ORIGINAL ARTICLE Erlotinib/hydroxypropyl-b-cyclodextrin inclusion complex: characterization and in vitro and in vivo evaluation Sa ´vio M. L. Gontijo 1 • Pedro P. G. Guimara ˜es 2 • Celso T. R. Viana 3 • A ˆ ngelo M. L. Denadai 4 • Alinne D. M. Gomes 2 • Paula P. Campos 5 • Silvia P. Andrade 3 • Rube ´n D. Sinisterra 2 • Maria E. Corte ´s 1 Received: 4 May 2015 / Accepted: 2 September 2015 / Published online: 8 September 2015 Ó Springer Science+Business Media Dordrecht 2015 Abstract Erlotinib (ERL) is a drug used in epidermoid carcinoma treatment. One of the ERL drawbacks is low water solubility, which limits its use in the development of safer and effective formulations. The present study used the strategy of inclusion complexation with hydroxypropyl-b- cyclodextrin (HP-b-CD) to increase the ERL water solu- bility, characterize the inclusion complex physico-chemi- cally, and evaluate the in vitro cytotoxicity and in vivo antiangiogenic effect. The data showed 1:1 molar ratio ERL:HP-b-CD inclusion complex formation both in solu- tion and in solid state. Phase-solubility analysis showed A L -type diagrams. Isothermal titrations calorimetry and nuclear Overhauser effect spectroscopy also support that formation. Despite free ERL higher cytotoxicity, higher values were associated with the complex compared with free ERL (37.5 lM), and the complex was more cytotoxic to A431 human epidermoid carcinoma cell than to osteo- blasts (non-cancerous cells). In addition, the inclusion complex exhibited antiangiogenic activity without affect- ing the activation and recruitment of neutrophils and macrophage. Overall, these results suggest that the ERL:HP-b-CD inclusion complex could be a promising approach for developing safe and effective ERL formula- tion by different routes of administration. Keywords Anti-cancer  Erlotinib  Hydroxypropyl-b- cyclodextrin  Inclusion complex Introduction Erlotinib (ERL) is a selective and reversible inhibitor of protein-tyrosine kinase, which is located in epidermal growth factor receptor (EGFR) and has antitumor activity in tumors overexpressing EGFR [1]. Increased transcrip- tion of EGFR has been detected in many diseased cell types [2]. The overexpression is a result of an increase in mRNA synthesis and it is present in various cell types, such as human epidermoid carcinoma cell (A431). Overexpression of EGFR is not present in the mucosa of healthy patients, but the receptor is expressed in various cells in the body, such as osteoblasts [3]. Specifically, ERL has been reported to mediate an antiangiogenic effect through the reduction of expression of pro-angiogenic genes, cell proliferation and vascular density. The angiogenic pathways are important targets for inhibiting tumor growth; a well-vali- dated marker for angiogenesis is hemoglobin [4]. Anti-in- flammatory activity has been associated with the antiangiogenic therapy mediated by inhibition of n-acetyl- b-D-glucosaminidase (NAG) production, an inflammatory & Maria E. Corte ´s mecortes@yahoo.com; mecortes@ufmg.br 1 Restorative Dentistry Department, Faculty of Dentistry, Universidade Federal de Minas Gerais, Av. Anto ˆnio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil 2 Chemistry Department, Institute of Exact Sciences, Universidade Federal de Minas Gerais, Av. Anto ˆnio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil 3 Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Anto ˆnio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil 4 Department of Pharmacy, Universidade Federal de Juiz de Fora, Av. Dr. Raimundo Monteiro de Rezende 330, Governador Valadares, MG CEP 35010-177, Brazil 5 Department of General Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Av. Anto ˆnio Carlos 6627, Belo Horizonte, MG CEP 31270-901, Brazil 123 J Incl Phenom Macrocycl Chem (2015) 83:267–279 DOI 10.1007/s10847-015-0562-3