RESUMO
The synthesis of a new family of ethylenediaminetetraacetic acid (EDTA) core dimers and G0 dendrimers end-capped with two and four ß-cyclodextrin (ßCD) moieties was performed by click-chemistry conjugation, varying the spacers attached to the core. The structure analyses were achieved in DMSO-d6 and the self-inclusion process was studied in D2O by 1H-NMR spectroscopy for all platforms. It was demonstrated that the interaction with adamantane carboxylic acid (AdCOOH) results in a guest-induced shift of the self-inclusion effect, demonstrating the full host ability of the ßCD units in these new platforms without any influence of the spacer. The results of the quantitative size and water solubility measurements demonstrated the equivalence between the novel EDTA-ßCD platforms and the classical PAMAM-ßCD dendrimer. Finally, we determined the toxicity for all EDTA-ßCD platforms in four different cell lines: two human breast cancer cells (MCF-7 and MDA-MB-231), human cervical adenocarcinoma cancer cells (HeLa), and human lung adenocarcinoma cells (SK-LU-1). The new EDTA-ßCD carriers did not present any cytotoxicity in the tested cell lines, which showed that these new classes of platforms are promising candidates for drug delivery.
Assuntos
Dendrímeros , beta-Ciclodextrinas , Humanos , Ácido Edético/farmacologia , Dendrímeros/química , beta-Ciclodextrinas/farmacologia , beta-Ciclodextrinas/química , Sistemas de Liberação de Medicamentos , Fenômenos Químicos , SolubilidadeRESUMO
Nanoscale design and construction of affinity-based drug delivery systems (ADDS) is an active research area with enormous potential for the improvement of cancer treatment. For the therapeutic load of these ADDS, a promising strategy is the design of pH-sensitive prodrugs based on the construction of conjugates between adamantane and doxorubicin (Ad-Dox), which stands out as an excellent model system to obtain novel supramolecular materials. Construction of these prodrugs involves a modification of three zones of doxorubicin which in principle does not affect the action mechanism: the carbonyl group C13 (hydrazone linker), the primary alcohol neighboring the carbonyl (ester linker) and the 3' amino group of daunosamine sugar (amide linker). These modifications are aimed to improve the efficacy and reduce the systemic toxicity of the drug chemotherapy by controlling its release in cancer cells. In this work, we performed 2D NMR experiments and molecular dynamics simulations to characterize the conformational changes of three constructed prodrugs. Our results demonstrated that ring A and the daunsamine sugar of the hydrazone and amide linkers conserve the half-chair state 9H8, while the ester linker disrupts this conformation. Our study also showed that the hydrazone-linked compound (Ad-h-Dox) does not modify the conformation of the original drug and maintains cytotoxic activity. Moreover, the inclusion complex (IC) of Ad-h-Dox with ß-cyclodextrin (ßCD) generated a highly soluble platform in water, whereas the ester-linked compound (Ad-e-Dox) causes the loss of biological activity. This study proves that Ad-h-Dox prodrug can be an optimum prodrug and act as a building block for a more complex drug transport system.
Assuntos
Adamantano/química , Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Pró-Fármacos/química , beta-Ciclodextrinas/química , Aminas/química , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Hexosaminas/química , Humanos , Hidrazonas/química , Espectroscopia de Ressonância Magnética , Conformação Molecular , Simulação de Dinâmica MolecularRESUMO
The toxicity of the poly(amidoamine) dendrimers (PAMAM) caused by the peripheral amino groups has been a limitation for their use as drug carriers in clinical applications. In this work, we completely modified the periphery of PAMAM dendrimer generation 1 (PAMAM G1) with ß-cyclodextrin (ß-CD) units through the Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) to obtain the PAMAM G1-ß-CD dendrimer with high yield. The PAMAM G1-ß-CD was characterized by 1H- and 13C-NMR and mass spectrometry studies. Moreover, the PAMAM G1-ß-CD dendrimer showed remarkably higher water solubility than native ß-CD. Finally, we studied the toxicity of PAMAM G1-ß-CD dendrimer in four different cell lines, human breast cancer cells (MCF-7 and MDA-MB-231), human cervical adenocarcinoma cancer cells (HeLa) and pig kidney epithelial cells (LLC-PK1). The PAMAM G1-ß-CD dendrimer did not present any cytotoxicity in cell lines tested which shows the potentiality of this new class of dendrimers.