Erlotinib/hydroxypropyl-β-cyclodextrin inclusion complex: characterization and in vitro and in vivo evaluation

Gontijo, Sávio Morato de Lacerda; Guimarães, Pedro Pires Goulart; Viana, Celso Tarso Rodrigues; Denadai, Ângelo Márcio Leite; Gomes, Alinne D. M.; Campos, Paula Peixoto; Andrade, Sílvia Passos; Sinisterra, Rubén D.; Cortés, María Esperanza

doi:10.1007/s10847-015-0562-3

Cited by 16 publications

(10 citation statements)

References 52 publications

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“…The interaction mechanisms of CDs with LGK974 were studied using isothermal titration calorimetry (ITC). ITC measures the thermodynamic changes of host-guest interactions, such as CD:drug complexes, and determines the strength of interaction (complexation constant) and stoichiometry in solution [29,30]. The average stoichiometry N of the complex in solution and its thermodynamic parameters of interaction (enthalpy ΔH°, entropy ΔS°, complexation constant K complex ) were determined.…”

Section: Resultsmentioning

confidence: 99%

“…The interaction between βSBECD and LGK974 is an exothermic process cooperatively accompanied by an entropy increase, leading to an especially strong interaction between the two species (K complex1:1 = 1720 ± 156 M −1 ) compared to other CD:guest systems [29–31]. The interaction between HPβCD and LGK974 is also an exothermic process, but the complexation constant (K complex1:1 = 170 ± 5.49 M −1 ) is measured to be 10 times lower than that of βSBECD:LGK974, indicating a weaker host:guest interaction.…”

Section: Resultsmentioning

confidence: 99%

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Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Guimarães

Tan

Tammela

et al. 2018

Journal of Controlled Release

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Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D 1H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Guimarães

Tan

Tammela

et al. 2018

Journal of Controlled Release

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“…Esses compostos se destacam pela capacidade de formar compostos de inclusão com substâncias diversas, geralmente aumentando a sua solubilidade, estabilidade e atividade biológica. [11][12] O uso de ciclodextrinas como agentes de nanoencapsulamento tem sido praticado com sucesso com diversas substâncias bioativas de origem vegetal, como alcaloides, 13 ácidos fenólicos, 14 compostos polifenólicos; 15 além de misturas complexas, como extratos de folha de oliva, 16 própolis 7b e hibisco, 17 sendo essas últimas, denominadas fitocomplexos.…”

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Antioxidant Activity Evaluation of Bryophyllum pinnatum (Lam.) Oken Fractions and their Phytocomplexes with β-cyclodextrin

et al. 2019

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The aim of this work was the synthesis, characterization and evaluation of the in vitro antioxidant activity of phytocomplexes formed by hexane, dichloromethane, ethyl acetate and n-butanol fractions of Bryophyllum pinnatum (Lam.) Oken, associated with -cyclodextrin (CD). After the synthesis, the phytocomplexes were characterized in solution and in solid state by UV-Vis spectroscopy and thermogravimetric analysis (TGA/DTG), which showed the preference of CD by the rich flavonoid fractions (ethyl acetate and n-butanol fractions). About the evaluation of the antioxidant activity, the two methodologies employed in the studies, named DPPH and FRAP, showed that the ethyl acetate fraction suffered an improvement of its activity in presence of CD, as result of interactions of the flavonoids with the cyclodextrin.

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“…One of the ERL drawbacks is low water solubility, which limits its use in the development of safer and effective formulations. The study by Gontijo et al used the strategy of inclusion complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) to increase the ERL water solubility [11]. Despite free ERL higher cytotoxicity, higher values were associated with the complex compared with free ERL (37.5 μM) and the complex was more cytotoxic to A431 human epidermoid carcinoma cell than to osteoblasts (non-cancerous cells).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Folate-Appended <i>β</i>-Cyclodextrin Using Phenanthroline as Linker for Cancer Targeting Drug Delivery

Russel¹,

Paul²,

Karim³

et al. 2019

IJOC

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Here we have synthesized cancer targeting drug delivery system that contains β-cyclodextrin as a drug carrier and folic acid as a targeting ligand. Folic acid was selected as a cancer targeting ligand because folic acid receptors are highly expressed in a variety of tumor types. β-cyclodextrin and folic acid were connected through a linker [1,10-phenanthroline or 5-(hydroxymethyl) furfural]. β-cyclodextrin and folic acid were attached to the linker by formation of Schiffbase and ester, respectively. Our targeted synthetic products were confirmed by NMR, Mass and IR spectroscopy. We anticipate that our synthetic products can confer cancer cell-specific drug delivery as well as desired properties such as nanoparticle formation.

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Erlotinib/hydroxypropyl-β-cyclodextrin inclusion complex: characterization and in vitro and in vivo evaluation

Cited by 16 publications

References 52 publications

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Antioxidant Activity Evaluation of Bryophyllum pinnatum (Lam.) Oken Fractions and their Phytocomplexes with β-cyclodextrin

Synthesis of Folate-Appended <i>β</i>-Cyclodextrin Using Phenanthroline as Linker for Cancer Targeting Drug Delivery

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Erlotinib/hydroxypropyl-β-cyclodextrin inclusion complex: characterization and in vitro and in vivo evaluation

Cited by 16 publications

References 52 publications

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Potent in vivo lung cancer Wnt signaling inhibition via cyclodextrin-LGK974 inclusion complexes

Antioxidant Activity Evaluation of Bryophyllum pinnatum (Lam.) Oken Fractions and their Phytocomplexes with β-cyclodextrin

Synthesis of Folate-Appended &lt;i&gt;β&lt;/i&gt;-Cyclodextrin Using Phenanthroline as Linker for Cancer Targeting Drug Delivery

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Synthesis of Folate-Appended <i>β</i>-Cyclodextrin Using Phenanthroline as Linker for Cancer Targeting Drug Delivery