title: Ultra-flexible nanocarriers for enhanced topical delivery of a highly lipophilic antioxidative molecule for skin cancer chemoprevention.
abstract: OBJECTIVE
  In this study, we developed cationic ultra-flexible nanocarriers (UltraFLEX-Nano) to surmount the skin barrier structure and to potentiate the topical delivery of a highly lipophilic antioxidative diindolylmethane derivative (DIM-D) for the inhibition of UV-induced DNA damage and skin carcinogenesis.
  
  
  METHODS
  UltraFLEX-Nano was prepared with 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-3-trimethylammonium-propane, cholesterol and tween-80 by ethanolic injection method; was characterized by Differential Scanning Calorimetric (DSC), Fourier Transform Infrared (FT-IR) and Atomic Force Microscopic (phase-imaging) analyses and permeation studies were performed in dermatomed human skin. The efficacy of DIM-D-UltraFLEX-Nano for skin cancer chemoprevention was evaluated in UVB-induced skin cancer model in vivo.
  
  
  RESULTS
  DIM-D-UltraFLEX-Nano formed a stable mono-dispersion (110.50±0.71nm) with >90% encapsulation of DIM-D that was supported by HPLC, DSC, FT-IR and AFM phase imaging. The blank formulation was non-toxic to human embryonic kidney cells. UltraFLEX-Nano was vastly deformable and highly permeable across the stratum corneum; there was significant (p<0.01) skin deposition of DIM-D for UltraFLEX-Nano that was superior to PEG solution (13.83-fold). DIM-D-UltraFLEX-Nano pretreatment delayed the onset of UVB-induced tumorigenesis (2 weeks) and reduced (p<0.05) the number of tumors observed in SKH-1 mice (3.33-fold), which was comparable to pretreatment with sunscreen (SPF30). Also, DIM-D-UltraFLEX-Nano caused decrease (p<0.05) in UV-induced DNA damage (8-hydroxydeoxyguanosine), skin inflammation (PCNA), epidermal hyperplasia (c-myc, CyclinD1), immunosuppression (IL10), cell survival (AKT), metastasis (Vimentin, MMP-9, TIMP1) but increase in apoptosis (p53 and p21).
  
  
  CONCLUSIONS
  UltraFLEX-Nano was efficient in enhancing the topical delivery of DIM-D. DIM-D-UltraFLEX-Nano was efficacious in delaying skin tumor incidence and multiplicity in SKH mice comparable to sunscreen (SPF30).
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Cedar H A
authors.initials: CHA
authors.lastname: Boakye
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Doddapaneni
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Arvind
authors.initials: A
authors.lastname: Bagde
authors.affiliation: Florida A&M College of Pharmacy, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Behl
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
authors.forename: Nusrat
authors.initials: N
authors.lastname: Chowdhury
authors.affiliation: Department of Veterinary Physiology and Pharmacology, Texas A&M University, TX 77843, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA. Electronic address: mandip.sachdeva@gmail.com.
authors.forename: Mandip
authors.initials: M
authors.lastname: Singh
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000031:analogs & derivatives / Q000737:chemistry; D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology / Q000528:radiation effects; D018890:Chemoprevention / Q000379:methods; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000494:pharmacology; D004339:Drug Compounding; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010539:Permeability; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000737:chemistry; D012867:Skin; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000975:Antioxidants; C530105:Ccnd1 protein, mouse; D004337:Drug Carriers; D005229:Fatty Acids, Monounsaturated; C556062:IL10 protein, mouse; D007211:Indoles; C489428:Myc protein, mouse; D018809:Proliferating Cell Nuclear Antigen; D016271:Proto-Oncogene Proteins c-myc; D000644:Quaternary Ammonium Compounds; D016159:Tumor Suppressor Protein p53; D016753:Interleukin-10; D019938:Cyclin D1; D015060:1,2-Dipalmitoylphosphatidylcholine; C081581:colfosceril palmitate; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane
keywords: Chemoprevention; Diindolymethane (DIM); Phytochemicals; Skin cancer; Skin delivery; Topical delivery; Ultra deformable nanocarriers