Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer.
Polymalic acid nanobioconjugate for simultaneous immunostimulation and inhibition of tumor growth in HER2/neu-positive breast cancer.
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DOI：
10.1016/j.jconrel.2013.06.001
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发表时间：
2013-11-10
期刊：
影响因子：
--
通讯作者：
Ljubimova JY
中科院分区：
文献类型：
--
作者：
Ding H;Helguera G;Rodríguez JA;Markman J;Luria-Pérez R;Gangalum P;Portilla-Arias J;Inoue S;Daniels-Wells TR;Black K;Holler E;Penichet ML;Ljubimova JY
乳腺癌仍然是美国女性癌症死亡的第二大原因。如果肿瘤过度表达癌蛋白 HER2/neu，则乳腺癌预后尤其差。 Polycefin 家族抗癌药物的一种新型纳米生物结合物基于可生物降解且无毒的聚苹果酸 (PMLA)，经过精心设计，可对 HER2/neu 阳性乳腺癌细胞进行多管齐下的攻击。抗体细胞因子融合蛋白由免疫刺激性细胞因子白细胞介素 2 (IL-2) 与人 HER2/neu 特异性抗体 [抗 HER2/neu IgG3-(IL-2)] 基因融合组成，共价连接到 PMLA 主链，以靶向表达 HER2/neu 的肿瘤，并确保将 IL-2 递送到肿瘤微环境。反义寡核苷酸（AON）与纳米药物缀合，抑制血管肿瘤蛋白层粘连蛋白411的表达，从而阻断肿瘤血管生成。结果表明，纳米生物缀合物能够特异性结合人 HER2/neu 并保留 IL-2 的生物活性。我们还展示了 HER2/neu 阳性乳腺癌细胞对纳米生物缀合物的摄取，并增强了体内肿瘤靶向性。此外，纳米生物缀合物能够在携带表达人 HER2/neu 的 D2F2/E2 鼠乳腺肿瘤的免疫活性小鼠中引发抗肿瘤活性。与单独使用抗体-细胞因子融合蛋白处理的动物或对照动物相比，使用 PMLA 融合纳米生物缀合物处理的动物的 IgG1 和 IgG2a 水平均显着增加，表明诱导了体液 (TH2) 和细胞介导的 (TH1) 免疫反应。使用具有融合 [抗 HER2/neu IgG3-(IL-2)] 抗体的领先纳米生物缀合物治疗后，动物体内存活时间显着延长，p < 0.05。这些分子在单一聚合平台上的组合预计将通过直接消除癌细胞、抑制肿瘤血管生成以及协调针对肿瘤的有效免疫反应来发挥作用。
Breast cancer remains the second leading cause of cancer death among women in the United States. The breast cancer prognosis is particularly poor in case of tumors overexpressing the oncoprotein HER2/neu. A new nanobioconjugate of the Polycefin family of anti-cancer drugs based on biodegradable and non-toxic polymalic acid (PMLA) was engineered for a multi-pronged attack on HER2/neu-positive breast cancer cells. An antibody cytokine fusion protein consisting of the immunostimulatory cytokine interleukin-2 (IL-2) genetically fused to an antibody specific for human HER2/neu [anti-HER2/neu IgG3-(IL-2)] was covalently attached to the PMLA backbone to target HER2/neu expressing tumors and ensuring the delivery of IL-2 to the tumor microenvironment. Antisense oligonucleotides (AON) were conjugated to the nanodrug to inhibit the expression of vascular tumor protein laminin-411 in order to block tumor angiogenesis. It is shown that the nanobioconjugate was capable of specifically binding human HER2/neu and retaining the biological activity of IL-2. We also showed the uptake of the nanobioconjugate by HER2/neu-positive breast cancer cells and enhanced tumor targeting in vivo. In addition, the nanobioconjugate was capable of eliciting anti-tumor activity in immunocompetent mice bearing D2F2/E2 murine mammary tumors that express human HER2/neu. Both IgG1 and IgG2a levels were significantly increased in animals treated with the PMLA-fusion nanobioconjugate compared to animals treated with the antibody–cytokine fusion protein alone or control animals, indicative of the induction of a humoral (TH2) and cell-mediated (TH1) immune responses. Animal survival in vivo was significantly longer after treatment with leading nanobioconjugate with fusion [anti-HER2/neu IgG3-(IL-2)] antibody, p < 0.05. The combination of these molecules on a single polymeric platform is expected to act through direct elimination of cancer cells, inhibition of tumor angiogenesis, and orchestration of a potent immune response against tumor.
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影响因子：
10.8
作者：
Fujita, Manabu;Lee, Bong-Seop;Ljubimova, Julia Y.
通讯作者：
Ljubimova, Julia Y.
影响因子：
14
作者：
Ding, Hui;Portilla-Arias, Jose;Patil, Rameshwar;Black, Keith L.;Ljubimova, Julia Y.;Holler, Eggehard
通讯作者：
Holler, Eggehard
DOI：
10.1073/pnas.1003919107
发表时间：
2010-10-19
影响因子：
11.1
作者：
Ding, Hui;Inoue, Satoshi;Ljubimova, Julia Y.
通讯作者：
Ljubimova, Julia Y.
影响因子：
4.8
作者：
Fujiwara, H;Kikkawa, Y;Sekiguchi, K
通讯作者：
Sekiguchi, K
影响因子：
5.7
作者：
Helguera, G;Rodríguez, JA;Penichet, ML
通讯作者：
Penichet, ML