RESUMO
Histamine (His) in humans is physiologically involved in neurotransmission and increases vascular permeability during the development of inflammatory response and immunity. It could be used to enhance drug-loaded nanoparticles (NPs) distribution. However, it cannot be freely delivered due to the risk of His-dose-dependent deleterious effects. His can be attached to the polymeric backbone during polymerization to overcome this limitation. In this study, His was used as an initiator of lactide polymerization, and the obtained macromolecules were subsequently used to prepare doxorubicin (DOX)-loaded NPs by nanoprecipitation and microfluidics for examination of anti-cancer properties. Notably, the in vitro activity towards gastric cancer cells (AGS) of the NPs composed of histamine-functionalized polylactides (PLAs) was greatly enhanced compared to control NPs built from hydroxyfunctionalized PLAs. Furthermore, Zonula occludens-1 (ZO-1) tight junction protein production was significantly diminished after treating cells with DOX-loaded NPs assembled with PLAs with histamine residues. These results demonstrate the synergistic effect in cytotoxicity towards gastric cancer cells of DOX and the histamine that are carried by NPs. It is believed that His-DOX NPs strategy may lead to effective, targeted, and low-toxic delivery of drugs into cancer cells.
Assuntos
Nanopartículas , Neoplasias Gástricas , Humanos , Histamina , Neoplasias Gástricas/tratamento farmacológico , Doxorrubicina/química , Linhagem Celular Tumoral , Nanopartículas/química , Sistemas de Liberação de Medicamentos/métodosRESUMO
The designing of biocompatible nanocarriers for the efficient delivery of their cargos to the desired targets remains a challenge. In this regard, the most promising strategy relies on the construction of pH- or thermo-responsive nanoparticles (NPs). However, it is also important to preserve the balance between the responsiveness of the carrier and their stability in physiological conditions. Therefore, we described a new family of copolymers of lactide and allyl-glycidyl ether which were subsequently modified by thiol-ene reaction to functionalize the resulting copolymer with acetylcysteine (ACC) or thioglycolic acid (tGA) moieties. Subsequently, these copolymers were used to obtain blank and doxorubicin (DOX) loaded NPs with an average diameter of about 50-100â¯nm. Interestingly, the NPs were stable in different pH conditions, however, the presence of ACC or tGA units in the polymeric chain allows for the reduction of the undesired burst release due to the supramolecular interactions between polymeric pedant groups and DOX. The release tests of DOX from NPs showed that DOX release rate decrease depending on the pH values and the copolymer functionalization in order of non-modified NPsâ¯>â¯ACC-modified NPsâ¯>â¯tGA functionalized NPs. Most importantly, the MTT assay showed that all blank NPs are non-toxic against the normal L929 cell line. Subsequently, the antitumor efficiency of the obtained NPs was tested towards L929 (murine fibroblast cell line), HeLa (cervical cancer), and AGS (human gastric adenocarcinoma cancer) cells. The results demonstrated that DOX-loaded NPs efficiently induce the reduction in the viability of the HeLa and AGS cell, and this reduction in the viability was even below 20 % for the AGS cells. Together with their biocompatibility, the obtained NPs offer a novel route for the preparation of nanocarriers for the controlled and efficient delivery of anticancer drugs.