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 Jun 9;9(15):4354-4374. doi: 10.7150/thno.35125. eCollection 2019.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Apoptosis / drug effects
  • Ascorbic Acid / chemistry*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Choriocarcinoma / drug therapy*
  • Choriocarcinoma / pathology*
  • Disease Models, Animal
  • Drug Liberation
  • Glutathione / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Methotrexate / pharmacology
  • Methotrexate / therapeutic use*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Micelles*
  • NF-kappa B / metabolism*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Oxidation-Reduction
  • Polyethylene Glycols / chemistry
  • Proton Magnetic Resonance Spectroscopy
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Succinimides / chemistry
  • Tissue Distribution / drug effects

Substances

  • Antineoplastic Agents
  • Micelles
  • NF-kappa B
  • Reactive Oxygen Species
  • Succinimides
  • Polyethylene Glycols
  • polyethylene glycol bis(succinimidyl succinate)
  • Glutathione
  • Ascorbic Acid
  • Methotrexate