Paclitaxel-loaded redox-sensitive nanoparticles based on hyaluronic acid-vitamin E succinate conjugates for improved lung cancer treatment

Int J Nanomedicine. 2018 Mar 15:13:1585-1600. doi: 10.2147/IJN.S155383. eCollection 2018.

Abstract

Background: Lung cancer is the primary cause of cancer-related death worldwide. A redox-sensitive nanocarrier system was developed for tumor-targeted drug delivery and sufficient drug release of the chemotherapeutic agent paclitaxel (PTX) for improved lung cancer treatment.

Methods: The redox-sensitive nanocarrier system constructed from a hyaluronic acid-disulfide-vitamin E succinate (HA-SS-VES, HSV) conjugate was synthesized and PTX was loaded in the delivery system. The physicochemical properties of the HSV nanoparticles were characterized. The redox-sensitivity, tumor-targeting and intracellular drug release capability of the HSV nanoparticles were evaluated. Furthermore, in vitro and in vivo antitumor activity of the PTX-loaded HSV nanoparticles was investigated in a CD44 over-expressed A549 tumor model.

Results: This HSV conjugate was successfully synthesized and self-assembled to form nanoparticles in aqueous condition with a low critical micelle concentration of 36.3 μg mL-1. Free PTX was successfully entrapped into the HSV nanoparticles with a high drug loading of 33.5% (w/w) and an entrapment efficiency of 90.6%. Moreover, the redox-sensitivity of the HSV nanoparticles was confirmed by particle size change of the nanoparticles along with in vitro release profiles in different reducing environment. In addition, the HA-receptor mediated endocytosis and the potency of redox-sensitivity for intracellular drug delivery were further verified by flow cytometry and confocal laser scanning microscopic analysis. The antitumor activity results showed that compared to redox-insensitive nanoparticles and Taxol®, PTX-loaded redox-sensitive nanoparticles exhibited much greater in vitro cytotoxicity and apoptosis-inducing ability against CD44 over-expressed A549 tumor cells. In vivo, the PTX-loaded HSV nanoparticles possessed much higher antitumor efficacy in an A549 mouse xenograft model and demonstrated improved safety profile. In summary, our PTX-loaded redox-sensitive HSV nanoparticles demonstrated enhanced antitumor efficacy and improved safety of PTX.

Conclusion: The results of our study indicated the redox-sensitive HSV nanoparticle was a promising nanocarrier for lung cancer therapy.

Keywords: nanoparticles; redox-sensitive; tumor targeting.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Drug Delivery Systems / methods*
  • Drug Liberation
  • Humans
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / chemistry
  • Lung Neoplasms / drug therapy*
  • Mice, Inbred BALB C
  • Micelles
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Oxidation-Reduction
  • Paclitaxel / administration & dosage*
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology
  • Particle Size
  • Xenograft Model Antitumor Assays
  • alpha-Tocopherol / analogs & derivatives
  • alpha-Tocopherol / chemistry

Substances

  • Antineoplastic Agents
  • CD44 protein, human
  • Hyaluronan Receptors
  • Micelles
  • Hyaluronic Acid
  • alpha-Tocopherol
  • Paclitaxel