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

Lili Wei, Chenyuan Wang, Xianjue Chen, Bing Yang, Kun Shi, Leah R. Benington, Lee Yong Lim, Sanjun Shi, Jingxin Mo

Research output: Contribution to journalArticle

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 m eth otrexate (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 I kappa B alpha from degradation, which in turn inhibited translocation of NF-kappa B 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.

Original languageEnglish
Pages (from-to)4354-4374
Number of pages21
JournalTheranostics
Volume9
Issue number15
DOIs
Publication statusPublished - 2019

Cite this

Wei, Lili ; Wang, Chenyuan ; Chen, Xianjue ; Yang, Bing ; Shi, Kun ; Benington, Leah R. ; Lim, Lee Yong ; Shi, Sanjun ; Mo, Jingxin. / Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-kappa B Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma. In: Theranostics. 2019 ; Vol. 9, No. 15. pp. 4354-4374.
@article{b8936ac71f674c0dbf2abfbf63abb227,
title = "Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-kappa B Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma",
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 m eth otrexate (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 I kappa B alpha from degradation, which in turn inhibited translocation of NF-kappa B 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-kappa B signaling pathway, ACTINOMYCIN-D, CELL-DEATH, DRUG, NANOPARTICLES, CHEMOTHERAPY, DERIVATIVES, METASTASES, NEOPLASIA, AUTOPHAGY",
author = "Lili Wei and Chenyuan Wang and Xianjue Chen and Bing Yang and Kun Shi and Benington, {Leah R.} and Lim, {Lee Yong} and Sanjun Shi and Jingxin Mo",
year = "2019",
doi = "10.7150/thno.35125",
language = "English",
volume = "9",
pages = "4354--4374",
journal = "Theranostics",
issn = "1838-7640",
publisher = "Ivyspring International Publisher",
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}

Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-kappa B Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma. / Wei, Lili; Wang, Chenyuan; Chen, Xianjue; Yang, Bing; Shi, Kun; Benington, Leah R.; Lim, Lee Yong; Shi, Sanjun; Mo, Jingxin.

In: Theranostics, Vol. 9, No. 15, 2019, p. 4354-4374.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dual-responsive, Methotrexate-loaded, Ascorbic acid-derived Micelles Exert Anti-tumor and Anti-metastatic Effects by Inhibiting NF-kappa B Signaling in an Orthotopic Mouse Model of Human Choriocarcinoma

AU - Wei, Lili

AU - Wang, Chenyuan

AU - Chen, Xianjue

AU - Yang, Bing

AU - Shi, Kun

AU - Benington, Leah R.

AU - Lim, Lee Yong

AU - Shi, Sanjun

AU - Mo, Jingxin

PY - 2019

Y1 - 2019

N2 - 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 m eth otrexate (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 I kappa B alpha from degradation, which in turn inhibited translocation of NF-kappa B 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.

AB - 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 m eth otrexate (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 I kappa B alpha from degradation, which in turn inhibited translocation of NF-kappa B 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.

KW - Orthotopic choriocarcinoma

KW - Ascorbyl phosphate palmitate derivative

KW - Methotrexate

KW - Dual-responsive micelles

KW - NF-kappa B signaling pathway

KW - ACTINOMYCIN-D

KW - CELL-DEATH

KW - DRUG

KW - NANOPARTICLES

KW - CHEMOTHERAPY

KW - DERIVATIVES

KW - METASTASES

KW - NEOPLASIA

KW - AUTOPHAGY

U2 - 10.7150/thno.35125

DO - 10.7150/thno.35125

M3 - Article

VL - 9

SP - 4354

EP - 4374

JO - Theranostics

JF - Theranostics

SN - 1838-7640

IS - 15

ER -