§Department of Population Health and Pathobiology, North Carolina State University, Raleigh, North Carolina 27607, United States.
ACS Nano. 2015 May 26;9(5):5072-81. doi: 10.1021/acsnano.5b00166. Epub 2015 May 4.
An A10 aptamer (Apt)-functionalized, sub-100 nm doxorubicin-polylactide (Doxo-PLA) nanoconjugate (NC) with controlled release profile was developed as an intravenous therapeutic strategy to effectively target and cytoreduce canine hemangiosarcoma (cHSA), a naturally occurring solid tumor malignancy composed solely of tumor-associated endothelium. cHSA consists of a pure population of malignant endothelial cells expressing prostate-specific membrane antigen (PSMA) and is an ideal comparative tumor model system for evaluating the specificity and feasibility of tumor-associated endothelial cell targeting by A10 Apt-functionalized NC (A10 NC). In vitro, A10 NCs were selectively internalized across a panel of PSMA-expressing cancer cell lines, and when incorporating Doxo, A10 Doxo-PLA NCs exerted greater cytotoxic effects compared to nonfunctionalized Doxo-PLA NCs and free Doxo. Importantly, intravenously delivered A10 NCs selectively targeted PSMA-expressing tumor-associated endothelial cells at a cellular level in tumor-bearing mice and dramatically increased the uptake of NCs by endothelial cells within the local tumor microenvironment. By virtue of controlled drug release kinetics and selective tumor-associated endothelial cell targeting, A10 Doxo-PLA NCs possess a desirable safety profile in vivo, being well-tolerated following high-dose intravenous infusion in mice, as supported by the absence of any histologic organ toxicity. In cHSA-implanted mice, two consecutive intravenous infusions of A10 Doxo-PLA NCs exerted rapid and substantial cytoreductive activities within a period of 7 days, resulting in greater than 70% reduction in macroscopic tumor-associated endothelial cell burden as a consequence of enhanced cell death and necrosis.
一种 A10 适体（Apt）功能化的、亚 100nm 的阿霉素-聚乳酸（Doxo-PLA）纳米复合物（NC）具有可控释放特性，被开发为一种静脉治疗策略，以有效靶向和减少犬血管肉瘤（cHSA），这是一种由肿瘤相关内皮组成的天然发生的实体瘤恶性肿瘤。cHSA 由表达前列腺特异性膜抗原（PSMA）的纯恶性内皮细胞组成，是评估 A10 Apt 功能化 NC（A10 NC）靶向肿瘤相关内皮细胞的特异性和可行性的理想比较肿瘤模型系统。体外，A10 NCs 可选择性地被一组表达 PSMA 的癌细胞系内化，并且当结合 Doxo 时，与非功能化的 Doxo-PLA NCs 和游离 Doxo 相比，A10 Doxo-PLA NCs 发挥更大的细胞毒性作用。重要的是，静脉给予的 A10 NCs 在荷瘤小鼠中以细胞水平选择性地靶向表达 PSMA 的肿瘤相关内皮细胞，并显著增加了内皮细胞在局部肿瘤微环境中对 NCs 的摄取。由于具有控制药物释放动力学和选择性肿瘤相关内皮细胞靶向性，A10 Doxo-PLA NCs 在体内具有理想的安全性特征，在小鼠中进行高剂量静脉输注后耐受性良好，这得益于不存在任何组织器官毒性。在植入 cHSA 的小鼠中，两次连续静脉输注 A10 Doxo-PLA NCs 在 7 天内迅速发挥实质性的细胞减少活性，导致由于增强的细胞死亡和坏死，宏观肿瘤相关内皮细胞负担减少了 70%以上。
