title: Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen: part II in vivo pharmacokinetics, antitumor efficacy and hepatotoxicity.
abstract: OBJECTIVE
  The present work focuses on the in vivo evaluation of tamoxifen and quercetin combination loaded into solid self-nanoemulsifying drug delivery system (s-Tmx-QT-SNEDDS).
  
  
  METHODS
  Lyophilization was employed to prepare s-Tmx-QT-SNEDDS using Aerosil 200 as carrier. The developed formulation was evaluated for in vitro cell cytotoxicity, in vivo pharmacokinetics, antitumor efficacy and toxicity studies.
  
  
  RESULTS
  In vivo pharmacokinetics revealed ~8-fold and ~4-fold increase in oral bioavailability of tamoxifen and quercetin, respectively as compared to free counterparts. s-Tmx-QT-SNEDDS exhibited significantly higher cell cytotoxicity, as compared to free drug combination revealing ~32-fold and ~22-fold higher dose reduction index for tamoxifen and quercetin, respectively estimated using median effect dose analysis. s-Tmx-QT-SNEDDS could suppress tumor growth in DMBA induced tumor bearing animals by ~80% in contrast to ~35% observed with tamoxifen citrate. The significant appreciation in antitumor efficacy was further supported by normalized levels of tumor angiogenesis markers (MMP-2 and MMP-9). Finally, complete obliteration in tamoxifen induced hepatotoxicity was observed upon administration of developed formulation in contrast to that of clinically available tamoxifen citrate when measured as function of hepatotoxicity markers and histopathological changes.
  
  
  CONCLUSIONS
  In nutshell, co-encapsulation of quercetin with tamoxifen in solid SNEDDS poses great potential in improving the therapeutic efficacy and safety of tamoxifen.
authors.affiliation: Centre for Pharmaceutical Nanotechnology Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Jain
authors.forename: Kaushik
authors.initials: K
authors.lastname: Thanki
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D002626:Chemistry, Pharmaceutical; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D016503:Drug Delivery Systems / Q000379:methods*; D045703:Emulsifying Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061986:MCF-7 Cells; D053758:Nanoparticles / Q000008:administration & dosage / Q000378:metabolism* / Q000633:toxicity; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D045703:Emulsifying Agents; D013629:Tamoxifen