Morphology, in vivo distribution and antitumor activity of bexarotene nanocrystals in lung cancer

Abstract The objective of this study was to develop and evaluate the morphology, biodistribution and antitumor activity of bexarotene nanocrystals delivery system. The morphology was investigated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscope and bexarotene nanocrystals exhibited the advantages of making the efficacy more steady and durable compared with control group in lung with less cardiac accumulation as shown by biodistribution studies in vivo. In addition, MTT assay, flow cytometry analysis, observation of morphological changes and apoptotic body demonstrated that bexarotene nanocrystals could significantly enhance the in vitro cytotoxicity and induced G1 cycle arrest and apoptosis against A549 cells. Also, bexarotene nanocrystals had significant antitumor activity in mice bearing A549 cell line. This finding was correlated with both in vitro and in vivo. Thereby, the overall results suggest that the bexarotene nanocrystals represent a potential source of medicine, which made bexarotene nanocrystals a promising candidate for the treatment of lung cancer.

[1]  Qiang Zhang,et al.  In vitro antitumor activity of silybin nanosuspension in PC-3 cells. , 2011, Cancer letters.

[2]  R. Löbenberg,et al.  Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[3]  S. Rossi,et al.  Nanoparticles based on N-trimethylchitosan: evaluation of absorption properties using in vitro (Caco-2 cells) and ex vivo (excised rat jejunum) models. , 2007, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[4]  N. Neamati,et al.  Activation of retinoid receptors RAR alpha and RXR alpha induces differentiation and apoptosis, respectively, in HL-60 cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[5]  H. Chan,et al.  Formation, characterization, and fate of inhaled drug nanoparticles. , 2011, Advanced drug delivery reviews.

[6]  F. Gao,et al.  Diallyl trisulfide induces apoptosis and inhibits proliferation of A549 cells in vitro and in vivo. , 2012, Acta biochimica et biophysica Sinica.

[7]  Gregor Cevc,et al.  Nanotechnology and the transdermal route: A state of the art review and critical appraisal. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[8]  Xiuwen Tang,et al.  Bexarotene: a promising anticancer agent , 2009, Cancer Chemotherapy and Pharmacology.

[9]  E. Jaffe,et al.  Bexarotene is active against subcutaneous panniculitis-like T-cell lymphoma in adult and pediatric populations. , 2012, Clinical lymphoma, myeloma & leukemia.

[10]  Dianrui Zhang,et al.  Bexarotene nanocrystal-Oral and parenteral formulation development, characterization and pharmacokinetic evaluation. , 2014, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[11]  K. Leong,et al.  In vitro and in vivo models for the study of oral delivery of nanoparticles. , 2013, Advanced drug delivery reviews.

[12]  Qiang Zhang,et al.  Development and in vitro evaluation of deacety mycoepoxydiene nanosuspension. , 2011, Colloids and surfaces. B, Biointerfaces.

[13]  M. Brewster,et al.  Intestinal uptake and biodistribution of novel polymeric micelles after oral administration. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[14]  Huan Wang,et al.  Design and evaluation of injectable niclosamide nanocrystals prepared by wet media milling technique , 2015, Drug development and industrial pharmacy.

[15]  Jung-Young Shin,et al.  Synergistic antitumor efficacy of sequentially combined paclitaxel with sorafenib in vitro and in vivo NSCLC models harboring KRAS or BRAF mutations. , 2012, Cancer letters.

[16]  Wei Gong,et al.  Preparation, physical characterization and pharmacokinetic study of paclitaxel nanocrystals , 2015, Drug development and industrial pharmacy.

[17]  J. Marshall,et al.  A phase I trial of bexarotene in combination with docetaxel in patients with advanced solid tumors. , 2011, Clinical lung cancer.

[18]  W. Lamph,et al.  The retinoid X receptor agonist bexarotene (Targretin) synergistically enhances the growth inhibitory activity of cytotoxic drugs in non-small cell lung cancer cells. , 2005, Lung cancer.

[19]  G. Prud’homme,et al.  Tranilast treatment decreases cell growth, migration and inhibits colony formation of human breast cancer cells. , 2011, Experimental and molecular pathology.

[20]  Cui Tang,et al.  Size-dependent absorption mechanism of polymeric nanoparticles for oral delivery of protein drugs. , 2012, Biomaterials.

[21]  Xiaoguang Chen,et al.  Lx2-32c, a novel taxane and its antitumor activities in vitro and in vivo. , 2008, Cancer letters.

[22]  N. Garti,et al.  Phosphatidylcholine embedded microemulsions: physical properties and improved Caco-2 cell permeability. , 2007, Journal of Controlled Release.

[23]  Böhm,et al.  Lab-scale production unit design for nanosuspensions of sparingly soluble cytotoxic drugs. , 1999, Pharmaceutical science & technology today.

[24]  John A Timbrell,et al.  In vitro cytotoxicity assays: comparison of LDH, neutral red, MTT and protein assay in hepatoma cell lines following exposure to cadmium chloride. , 2006, Toxicology letters.

[25]  R. Neubert,et al.  Potentials of new nanocarriers for dermal and transdermal drug delivery. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[26]  Filippos Kesisoglou,et al.  Nanosizing--oral formulation development and biopharmaceutical evaluation. , 2007, Advanced drug delivery reviews.

[27]  R. Müller,et al.  Twenty years of drug nanocrystals: where are we, and where do we go? , 2012, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[28]  N. Neamati,et al.  Activation of retinoid receptors RARα and RXRα induces differentiation and apoptosis, respectively, in HL-60 cells , 1996 .

[29]  Preeti K. Suresh,et al.  Nanosuspension: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to amphotericin B. , 2011, Nanomedicine : nanotechnology, biology, and medicine.

[30]  G. Liversidge,et al.  Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs , 1995 .