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Solidified Self-Nanoemulsifying Formulation for Oral Delivery of Combinatorial Therapeutic Regimen: Part II In vivo Pharmacokinetics, Antitumor Efficacy and Hepatotoxicity

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Abstract

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.

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References

  1. Jain AK, Thanki K, Jain S. Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral Bioavailability, antitumor efficacy, and drug-Induced toxicity. Mol Pharmaceutics. 2013. doi:10.1021/mp400311j.

    Google Scholar 

  2. Thanki K, Gangawal RP, Sangamwar AT, Jain S. Oral delivery of anticancer drugs: challenges and opportunities. J Control Rel. 2013;170(1):15–40.

    Article  CAS  Google Scholar 

  3. Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205–13.

    Article  CAS  PubMed  Google Scholar 

  4. Jain AK, Swarnakar NK, Godugu C, Singh RP, Jain S. The effect of the oral administration of polymeric nanoparticles on the efficacy and toxicity of tamoxifen. Biomaterials. 2012;32(2):503–15.

    Article  Google Scholar 

  5. Lettéron P, Labbe G, Degott C, Berson A, Fromenty B, Delaforge M, et al. Mechanism for the protective effects of silymarin against carbon tetrachloride-induced lipid peroxidation and hepatotoxicity in mice: evidence that silymarin acts both as an inhibitor of metabolic activation and as a chain-breaking antioxidant. Biochem Pharmacol. 1990;39(12):2027–34.

    Article  PubMed  Google Scholar 

  6. McVie JG, Simonetti GP, Stevenson D, Briggs RJ, Guelen PJ, de Vos D. The bioavailability of Tamoplex (tamoxifen). Part 1. A pilot study. Methods Find Exp Clin Pharmacol. 1986;8(8):505–12.

    CAS  PubMed  Google Scholar 

  7. Tukker JJ, Blankenstein MA, Nortier JW. Comparison of bioavailability in man of tamoxifen after oral and rectal administration. J Pharm Pharmacol. 1986;38(12):888–92.

    Article  CAS  PubMed  Google Scholar 

  8. Middleton E, Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev. 2000;52(4):673–751.

    CAS  PubMed  Google Scholar 

  9. Boots AW, Haenen G, Bast A. Health effects of quercetin: from antioxidant to nutraceutical. Eur J Pharmacol. 2008;585(2–3):325–37.

    Google Scholar 

  10. Piantelli M, Maggiano N, Ricci R, Larocca LM, Capelli A, Scambia G, et al. Tamoxifen and quercetin interact with type II estrogen binding sites and inhibit the growth of human melanoma cells. J Invest Dermatol. 1995;105(2):248–53.

    Article  CAS  PubMed  Google Scholar 

  11. Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, et al. Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential. Int J Cancer. 2000;87(4):595–600.

    Article  CAS  PubMed  Google Scholar 

  12. Sartippour MR, Pietras R, Marquez-Garban DC, Chen HW, Heber D, Henning SM, et al. The combination of green tea and tamoxifen is effective against breast cancer. Carcinogenesis. 2006;27(12):2424–33.

    Article  CAS  PubMed  Google Scholar 

  13. Ma ZS, Thanh HOAH, Chee Pang NG, Phuc Tien DO, Thanh HN, Hung H. Reduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferation. Int J Oncol. 2004;24(5):1297–304.

    CAS  PubMed  Google Scholar 

  14. Brookes PS, Digerness SB, Parks DA, Darley-Usmar V. Mitochondrial function in response to cardiac ischemia-reperfusion after oral treatment with quercetin. Free Radic Biol Med. 2002;32(11):1220–8.

    Article  CAS  PubMed  Google Scholar 

  15. Liu S, Hou W, Yao P, Li N, Zhang B, Hao L, et al. Heme oxygenase-1 mediates the protective role of quercetin against ethanol-induced rat hepatocytes oxidative damage. Toxicol In Vitro. 2012;26(1):74–80.

    Article  CAS  PubMed  Google Scholar 

  16. Gupta C, Vikram A, Tripathi DN, Ramarao P, Jena GB. Antioxidant and antimutagenic effect of quercetin against DEN induced hepatotoxicity in rat. Phytother Res. 2010;24(1):119–28.

    Article  CAS  PubMed  Google Scholar 

  17. Abo-Salem OM, Abd-Ellah MF, Ghonaim MM. Hepatoprotective activity of quercetin against acrylonitrile induced hepatotoxicity in rats. J Biochem Mol Toxicol. 2011;25(6):386–92.

