Self-Assembled Dual-Targeted Epirubicin-Hybrid Polydopamine Nanoparticles for Combined Chemo-Photothermal Therapy of Triple-Negative Breast Cancer

Int J Nanomedicine. 2020 Sep 11:15:6791-6811. doi: 10.2147/IJN.S260477. eCollection 2020.

Abstract

Purpose: Folic acid and cyclic arginylglycylaspartic acid peptides were introduced to the surface of negatively charged lipid-coated hybrid polydopamine-cysteine cores for the delivery of epirubicin (EPI) (E/PCF-NPs). The combined chemo-photothermal therapy using E/PCF-NPs for triple-negative breast cancer was evaluated.

Materials and methods: The temperature elevation and thermal toxicity of nanoparticles were studied. The morphology and properties of E/PCF-NPs were characterized by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy. Physicochemical properties, including particle size, zeta potential, drug loading, entrapment efficiency (EE%), stability and in vitro release, were determined. The cell viability, reactive oxygen species (ROS) levels, ratios of oxidized nicotinamide adenine dinucleotide to its reduced form (NAD+/NADH), apoptosis assays, and cellular uptake of E/PCF-NPs were determined on 4T1 cells. Pharmacokinetic studies and tissue distributions were performed and detected by an ultra-high performance liquid chromatography/mass spectrometry system. The antitumor effects of E/PCF-NPs under near-infrared (NIR) laser irradiation were also evaluated.

Results: The sphere-like morphology of E/PCF-NPs showed a high EE%, uniform size of 106.7 nm, remarkable stability, and highly improved cytotoxicity under NIR laser, when compared to that of photothermal treatment alone. In vitro release of EPI from E/PCF-NPs was pH sensitive, and a greater response was achieved under NIR laser irradiation. Compared to chemotherapy or photothermal treatment alone, the combined treatment in vitro significantly inhibited the survival rate of 4T1 cells to 17.7%, induced ROS generation, and reduced NAD+/NADH significantly. Treatment with E/PCF-NPs under irradiation induced 4T1 cell apoptosis in approximately 93.6% cells. In vitro cellular uptake of E/PCF-NPs was time-dependent. The long-circulating and higher tumor accumulation of E/PCF-NPs resulted in complete ablation of breast tumor tissue through the enhanced photothermal effect by NIR laser irradiation-mediated cell apoptosis.

Conclusion: E/PCF-NPs show enhanced anti-cancer effects due to synergistic effects of chemotherapy with photothermal therapy and may be potential therapeutic agents for cancer treatment.

Keywords: L-cysteine; epirubicin; pharmacokinetics; polydopamine nanoparticles; triple-negative breast cancer.

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Survival / drug effects
  • Epirubicin / administration & dosage*
  • Epirubicin / pharmacokinetics
  • Female
  • Humans
  • Hyperthermia, Induced / methods
  • Indoles / administration & dosage
  • Indoles / chemistry*
  • Lasers
  • Mice, Inbred BALB C
  • NAD / metabolism
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Particle Size
  • Phototherapy / methods*
  • Polymers / administration & dosage
  • Polymers / chemistry*
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Temperature
  • Tissue Distribution
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy

Substances

  • Antibiotics, Antineoplastic
  • Indoles
  • Polymers
  • Reactive Oxygen Species
  • polydopamine
  • NAD
  • Epirubicin

Grants and funding

This research was supported by the National Natural Science Foundation of China (No. 81603054 and 81760639), the Jiangxi Provincial Department of Science and Technology (20171BAB215066, 20202ACBL216015, and 20202BABL206157), the Jiangxi Provincial Department of Education (GJJ190666 and GJJ190663), Research project of traditional Chinese medicine of Jiangxi health and Family Planning Commission (2016A008), Young Jinggang Scholar of Jiangxi Province and “1050” Talents Program (Jing Zhang and Xiang Li), New Century Talents Project of Jiangxi Province (Xiang Li and Jing Zhang), and the Jiangxi University of Traditional Chinese Medicine (JXSYLXK-ZHYAO055, JXSYLXK-ZHYAO056, and JXSYLXK-ZHYAO019).