Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid

PLoS One. 2014 Mar 10;9(3):e89919. doi: 10.1371/journal.pone.0089919. eCollection 2014.


Background: The poor bioavailability of Berberine (BBR) and Betulinic acid (BA) limits the development of these promising anticancer agents for clinical use. In the current study, BBR and BA in spray dried (SD) mucoadhesive microparticle formulations were prepared.

Methods: A patented dual channel spray gun technology established in our laboratory was used for both formulations. Gastrointestinal (GI) permeability studies were carried out using Caco-2 cell monolayer grown in in-vitro system. The oral bioavailability and pharmacokinetic profile of SD formulations were studied in Sprague Dawley rats. A549 orthotopic and H1650 metastatic NSCLC models were utilized for the anticancer evaluations.

Results: Pharmacokinetic studies demonstrated that BBR and BA SD formulations resulted in 3.46 and 3.90 fold respectively, significant increase in plasma Cmax concentrations. AUC levels were increased by 6.98 and 7.41 fold in BBR and BA SD formulations, respectively. Compared to untreated controls groups, 49.8 & 53.4% decrease in the tumor volumes was observed in SD formulation groups of BBR and BA, respectively. Molecular studies done on excised tumor (A549) tissue suggested that BBR in SD form resulted in a significant decrease in the survivin, Bcl-2, cyclin D1, MMP-9, HIF-1α, VEGF and CD31 expressions. Cleaved caspase 3, p53 and TUNEL expressions were increased in SD formulations. The RT-PCR analysis on H1650 tumor tissue suggested that p38, Phospho-JNK, Bax, BAD, cleaved caspase 3&8 mRNA expressions were significantly increased in BA SD formulations. Chronic administration of BBR and BA SD formulations did not show any toxicity.

Conclusions: Due to significant increase in oral bioavailability and superior anticancer effects, our results suggest that spray drying is a superior alternative formulation approach for oral delivery of BBR and BA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Berberine / administration & dosage
  • Berberine / pharmacokinetics*
  • Berberine / pharmacology*
  • Berberine / therapeutic use
  • Biological Availability
  • Blotting, Western
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Chemistry, Pharmaceutical
  • Clone Cells
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice, Nude
  • Pentacyclic Triterpenes
  • Rats, Sprague-Dawley
  • Triterpenes / administration & dosage
  • Triterpenes / pharmacokinetics*
  • Triterpenes / pharmacology*
  • Triterpenes / therapeutic use
  • Vascular Endothelial Growth Factor A / metabolism


  • Antineoplastic Agents
  • Pentacyclic Triterpenes
  • Triterpenes
  • Vascular Endothelial Growth Factor A
  • Berberine
  • betulinic acid