于一体的纳米平台，在EGFR表达的肝细胞癌的靶向化疗中具有很高的潜力。
