Chitosan-based nano-in-microparticle carriers for enhanced oral delivery and anticancer activity of propolis

Int J Biol Macromol. 2016 Nov;92:254-269. doi: 10.1016/j.ijbiomac.2016.07.024. Epub 2016 Jul 7.


This study reports a promising approach to enhance the oral delivery of propolis, improve its aqueous solubility and bioavailability, and allow its controlled release as well as enhancing its anticancer activity. Propolis was standardized then its solubility was improved via formulation into optimized solid dispersion (SD) matrices, and its release was controlled through incorporation into nanoparticles (NPs) of optimized composition followed by further inclusion into chitosan (Cs) microparticles. The anticancer activity of the newly developed propolis-loaded nano-in-microparticles (NIMs) was evaluated against human liver cancer (HepG2) and human colorectal cancer (HCT 116) cells. The prepared SDs, NPs and NIMs were characterized using SEM, TEM, DLS, FTIR, DSC and UV-vis spectrophotometry. The therapeutic efficiency of formulated propolis was bio-assessed via cytotoxicity measurements, mitochondrial dysfunction, apoptosis-induced cell death and cell cycle arrest. The results demonstrated a considerable enhancement in propolis solubility with a controlled release profile in different GIT environments. In-vitro cytotoxicity studies showed that the propolis-loaded NIMs induce more cytotoxic effect on HepG2 cells than HCT-116 cells and mediated three-fold higher therapeutic efficiency than free propolis. The apoptosis assay indicated that the propolis-loaded NIMs induce apoptosis of HepG2 cells and significantly decrease their number in the proliferative G0/G1, S and G2/M phases.

Keywords: Colon cancer; Liver cancer; Nano-in-Microparticles; Oral delivery; PLGA; Pluronic F-108; Propolis; Solid dispersion.

MeSH terms

  • Administration, Oral
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology*
  • Calorimetry, Differential Scanning
  • Cell Cycle Checkpoints
  • Chitosan / chemistry*
  • Chromatography, High Pressure Liquid
  • Drug Carriers / chemistry*
  • Drug Delivery Systems / methods*
  • Drug Liberation
  • HCT116 Cells
  • Hep G2 Cells
  • Humans
  • Microspheres*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Nanoparticles / chemistry*
  • Nanoparticles / ultrastructure
  • Phenols / analysis
  • Propolis / pharmacokinetics*
  • Propolis / pharmacology
  • Reference Standards
  • Solubility
  • Spectroscopy, Fourier Transform Infrared
  • Staining and Labeling


  • Antineoplastic Agents
  • Drug Carriers
  • Phenols
  • Propolis
  • Chitosan