RESUMO
Owing to their unique physicochemical properties, nanomaterials have become a focus of multidisciplinary research efforts including investigations of their interactions with tumor cells and stromal compartment of tumor microenvironment (TME) toward the development of next-generation anticancer therapies. Here, we report that agglomerates of radially assembled Al hydroxide crumpled nanosheets exhibit anticancer activity due to their selective adsorption properties and positive charge. This effect was demonstrated in vitro by decreased proliferation and viability of tumor cells, and further confirmed in two murine cancer models. Moreover, Al hydroxide nanosheets almost completely inhibited the growth of murine melanoma in vivo in combination with a minimally effective dose of doxorubicin. Our direct molecular dynamics simulation demonstrated that Al hydroxide nanosheets can cause significant ion imbalance in the living cell perimembranous space through the selective adsorption of extracellular anionic species. This approach to TME dysregulation could lay the foundation for development of novel anticancer therapy strategies.
Assuntos
Hidróxido de Alumínio/farmacologia , Proliferação de Células/efeitos dos fármacos , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Hidróxido de Alumínio/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Células MCF-7 , Camundongos , Simulação de Dinâmica Molecular , Nanoconchas/química , Microambiente Tumoral/efeitos dos fármacosRESUMO
The tumour microenvironment regulates tumour progression and the spread of cancer in the body. Targeting the stromal cells that surround cancer cells could, therefore, improve the effectiveness of existing cancer treatments. Here, we show that magnetic nanoparticle clusters encapsulated inside a liposome can, under the influence of an external magnet, target both the tumour and its microenvironment. We use the outstanding T2 contrast properties (r2=573-1,286 s(-1) mM(-1)) of these ferri-liposomes, which are â¼95 nm in diameter, to non-invasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drug-loaded ferri-liposomes and the uptake of a model probe by cells. Furthermore, we used the ferri-liposomes to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug.