Optimization, Characterization and in vivo Evaluation of Paclitaxel-Loaded Folate-Conjugated Superparamagnetic Iron Oxide Nanoparticles

Int J Nanomedicine. 2021 Mar 19:16:2283-2295. doi: 10.2147/IJN.S287434. eCollection 2021.

Abstract

Background: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction.

Methods: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2'-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated.

Results: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1±3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01±1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1±1.66% and 14.8±1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys.

Conclusion: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.

Keywords: anti-nasopharyngeal carcinoma; folic acid; paclitaxel; response surface methodology; superparamagnetic iron oxide nanoparticles; targeted drug delivery.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Drug Liberation
  • Folic Acid / chemistry*
  • Humans
  • Imines / chemistry
  • Inhibitory Concentration 50
  • Magnetic Iron Oxide Nanoparticles / chemistry*
  • Magnetic Iron Oxide Nanoparticles / ultrastructure
  • Nasopharyngeal Carcinoma / drug therapy
  • Nasopharyngeal Carcinoma / pathology
  • Paclitaxel / blood
  • Paclitaxel / pharmacokinetics
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Particle Size
  • Polyethylene Glycols / chemistry
  • Polyethylenes / chemistry
  • Rats
  • Spectrophotometry, Ultraviolet
  • Spectroscopy, Fourier Transform Infrared
  • Static Electricity
  • Succinates / chemistry
  • Tissue Distribution / drug effects

Substances

  • Antineoplastic Agents
  • Imines
  • Polyethylenes
  • Succinates
  • poly(ethylene imine)
  • poly(ethylene succinate)
  • Polyethylene Glycols
  • Folic Acid
  • Paclitaxel