Theranostics 2019; 9(15):4354-4374. doi:10.7150/thno.35125 This issue Cite

Research Paper

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

Lili Wei#2, Chenyuan Wang#4,9, Xianjue Chen5, Bing Yang6, Kun Shi7, Leah R. Benington8, Lee Yong Lim8, Sanjun Shi3✉, Jingxin Mo1,2✉

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

Citation:
Wei L, Wang C, Chen X, Yang B, Shi K, Benington LR, Lim LY, Shi S, Mo J. 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 2019; 9(15):4354-4374. doi:10.7150/thno.35125. https://www.thno.org/v09p4354.htm
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Abstract

Graphic abstract

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.

Keywords: Orthotopic choriocarcinoma, Ascorbyl phosphate palmitate derivative, Methotrexate, Dual-responsive micelles, NF-κB signaling pathway


Citation styles

APA
Wei, L., Wang, C., Chen, X., Yang, B., Shi, K., Benington, L.R., Lim, L.Y., Shi, S., Mo, J. (2019). 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, 9(15), 4354-4374. https://doi.org/10.7150/thno.35125.

ACS
Wei, L.; Wang, C.; Chen, X.; Yang, B.; Shi, K.; Benington, L.R.; Lim, L.Y.; Shi, S.; Mo, J. 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 2019, 9 (15), 4354-4374. DOI: 10.7150/thno.35125.

NLM
Wei L, Wang C, Chen X, Yang B, Shi K, Benington LR, Lim LY, Shi S, Mo J. 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 2019; 9(15):4354-4374. doi:10.7150/thno.35125. https://www.thno.org/v09p4354.htm

CSE
Wei L, Wang C, Chen X, Yang B, Shi K, Benington LR, Lim LY, Shi S, Mo J. 2019. 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. 9(15):4354-4374.

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