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Nanocrystalline and amorphous solid dispersions formulations for improvement of antitumor therapies

Grant number: 19/04998-2
Support Opportunities:Regular Research Grants
Duration: November 01, 2020 - April 30, 2023
Field of knowledge:Health Sciences - Pharmacy - Pharmaceutical Technology
Principal Investigator:Gabriel Lima Barros de Araujo
Grantee:Gabriel Lima Barros de Araujo
Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil


High dosages, unspecific targeting, clinical variability, high cost of formulations, poor water solubility, toxicity of cosolvents are recurrent problems in the development of antitumor drug therapies. Nanocrystal and Amorphous solid dispersions (ASD) are outstanding solid-state technologies suitable to overcome those problems helping to accelerate preclinical and clinical development and improve the rate of success. In this project, nanocrystals and amorphous solid dispersions of the antitumor drugs will be developed aiming at the development of better anticancer formulations with improved pharmaceutical properties. Flubendazole and niclosamide are well known antihelmintic drugs with very limited bioavailability that have been shown to pursue promising activity against a several of cancer models. Due to their poor solubility there are the urgent need for formulations that can enable administration and target delivery. Brilliant Blue G is a dye has been recently demonstrated to inhibit metastasis dissemination of neuroblastoma cells; however, the need of high dosage and it is association with undesirable and unspecific tissue targeting can compromise its use. Tyrosine Kinase Inhibitors (TKIs) are a new class of site-specific antitumor drugs that are revolutionizing the oral treatment of cancer. Marketed formulations of TKIs, however, presents clinical variability, high doses and pharmacokinetic variation due to their poor water solubility. New approaches to accelerate the development of new nanocrystal and ASD formulations such as advanced studies in solid state chemistry, thermal analysis, High-Energy X-ray Diffraction and Pair Distribution Function (PDF) will be explored to achieve efficient and stable formulations. A longer-range goal of this work is to contribute to the advancement of the use of nanocrystal and amorphous formulations in cancer therapy. The best formulations will be tested by using in silico, in vitro and in vivo models to demonstrate the proof of concept. (AU)

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Scientific publications (7)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
GONCALVES, DEBORA DE SOUZA; YUKUYAMA, MEGUMI NISHITANI; SAITO MIYAGI, MARIANA YASUE; VIEIRA SILVA, TAMARA JULIANE; LAMEU, CLAUDIANA; BOU-CHACRA, NADIA ARACI; BARROS DE ARAUJO, GABRIEL LIMA. Revisiting Flubendazole Through Nanocrystal Technology: Statistical Design, Characterization and Its Potential Inhibitory Effect on Xenografted Lung Tumor Progression in Mice. JOURNAL OF CLUSTER SCIENCE, v. N/A, p. 12-pg., . (15/19128-2, 19/04998-2, 18/22713-2)
MIYAGI, MARIANA YASUE SAITO; FARIA, RAFAEL DE OLIVEIRA; DE SOUZA, GABRIEL BATISTA; LAMEU, CLAUDIANA; TAGAMI, TATSUAKI; OZEKI, TETSUYA; BEZZON, VINICIUS DANILO NONATO; YUKUYAMA, MEGUMI NISHITANI; BOU-CHACRA, NADIA ARACI; DE ARAUJO, GABRIEL LIMA BARROS. Optimizing adjuvant inhaled chemotherapy: Synergistic enhancement in paclitaxel cytotoxicity by flubendazole nanocrystals in a cycle model approach. International Journal of Pharmaceutics, v. 644, p. 13-pg., . (22/02193-0, 19/04998-2)
BEZZON, VINICIUS DANILO NONATO; PINTO, ROGERIO DA SILVA; DE ARA, GABRIEL LIMA BARROS; DE LIMA, JOAO CARDOSO; FERREIRA, FABIO FURLAN. Describing the Influence of Ball-milling on the Amorphization of Flubendazole Using the PDF and RMC Methods with X-ray Powder Diffraction Data. Journal of Pharmaceutical Sciences, v. 111, n. 11, p. 10-pg., . (18/11990-5, 19/04998-2)
DE ASSIS, JOAO M. C.; BARBOSA, EDUARDO J.; BEZZON, VINCIUS D. N.; LOURENCO, FELIPE R.; CARVALHO, FLAVIO M. . S.; MATOS, J. R.; BOU-CHACRA, NADIA ARACI; BENMORE, CHRIS J.; BYRN, STEPHEN R.; COSTA, FANNY N.; et al. Hot-melt extrudability of amorphous solid dispersions of flubendazole-copovidone: An exploratory study of the effect of drug loading and the balance of adjuvants on extrudability and dissolution. International Journal of Pharmaceutics, v. 614, p. 10-pg., . (18/11990-5, 19/04998-2)
BEZZON, VINICIUS D. N.; FERREIRA, FABIO F.; SMITH, PAMELA; BENMORE, CHRIS J.; BYRN, STEPHEN R.; DE ARAUJO, GABRIEL L. B.. Amorphous dispersions of flubendazole in hydroxypropyl methylcellulose: Formulation stability assisted by pair distribution function analysis. International Journal of Pharmaceutics, v. 600, . (19/04998-2, 18/11990-5)
YUKUYAMA, MEGUMI NISHITANI; FERREIRA GUIMARAES, LARA MENDES; SEGOVIA, RAFAEL SCHELIGA; LAMEU, CLAUDIANA; BARROS DE ARAUJO, GABRIEL LIMA; LOBENBERG, RAIMAR; DE SOUZA, ALINE; BAZAN HENOSTROZA, MIRLA ANALI; FOLCHINI, BEATRIZ RABELO; PERONI, CAMILLA MIDORI; et al. Malignant wound-The influence of oil components in flubendazole-loaded nanoemulsions in A549 lung cancer xenograft-bearing mice. JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY, v. 78, p. 10-pg., . (18/22713-2, 20/15981-0, 19/04998-2, 15/19128-2)
YUKUYAMA, MEGUMI NISHITANI; ZUO, JIEYU; PARK, CHULHUN; YOUSEF, MALAZ; BAZAN HENOSTROZA, MIRLA ANALI; BARROS DE ARAUJO, GABRIEL LIMA; BOU-CHACRA, NADIA ARACI; LOBENBERG, RAIMAR. Biphasic dissolution combined with modified cylinder method-A new promising method for dissolution test in drug-loaded nanoemulsions. International Journal of Pharmaceutics, v. 632, p. 9-pg., . (18/22713-2, 20/15981-0, 19/04998-2, 17/08332-3)

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