RESUMO
The aim of this work was to investigate the potential of a new 3,6-O,O'-dimyristoyl derivative amphiphilic chitosan (DMCh), in improving the solubility of camptothecin (CPT), a hydrophobic anticancer drug, and its potential oral delivery. FTIR, 1H NMR and solid-state 13C NMR spectroscopy were used to characterize DMCh and to determine its average degree of substitution (DS¯=6.8%). DMCh/CPT micelles size ranged from (281-357nm), zeta potential (+32-50mV) of encapsulation efficiency of 42-100%. The in vitro cell viability showed that DMCh/CPT micelles were able to reduce the toxicity of CPT. The in vitro permeability of CPT through Caco-2 and Caco-2/HT29-MTX intestinal models was increased up to ten fold when formulated into DMCh micelles, underlining the mucoadhesive properties of the nanocarrier. DMCh/CPT micelles are able to enhance CPT solubility and bioavailability while reduce its cytotoxicity, showing the great potential for intestinal delivery of hydrophobic drugs.
Assuntos
Camptotecina/metabolismo , Quitosana/química , Portadores de Fármacos/farmacologia , Células CACO-2 , Camptotecina/administração & dosagem , Camptotecina/química , Portadores de Fármacos/química , Humanos , Micelas , Tamanho da Partícula , Permeabilidade/efeitos dos fármacos , SolubilidadeRESUMO
DNA topoisomerase I from Plasmodium falciparum (PfTopoI), a potential selective target for chemotherapy and drug development against malaria, is used here, together with human Topo I (HssTopoI), for docking, molecular dynamics (MD) studies and experimental assays. Six synthetic isoflavonoid derivatives and the known PfTopoI inhibitors camptothecin and topotecan were evaluated in parallel. Theoretical results suggest that these compounds dock in the binding site of camptothecin and topotecan inside both enzymes and that LQB223 binds selectively in PfTopoI. In vitro tests against P. falciparum blood parasites corroborated the theoretical findings. The selectivity index (SI) of LQB223 ≥ 98 suggests that this molecule is the most promising in the group of compounds tested. In vivo experiments in mice infected with P. berghei showed that LQB223 has an antimalarial activity similar to that of chloroquine.
Assuntos
Antimaláricos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Isoflavonas/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/enzimologia , Inibidores da Topoisomerase/farmacologia , Animais , Antimaláricos/química , Antimaláricos/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistência a Medicamentos/efeitos dos fármacos , Feminino , Humanos , Concentração Inibidora 50 , Isoflavonas/química , Isoflavonas/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Parasitos/efeitos dos fármacos , Plasmodium berghei/efeitos dos fármacos , Termodinâmica , Inibidores da Topoisomerase/química , Topotecan/química , Topotecan/farmacologiaRESUMO
Although there are several studies reporting the promising biological efficiency of mesoporous silica nanoparticles (loaded with antitumoral drugs) against cancer cells and tumors, there are no reports on the influence of the bio-nano interface interactions on the molecular diffusion process occurring along their pores. In this context, we show here that the protein coating formed on multifunctionalized colloidal mesoporous silica nanoparticles (MSNs) dispersed in a cell culture medium decreases the release of camptothecin (CPT, a hydrophobic antitumoral drug) from the pores of MSNs. This effect is related to the adsorption of biomolecules on the nanoparticle surface, which partially blocks the pores. Parallely, the hydrophobic functionalization inside the pores can offer suitable sites for the adsorption of other molecules present in the cell culture medium depending on the hydrophobicity, size, and conformation aspects of these molecules and adsorption sites of MSNs. Thus, the molecular cargo loaded in the pores (i.e. CPT) can be replaced by specific molecules present in the dispersion medium. As a consequence, we show that a non-permeable cellular staining molecule such as SYTOX green can be incorporated in MSNs through this mechanism and internalized by cells in an artificial fashion. By extrapolating this phenomenon for applications in vivo, one has to consider now the possible manifestation of unpredicted biological effects from the use of porous silica nanoparticles and others with similar structure due to these internalization aspects.
Assuntos
Nanopartículas/química , Dióxido de Silício/química , Adsorção , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/toxicidade , Camptotecina/química , Camptotecina/metabolismo , Camptotecina/toxicidade , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Células HCT116 , Humanos , Interações Hidrofóbicas e Hidrofílicas , Microscopia Confocal , Porosidade , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismoRESUMO
This work reports the production of a liposomal formulation, having a lipidic membrane with known chemical composition and a low proton permeability, as confirmed by physicochemical characterization of the maintenance of a transmembranic pH gradient. These liposomes consist of DSPC, DSPE-PEG, DSPG and cholesterol, with low internal pH. To verify the low proton permeability of these liposomal bilayers, a study of proton migration according to the fluorescence quenching of 9-aminoacridine (9AA), as well as CPT-11 encapsulation, were used to monitor the acidification of the intravesicular space. Both experiments showed that this liposomal formulation is able to maintain a transmembranic proton gradient.