    Article  CAS  PubMed  Google Scholar 

  18. Tabassum H, Parvez S, Rehman H, Banerjee BD, Raisuddin S. Catechin as an antioxidant in liver mitochondrial toxicity: inhibition of tamoxifen induced protein oxidation and lipid peroxidation. J Biochem Mol Toxicol. 2007;21(3):110–7.

    Article  CAS  PubMed  Google Scholar 

  19. Granado-Serrano AB, Martin MA, Bravo L, Goya L, Ramos S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J Nutr. 2006;136(11):2715–21.

    CAS  PubMed  Google Scholar 

  20. Caltagirone S, Ranelletti FO, Rinelli A, Maggiano N, Colasante A, Musiani P, et al. Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer. Am J Respir Cell Mol Biol. 1997;17(1):51–9.

    Article  CAS  PubMed  Google Scholar 

  21. Ma ZS, Huynh TH, Ng CP, Do PT, Nguyen TH, Huynh H. Reduction of CWR22 prostate tumor xenograft growth by combined tamoxifen-quercetin treatment is associated with inhibition of angiogenesis and cellular proliferation. Int J Oncol. 2004;24(5):1297–304.

    CAS  PubMed  Google Scholar 

  22. Lama G, Angelucci C, Bruzzese N, Nori SL, D’Atri S, Turriziani M, et al. Sensitivity of human melanoma cells to oestrogens, tamoxifen and quercetin: is there any relationship with type I and II oestrogen binding site expression? Melanoma Res. 1998;8(4):313–22.

    Article  CAS  PubMed  Google Scholar 

  23. Date AA, Nagarsenker MS, Patere S, Dhawan V, Gude RP, Hassan PA, et al. Lecithin-based novel cationic nanocarriers (Leciplex) II: improving therapeutic efficacy of quercetin on oral administration. Mol Pharmaceutics. 2011;8(3):716–26.

    Article  CAS  Google Scholar 

  24. Jain S, Jain AK, Pohekar M, Thanki K. Novel self-emulsifying formulation of quercetin for improved in vivo antioxidant potential: implications on drug induced cardiotoxicity and nephrotoxicity. Free Radic Biol Med. 2013;65C:117–30.

    Article  Google Scholar 

  25. Zhigaltsev IV, Maurer N, Akhong Q-F, Leone R, Leng E, Wang J, et al. Liposome-encapsulated vincristine, vinblastine and vinorelbine: a comparative study of drug loading and retention. J Control Rel. 2005;104(1):103–11.

    Article  CAS  Google Scholar 

  26. Bayne WF, Mayer LD, Swenson CE. Pharmacokinetics of CPX–351 (cytarabine/daunorubicin HCl) liposome injection in the mouse. J Pharm Sci. 2009;98(7):2540–8.

    Article  CAS  PubMed  Google Scholar 

  27. Misra R, Sahoo SK. Coformulation of doxorubicin and curcumin in poly (D, L-lactide-co-glycolide) nanoparticles suppresses the development of multidrug resistance in K562 cells. Mol Pharmaceutics. 2011;8(3):852–66.

    Article  CAS  Google Scholar 

  28. Acharya S, Sahoo SK. Sustained targeting of Bcr–Abl+ leukemia cells by synergistic action of dual drug loaded nanoparticles and its implication for leukemia therapy. Biomaterials. 2011;32(24):5643–62.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang L, Radovic–Moreno AF, Alexis F, Gu FX, Basto PA, Bagalkot V, et al. Co–delivery of hydrophobic and hydrophilic drugs from nanoparticle–aptamer bioconjugates. Chemmedchem. 2007;2(9):1268–71.

    Article  CAS  PubMed  Google Scholar 

  30. Song XR, Cai Z, Zheng Y, He G, Cui FY, Gong DQ, et al. Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles. Eur J Pharm Sci. 2009;37(3):300–5.

    Article  CAS  PubMed  Google Scholar 

  31. Lammers T, Subr V, Ulbrich K, Peschke P, Huber PE, Hennink WE, et al. Simultaneous delivery of doxorubicin and gemcitabine to tumors in vivo using prototypic polymeric drug carriers. Biomaterials. 2009;30(20):3466–75.

    Article  CAS  PubMed  Google Scholar 

  32. Krakovičová H, Etrych T, Ulbrich K. HPMA-based polymer conjugates with drug combination. Eur J Pharm Sci. 2009;37(3):405–12.

