RESUMEN
Nowadays, nanomedicine brings new opportunities for diagnosis and treatment through innovative combinations of materials structured at the nanoscale, biomolecules and physicochemical processes. If the intrinsic properties of nanomaterials appear of major importance in this new discipline, the functionalization of these nanotools with biomolecules improves both their biocompatibility and efficacy. This is the case of carbohydrate derivatives, natural or synthetic, which are increasingly being used in nanostructures for medical purposes. As in current medicine, sugars are used to mimic their physiological roles. Indeed, carbohydrates enhance the solubility and reduce the clearance of drugs. They are used to mask immunogenic components of nano-objects and escape the body defenses and finally facilitate the delivery to the target tissue. All these properties explain the growing importance of sugars in nanomedicine.
Asunto(s)
Antineoplásicos , Carbohidratos , Portadores de Fármacos , Nanomedicina/métodos , Animales , Antineoplásicos/química , Carbohidratos/química , Portadores de Fármacos/química , HumanosRESUMEN
In this mini-review, we focus on different strategies to bring nanotools specifically to cancer cells. We discuss about a better targeting of tumor, combining the characteristics of tumor environment, the increase in nanoparticles life time, the biomarkers overexpressed on cancer cells and different physical methods for non invasive therapies. Here we detail the necessity of a synergy between passive and active targeting for an actual specificity of cancer cells.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/análisis , Neoplasias/tratamiento farmacológico , Animales , Humanos , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Oxígeno/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND AND PURPOSE: Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis. EXPERIMENTAL APPROACH: We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis. KEY RESULTS: Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC. CONCLUSIONS AND IMPLICATIONS: Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug.
Asunto(s)
Antimaláricos/metabolismo , Eritrocitos/parasitología , Fosfatidilcolinas/biosíntesis , Plasmodium falciparum/metabolismo , Tiazoles/metabolismo , Animales , Transporte Biológico/fisiología , Colina/metabolismo , Humanos , Estructura Molecular , Plasmodium falciparum/efectos de los fármacos , Tiazoles/químicaRESUMEN
Earlier studies indicated that density-arrested cancer cells released an unidentified growth inhibitor whose secretion was prevented by overexpression of the lysosomal protease cathepsin D (cath D). In this study, this growth inhibitor was purified by affinity chromatography and identified as the heat shock cognate 70 protein (hsc70) based on its peptide microsequencing and specific antibody recognition. Among intracellular proteins, including other heat shock proteins, only constitutive hsc70 was secreted in response to the high-cell density. Moreover, hsc70 secretion from cancer cells was generated by serum deprivation, whereas its cellular concentration did not change. Prevention of Hsc70 secretion by cath D overexpression was associated with the formation of multilayer cell cultures, thus indicating a loss of contact inhibition. In addition, we showed that supplementing the culture medium with purified hsc70 inhibited cell proliferation in the nanomolar range. Conversely, removal of this extracellular hsc70 from the medium by either retention on ADP-agarose or competition at the Hsc70 binding site restored cell proliferation. Hsc70 appears active in human breast cancer cells and hypersecreted by direct cath D inhibition. These results suggest a new role of this secreted hsc70 chaperone in cell proliferation that might account for the higher tumor growth of cancer cells overexpressing cath D.