TY - JOUR

T1 - Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen

T2 - part II in vivo pharmacokinetics, antitumor efficacy and hepatotoxicity

AU - Jain, Amit K

AU - Thanki, Kaushik

AU - Jain, Sanyog

PY - 2014/4

Y1 - 2014/4

N2 - PURPOSE: 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.

AB - PURPOSE: 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.

KW - Administration, Oral

KW - Animals

KW - Antineoplastic Agents

KW - Chemistry, Pharmaceutical

KW - Combinatorial Chemistry Techniques

KW - Drug Delivery Systems

KW - Emulsifying Agents

KW - Female

KW - Humans

KW - Liver

KW - MCF-7 Cells

KW - Nanoparticles

KW - Random Allocation

KW - Rats

KW - Rats, Sprague-Dawley

KW - Tamoxifen

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1007/s11095-013-1214-1

DO - 10.1007/s11095-013-1214-1

M3 - Journal article

C2 - 24135934

VL - 31

SP - 946

EP - 958

JO - Pharmaceutical Research

JF - Pharmaceutical Research

SN - 0724-8741

IS - 4

ER -