Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-κB Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma.,Theranostics

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Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-κB Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma.
Theranostics ( IF 12.4 ) Pub Date : 2019-01-01 , DOI: 10.7150/thno.35125
Lili Wei ₁ , Chenyuan Wang _{2,

3} , Xianjue Chen ₄ , Bing Yang ₅ , Kun Shi ₆ , Leah R Benington ₇ , Lee Yong Lim ₇ , Sanjun Shi ₈ , Jingxin Mo _{1,

9}

Affiliation

Department of Pharmacy, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China.
Department of Reproductive Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510623, China.
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510623, China.
School of Chemistry, University of New South Wales, Sydney, NSW 2052, Australia.
Department of Gynecology, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China.
Department of Gynecology, Guangzhou Women and Children's Medical Center, Guangzhou 510623, China.
Division of Pharmacy, School of Allied Health, University of Western Australia, Perth, WA 6009, Australia.
Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
Clinical Research Center for Neurological Diseases of Guangxi Province, The Affiliated Hospital of Guilin Medical University, Guilin 541001, China.

Gestational trophoblastic neoplasia (GTN), the most aggressive form of which is choriocarcinoma, can result from over-proliferation of trophoblasts. Treating choriocarcinoma requires high doses of systemic chemotherapeutic agents, which result in nonspecific drug distribution and severe toxicity. To overcome these disadvantages and enhance chemotherapeutic efficacy, we synthesized redox- and pH-sensitive, self-assembling, ascorbic acid-derived (PEG-ss-aAPP) micelles to deliver the drug methotrexate (MTX). Methods: We developed and tested self-assembling PEG-ss-aAPP micelles, which release their drug cargo in response to an intracellular reducing environment and the acidity of the early lysosome or tumoral microenvironment. Uptake into JEG3 choriocarcinoma cancer cells was examined using confocal microscopy and transmission electron microscopy. We examined the ability of MTX-loaded PEG-ss-aAPP micelles to inhibit metastasis in an orthotopic mouse model of human choriocarcinoma. Results: Drug-loaded micelles had encapsulation efficiency above 95%. Particles were spherical based on transmission electron microscopy, with diameters of approximately 229.0 nm based on dynamic light scattering. The drug carrier responded sensitively to redox and pH changes, releasing its cargo in specific environments. PEG-ss-aAPP/MTX micelles efficiently escaped from lysosome/endosomes, and they were effective at producing reactive oxygen species, strongly inducing apoptosis and inhibiting invasion and migration. These effects correlated with the ability of PEG-ss-aAPP/MTX micelles to protect IκBα from degradation, which in turn inhibited translocation of NF-κB p65 to the nucleus. In an orthotopic mouse model of human choriocarcinoma, PEG-ss-aAPP/MTX micelles strongly inhibited primary tumor growth and significantly suppressed metastasis without obvious side effects. Conclusions: Our results highlight the potential of PEG-ss-aAPP micelles for targeted delivery of chemotherapeutic agents against choriocarcinoma.

中文翻译：

通过在人绒毛膜癌的原位小鼠模型中抑制NF-κB信号传导，双重响应的，负载甲氨蝶呤的抗坏血酸衍生的胶束发挥抗肿瘤和抗转移的作用。

滋养细胞过度增殖可导致妊娠滋养细胞赘生物（GTN），其最具有侵略性的形式是绒癌。治疗绒毛膜癌需要高剂量的全身化学治疗剂，这导致药物的非特异性分布和严重的毒性。为了克服这些缺点并增强化学疗法的功效，我们合成了对氧化还原和pH敏感的自组装抗坏血酸衍生（PEG-ss-aAPP）胶束，以递送甲氨蝶呤（MTX）药物。方法：我们开发并测试了自组装PEG-ss-aAPP胶束，该胶束在细胞内还原性环境和早期溶酶体或肿瘤微环境的酸度下释放药物。使用共聚焦显微镜和透射电子显微镜检查JEG3绒毛膜癌细胞的摄取。我们检查了MTX加载的PEG-ss-aAPP胶束抑制人类绒毛膜癌的原位小鼠模型中转移的能力。结果：载药胶束的包封率达到95％以上。基于透射电子显微镜，颗粒是球形的，基于动态光散射，颗粒的直径约为229.0nm。药物载体对氧化还原和pH值变化敏感，在特定环境中释放其货物。PEG-ss-aAPP / MTX胶束有效地从溶酶体/内体中逸出，并有效产生活性氧，强烈诱导细胞凋亡并抑制侵袭和迁移。这些作用与PEG-ss-aAPP / MTX胶束保护IκBα免受降解的能力有关，后者进而抑制了NF-κBp65向核的移位。在人绒癌的原位小鼠模型中，PEG-ss-aAPP / MTX胶束强烈抑制原发性肿瘤生长并显着抑制转移而没有明显的副作用。结论：我们的结果突出了PEG-ss-aAPP胶束在靶向治疗绒毛膜癌的化学治疗剂中的潜力。

更新日期：2019-01-01

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