Novel Gefitinib Formulation with Improved Oral Bioavailability in Treatment of A431 Skin Carcinoma

Overview

Journal Pharm Res

Specialties Pharmacology
Pharmacy

Date 2015 Aug 20

PMID 26286185

Citations 12

Authors

Chandraiah Godugu

Ravi Doddapaneni

Apurva R Patel

Rakesh Singh

Roger Mercer

Mandip Singh

Affiliations

Soon will be listed here.

Abstract

Purpose: Oral administration of anticancer agents presents a series of advantages for patients. However, most of the anticancer drugs have poor water solubility leading to low bioavailability.

Methods: Controlled released spray dried matrix system of Gefitinib with hydroxypropyl β-cyclodextrin, chitosan, hydroxy propyl methyl cellulose, vitamin E TPGS, succinic acid were used for the design of formulations to improve the oral absorption of Gefitinib. Spray drying with a customized spray gun which allows simultaneous/pulsatile flow of two different liquid systems through single nozzle was used to prepare Gefitinib spray dried formulations (Gef-SD). Formulation was characterized by in vitro drug release and Caco-2 permeability studies. Pharmacokinetic studies were performed in Sprague Dawley rats. Efficacy of Gef-SD was carried out in A431 xenografts models in nude mice.

Results: In Gef-SD group 9.14-fold increase in the AUC was observed compared to free Gef. Improved pharmacokinetic profile of Gef-SD translated into increase (1.75 fold compared to Gef free drug) in anticancer effects. Animal survival was significantly increased in Gef formulation treated groups, with superior reduction in the tumor size (1.48-fold) and volumes (1.75-fold) and also increase in the anticancer effects (TUNEL positive apoptotic cells) was observed in Gef-SD treated groups. Further, western blot, immunohistochemical and proteomics analysis demonstrated the increased pharmacodynamic effects of Gef-SD formulations in A431 xenograft tumor models.

Conclusion: Our studies suggested that Gefitinib can be successfully incorporated into control release microparticles based oral formulation with enhanced pharmacokinetic and pharmacodynamic activity. This study demonstrates the novel application of Gef in A431 tumor models.

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References

Lee T, Pastorino L, Lu K . Peptidyl-prolyl cis-trans isomerase Pin1 in ageing, cancer and Alzheimer disease. Expert Rev Mol Med. 2011; 13:e21. DOI: 10.1017/S1462399411001906. View

Godugu C, Patel A, Doddapaneni R, Somagoni J, Singh M . Approaches to improve the oral bioavailability and effects of novel anticancer drugs berberine and betulinic acid. PLoS One. 2014; 9(3):e89919. PMC: 3948684. DOI: 10.1371/journal.pone.0089919. View

Anand S, Honari G, Hasan T, Elson P, Maytin E . Low-dose methotrexate enhances aminolevulinate-based photodynamic therapy in skin carcinoma cells in vitro and in vivo. Clin Cancer Res. 2009; 15(10):3333-43. PMC: 2744072. DOI: 10.1158/1078-0432.CCR-08-3054. View

Patel A, Chougule M, Lim E, Francis K, Safe S, Singh M . Theranostic tumor homing nanocarriers for the treatment of lung cancer. Nanomedicine. 2013; 10(5):1053-63. PMC: 4061286. DOI: 10.1016/j.nano.2013.12.002. View

Yang L, Chen Y, Cui T, Knosel T, Zhang Q, Albring K . Desmoplakin acts as a tumor suppressor by inhibition of the Wnt/β-catenin signaling pathway in human lung cancer. Carcinogenesis. 2012; 33(10):1863-70. DOI: 10.1093/carcin/bgs226. View

Karlenius T, Tonissen K . Thioredoxin and Cancer: A Role for Thioredoxin in all States of Tumor Oxygenation. Cancers (Basel). 2013; 2(2):209-32. PMC: 3835076. DOI: 10.3390/cancers2020209. View

Goncalves A, Finetti P, Sabatier R, Gilabert M, Adelaide J, Borg J . Poly(ADP-ribose) polymerase-1 mRNA expression in human breast cancer: a meta-analysis. Breast Cancer Res Treat. 2010; 127(1):273-81. DOI: 10.1007/s10549-010-1199-y. View

Sawabu T, Seno H, Kawashima T, Fukuda A, Uenoyama Y, Kawada M . Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway. Mol Carcinog. 2006; 46(2):155-64. DOI: 10.1002/mc.20211. View

Chougule M, Patel A, Patlolla R, Jackson T, Singh M . Epithelial transport of noscapine across cell monolayer and influence of absorption enhancers on in vitro permeation and bioavailability: implications for intestinal absorption. J Drug Target. 2014; 22(6):498-508. DOI: 10.3109/1061186X.2014.894046. View

10.

Boakye C, Doddapaneni R, Shah P, Patel A, Godugu C, Safe S . Chemoprevention of skin cancer with 1,1-Bis (3'-indolyl)-1-(aromatic) methane analog through induction of the orphan nuclear receptor, NR4A2 (Nurr1). PLoS One. 2013; 8(8):e69519. PMC: 3737220. DOI: 10.1371/journal.pone.0069519. View

11.

Patel A, Chougule M, I T, Patlolla R, Wang G, Singh M . Efficacy of aerosolized celecoxib encapsulated nanostructured lipid carrier in non-small cell lung cancer in combination with docetaxel. Pharm Res. 2013; 30(5):1435-46. PMC: 3618607. DOI: 10.1007/s11095-013-0984-9. View

12.

Goldberg M, Sharp P . Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression. J Exp Med. 2012; 209(2):217-24. PMC: 3280873. DOI: 10.1084/jem.20111487. View

13.

Katada K, Tomonaga T, Satoh M, Matsushita K, Tonoike Y, Kodera Y . Plectin promotes migration and invasion of cancer cells and is a novel prognostic marker for head and neck squamous cell carcinoma. J Proteomics. 2012; 75(6):1803-15. DOI: 10.1016/j.jprot.2011.12.018. View

14.

Wang W, Eddy R, Condeelis J . The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer. 2007; 7(6):429-40. PMC: 4270061. DOI: 10.1038/nrc2148. View

15.

Herbst R, Fukuoka M, Baselga J . Gefitinib--a novel targeted approach to treating cancer. Nat Rev Cancer. 2004; 4(12):956-65. DOI: 10.1038/nrc1506. View

16.

Ranson M, Hammond L, Ferry D, Kris M, Tullo A, Murray P . ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol. 2002; 20(9):2240-50. DOI: 10.1200/JCO.2002.10.112. View

17.

Sollohub K, Cal K . Spray drying technique: II. Current applications in pharmaceutical technology. J Pharm Sci. 2009; 99(2):587-97. DOI: 10.1002/jps.21963. View

18.

Huang S, Harari P . Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs. 2000; 17(3):259-69. DOI: 10.1023/a:1006384521198. View

19.

Faivre L, Gomo C, Mir O, Taieb F, Schoemann-Thomas A, Ropert S . A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879(23):2345-50. DOI: 10.1016/j.jchromb.2011.06.026. View

20.

Cox T, Bird D, Baker A, Barker H, Ho M, Lang G . LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013; 73(6):1721-32. PMC: 3672851. DOI: 10.1158/0008-5472.CAN-12-2233. View