Development and In Vitro Evaluation of Linear PEI-Shelled Heparin/Berberine Nanoparticles in Human Osteosarcoma U-2 OS Cells

Molecules. 2018 Nov 28;23(12):3122. doi: 10.3390/molecules23123122.


Berberine (BBR), a natural isoquinoline alkaloid derived from Chinese herbs, exerts many biological effects, including antiviral, antimicrobial, antidiarrhea, anti-inflammatory, and antitumor effects. In this study, a novel berberine nanoparticle (NP) consisting of heparin (HP) and BBR with or without being shelled with linear polyethyleneimine (LPEI) was developed to enhance its antitumor activity on osteosarcoma U-2 OS cells. With varying ratios of HP to BBR, HP/BBR NPs had a size ranging from 218.4 ± 3.9 to 282.0 ± 5.1 nm and zeta potential from -35.7 ± 0.4 to -51.9 ± 1.8 mV. After shelling with LPEI, the resultant NPs (HP/BBR/LPEI) possessed a size ranging from 226.3 ± 3.0 to 405.7 ± 85.2 nm and zeta potential from -46.5 ± 0.3 to -35.6 ± 0.5 mV; the encapsulation rate of BBR was close to 80%. The release profiles of both NPs were revealed to be slower than that of BBR solution. Results also showed that BBR and its two derived NPs reduced the viability of U-2 OS cells, and BBR NPs increased the cellular uptake of BBR. Cells were arrested at the G₁ phase when treated individually with BBR and the two NPs (HP/BBR and HP/BBR/LPEI) and DNA condensation was induced. In addition, BBR and BBR NPs reduced the expression of mouse double minute 2 homolog (MDM2) but increased that of p53, and BBR NPs enhanced apoptotic effects. In short, heparin-based nanoparticles could be potential carriers for osteosarcoma treatment.

Keywords: Berberine; apoptosis; heparin; linear PEI; osteosarcoma.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Berberine* / chemistry
  • Berberine* / pharmacology
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Drug Carriers* / chemistry
  • Drug Carriers* / pharmacology
  • Heparin* / chemistry
  • Heparin* / pharmacology
  • Humans
  • Nanoparticles* / chemistry
  • Nanoparticles* / therapeutic use
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Polyethyleneimine* / chemistry
  • Polyethyleneimine* / pharmacology


  • Antineoplastic Agents
  • Drug Carriers
  • Berberine
  • Polyethyleneimine
  • Heparin