Enhanced cytotoxicity of optimized liposomal genistein via specific induction of apoptosis in breast, ovarian and prostate carcinomas

J Drug Target. 2013 Dec;21(10):1001-11. doi: 10.3109/1061186X.2013.847099. Epub 2013 Oct 24.

Abstract

Clinical use of genistein against cancer is limited by its extremely low aqueous solubility, poor bioavailability and pharmacokinetics. Based on structural analogy with steroidal compounds, liposomal vehicle compositions were designed and optimized for maximum incorporation of genistein's flavonoid structure. Model conventional and stealth liposomes of genistein (GenLip)--incorporating unsaturated phospholipids and cholesterol--have demonstrated enhanced drug solubilization (over 350-folds > aqueous drug solution), shelf-life stability, and extended release profile. Owing to effective cellular delivery, preservation of genistein's antioxidant activity was confirmed through marked neutralization of peroxides via GenLip, in both quantitative and microscopic fluorescent-probe oxidation assays. Furthermore, significant broad-spectrum anticancer efficacy of GenLip, in murine and human cancer cell lines (p < 0.05-0.001), was achieved in a concentration and time-dependent manner--approx. 5-7 lower IC50 values versus all non-incorporated drug controls. Indicative of key pro-apoptotic activity, GenLip produced DNA laddering, with 1/3 of free drug solution content, and resulted in the highest induction level of P53-independent apoptotic pathway markers, compared to all treatments, in our assays (namely, mitochondrial polarization, and caspase-3/7 enzymes). Our proof-of-principle pharmaceutical design of genistein-loaded liposomes shows optimal loading capacity and physico-chemical properties, which improved cellular delivery and specific pro-apototic effectiveness of incorporated drug, against various cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Antioxidants / administration & dosage
  • Antioxidants / pharmacology
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cholesterol / chemistry
  • Dose-Response Relationship, Drug
  • Drug Delivery Systems
  • Drug Stability
  • Female
  • Genistein / administration & dosage
  • Genistein / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Liposomes
  • Male
  • Mice
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Phospholipids / chemistry
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / pathology
  • Solubility
  • Time Factors

Substances

  • Antineoplastic Agents
  • Antioxidants
  • Liposomes
  • Phospholipids
  • Cholesterol
  • Genistein