Enhanced Percutaneous Delivery of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) Methane for Skin Cancer Chemoprevention.

Abstract

Skin cancer has high incidence in the United States and is mainly caused by ultraviolet B (UVB) radiation. In this study, we demonstrated the role of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (DIM-D) in the prevention of skin photocarcinogenesis using an in vivo UVB-induced skin cancer model. We also evaluated the efficiency of oleic acid-modified nanostructured lipid carriers to deliver DIM-D across the skin barrier into the epidermis for chemopreventive activity. Nanocarriers were 203.00 ± 21.21 nm in diameter with polydispersity, zeta potential and entrapment efficiency of 0.33 ± 0.01, 37.17 ± 0.90 mV and 93.64 ± 0.65%, respectively. Oleic acid-modified nanocarriers were incorporated into Hydroxypropyl methylcellulose to form DIM-D-Nanogel (DIM-D-N). DIM-D-N pretreatment prior to UVB exposure delayed tumor initiation and reduced tumor multiplicity (p < 0.05) at the end of the study compared to Epigallocatechin gallate (EGCG) gel pretreatment. DIM-D-N pretreatment decreased UVB-induced damage to skin lipids and proteins (p < 0.05), respectively by 7.63 and 2.56-fold less than EGCG gel pretreatment and by 17.86 and 11.92-fold less than UVB-only treatment. Histology showed rete-ridge extension, epidermal thickening and hyperkeratosis for UVB-only treatment and EGCG gel pretreatment; DIM-D-N pretreatment showed similar features as the negative control. Western blot analysis showed increased Nurr1 expression (p < 0.05) for DIM-D-N pretreated group compared to EGCG gel (4.68-fold). DIM-D-N pretreatment reduced BCI-2 expression (p < 0.05) but increased Bax and cPARP. Knock down studies with Nurr1 siRNA reduced the expressions of Nurr1 and cPARP by 8.18 and 1.45-fold, respectively (p < 0.05). Our results suggest the role of DIM-D in skin cancer chemoprevention mediated by possible molecular therapeutic targets such as Nurr1.

• Authors: Cedar H A Boakye, Punit P Shah, Ravi Doddapaneni, Apurva R Patel, Stephen Safe, Mandip Singh
• Journal: Journal of biomedical nanotechnology (J Biomed Nanotechnol) Vol. 11 Issue 7 Pg. 1269-81 (Jul 2015) ISSN: 1550-7033 [Print] United States
• PMID: 26307849 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 1,1-bis(3'-indolyl)methane
• Antineoplastic Agents
• Indoles
• Nanocapsules

Topics

• Animals
• Antineoplastic Agents (administration & dosage, chemistry)
• Cell Line, Tumor
• Diffusion
• Drug Synergism
• Female
• Indoles (administration & dosage, chemistry)
• Mice
• Mice, Nude
• Nanocapsules (chemistry, ultrastructure)
• Neoplasms, Radiation-Induced (etiology, metabolism, prevention & control)
• Particle Size
• Skin Absorption
• Skin Neoplasms (etiology, metabolism, prevention & control)
• Ultraviolet Rays (adverse effects)