Self-Nanoemulsifying Drug Delivery System of Genkwanin: A Novel Approach for Anti-Colitis-Associated Colorectal Cancer

Drug Des Devel Ther. 2021 Feb 12:15:557-576. doi: 10.2147/DDDT.S292417. eCollection 2021.

Abstract

Purpose: The aim of the present study was to develop an optimized Genkwanin (GKA)-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation to enhance the solubility, intestinal permeability, oral bioavailability and anti-colitis-associated colorectal cancer (CAC) activity of GKA.

Methods: We designed a SNEDDS comprised oil phase, surfactants and co-surfactants for oral administration of GKA, the best of which were selected by investigating the saturation solubility, constructing pseudo-ternary phase diagrams, followed by optimizing thermodynamic stability, emulsification efficacy, self-nanoemulsification time, droplet size, transmission electron microscopy (TEM), drug release and intestinal permeability. In addition, the physicochemical properties and pharmacokinetics of GKA-SNEDDS were characterized, and its anti-colitis-associated colorectal cancer (CAC) activity and potential mechanisms were evaluated in AOM/DSS-induced C57BL/6J mice model.

Results: The optimized nanoemulsion formula (OF) consists of Maisine CC, Labrasol ALF and Transcutol HP in a weight ratio of 20:60:20 (w/w/w), in which ratio the OF shows multiple improvements, specifically small mean droplet size, excellent stability, fast release properties as well as enhanced solubility and permeability. Pharmacokinetic studies demonstrated that compared with GKA suspension, the relative bioavailability of GKA-SNEDDS was increased by 353.28%. Moreover, GKA-SNEDDS not only significantly prevents weight loss and improves disease activity index (DAI) but also reduces the histological scores of inflammatory cytokine levels as well as inhibiting the formation of colon tumors via inducing tumor cell apoptosis in the AOM/DSS-induced CAC mice model.

Conclusion: Our results show that the developed GKA-SNEDDS exhibited enhanced oral bioavailability and excellent anti-CAC efficacy. In summary, GKA-SNEDDS, using lipid nanoparticles as the drug delivery carrier, can be applied as a potential drug delivery system for improving the clinical application of GKA.

Keywords: anticancer efficacy; insoluble herbal drug; intestinal permeability; nanoparticle-based drug delivery system; pharmacokinetics.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Cell Proliferation / drug effects
  • Colitis / drug therapy*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Daphne / chemistry
  • Dose-Response Relationship, Drug
  • Drug Compounding
  • Drug Delivery Systems*
  • Emulsions
  • Flavones / administration & dosage
  • Flavones / chemistry
  • Flavones / pharmacology*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Nanoparticles / administration & dosage
  • Nanoparticles / chemistry*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Solubility
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents, Phytogenic
  • Emulsions
  • Flavones
  • genkwanin