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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.
- Source :
-
Theranostics [Theranostics] 2019 Jun 09; Vol. 9 (15), pp. 4354-4374. Date of Electronic Publication: 2019 Jun 09 (Print Publication: 2019). - Publication Year :
- 2019
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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.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
- Subjects :
- Animals
Antineoplastic Agents pharmacology
Apoptosis drug effects
Cell Line, Tumor
Cell Movement drug effects
Disease Models, Animal
Drug Liberation
Glutathione metabolism
Humans
Hydrogen-Ion Concentration
Methotrexate pharmacology
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Neoplasm Metastasis
Oxidation-Reduction
Polyethylene Glycols chemistry
Proton Magnetic Resonance Spectroscopy
Reactive Oxygen Species metabolism
Succinimides chemistry
Tissue Distribution drug effects
Antineoplastic Agents therapeutic use
Ascorbic Acid chemistry
Choriocarcinoma drug therapy
Choriocarcinoma pathology
Methotrexate therapeutic use
Micelles
NF-kappa B metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 9
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 31285766
- Full Text :
- https://doi.org/10.7150/thno.35125