    Article  PubMed  Google Scholar 

  33. Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, et al. Co–delivery of doxorubicin and Bcl–2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug–resistant cancer cells. Small. 2009;5(23):2673–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Kaneshiro TL, Lu Z-R. Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier. Biomaterials. 2009;30(29):5660–6.

    Article  CAS  PubMed  Google Scholar 

  35. Pouton CW. Formulation of self-emulsifying drug delivery systems. Adv Drug Deliv Rev. 1997;25(1):47–58.

    Article  CAS  Google Scholar 

  36. Neslihan Gursoy R, Benita S. Self-emulsifying drug delivery systems (SEDDS) for improved oral delivery of lipophilic drugs. Biomed Pharmacother. 2004;58(3):173–82.

    Article  CAS  PubMed  Google Scholar 

  37. Tang B, Cheng G, Gu JC, Xu CH. Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms. Drug Discov Today. 2008;13(13):606–12.

    Article  CAS  PubMed  Google Scholar 

  38. Jain S, Chauhan DS, Jain AK, Swarnakar NK, Harde H, Mahajan RR, et al. Stabilization of the nanodrug delivery systems by lyophilization using universal step-wise freeze drying cycle. Indian Patent Application No 2559/DEL/2011 filed on September 06, 2011.

  39. Swarnakar NK, Thanki K, Jain S. Effect of co-administration of CoQ10-loaded nanoparticles on the efficacy and cardiotoxicity of doxorubicin-loaded nanoparticles. RSC Adv. 2013;3:14671–85.

    Article  CAS  Google Scholar 

  40. Jain AK, Swarnakar NK, Das M, Godugu C, Singh RP, Rao PR, et al. Augmented anticancer efficacy of doxorubicin loaded polymeric nanoparticles after oral administration in breast cancer induced animal model. Mol Pharm. 2011;8(4):1140–51.

    Article  CAS  PubMed  Google Scholar 

  41. Chung SY, Sung MK, Kim NH, Jang JO, Go EJ, Lee HJ. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharm Res. 2005;28(7):823–8.

    Article  CAS  PubMed  Google Scholar 

  42. Shin SC, Choi JS, Li X. Enhanced bioavailability of tamoxifen after oral administration of tamoxifen with quercetin in rats. Int J Pharm. 2006;313(1):144–9.

    Article  CAS  PubMed  Google Scholar 

  43. Bachynsky MO, Shah NH, Patel CI, Malick AW. Factors affecting the efficiency of a self-emulsifying oral delivery system. Drug Dev Ind Pharm. 1997;23(8):809–16.

    Article  CAS  Google Scholar 

  44. Oliver G, Alitalo K. The lymphatic vasculature: recent progress and paradigms. Annu Rev Cell Dev Biol. 2005;21:457–83.

    Article  CAS  PubMed  Google Scholar 

  45. Nilsson UW, Dabrosin C. Estradiol and tamoxifen regulate endostatin generation via matrix metalloproteinase activity in breast cancer in vivo. Cancer Res. 2006;66(9):4789–94.

    Article  CAS  PubMed  Google Scholar 

  46. Tan W-F, Lin L-P, Li M-H, Zhang Y-X, Tong Y-G, Xiao D, et al. Quercetin, a dietary-derived flavonoid, possesses antiangiogenic potential. Eur J Pharmacol. 2003;459(2):255–62.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments and Disclosures

The authors are thankful to Director, NIPER for providing the necessary infrastructure and facilities and Department of Science & Technology (DST), Government of India, New Delhi, and financial support. A.K.J and K.T. are grateful to Council of Scientific and Industrial Research (CSIR), GoI, New Delhi, for providing research fellowships. Histopathological examination carried out at the Medicos Lab, Chandigarh, India is also duly acknowledged.

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Authors and Affiliations

  1. 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

    Amit K. Jain, Kaushik Thanki & Sanyog Jain

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  1. Amit K. Jain
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  3. Sanyog Jain
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Correspondence to Sanyog Jain.

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Jain, A.K., Thanki, K. & Jain, S. Solidified Self-Nanoemulsifying Formulation for Oral Delivery of Combinatorial Therapeutic Regimen: Part II In vivo Pharmacokinetics, Antitumor Efficacy and Hepatotoxicity. Pharm Res 31, 946–958 (2014). https://doi.org/10.1007/s11095-013-1214-1

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