RESUMEN
Diabetic retinopathy (DR) is a neurodegenerative disease characterized by the presence of microcirculatory lesions. Among them, microaneurysms (MAs) are the first observable hallmark of early ophthalmological changes. The present work aims to study whether the quantification of MAs, hemorrhages (Hmas) and hard exudates (HEs) in the central retinal field could have a predictive value on DR severity. These retinal lesions were quantified in a single field NM-1 of 160 retinographies of diabetic patients from the IOBA's reading center. Samples included different disease severity levels and excluded proliferating forms: no DR (n = 30), mild non-proliferative (n = 30), moderate (n = 50) and severe (n = 50). Quantification of MAs, Hmas, and HEs revealed an increasing trend as DR severity progresses. Differences between severity levels were statistically significant, suggesting that the analysis of the central field provides valuable information on severity level and could be used as a clinical tool to assess DR grading in the eyecare routine. Even though further validation is needed, counting microvascular lesions in a single retinal field can be proposed as a rapid screening system to classify DR patients with different stages of severity according to the international classification.
RESUMEN
Integration of photosensitizers (PSs) within nanoscale delivery systems offers great potential for overcoming some of the "Achiles' heels" of photodynamic therapy (PDT). Herein, we have encapsulated a mitochondria-targeted coumarin PS into amphoteric polyurethane-polyurea hybrid nanocapsules (NCs) with the aim of developing novel nanoPDT agents. The synthesis of coumarin-loaded NCs involved the nanoemulsification of a suitable prepolymer in the presence of a PS without needing external surfactants, and the resulting small nanoparticles showed improved photostability compared with the free compound. Nanoencapsulation reduced dark cytotoxicity of the coumarin PS and significantly improved in vitro photoactivity with red light toward cancer cells, which resulted in higher phototherapeutic indexes compared to free PS. Importantly, this nanoformulation impaired tumoral growth of clinically relevant three-dimensional multicellular tumor spheroids. Mitochondrial photodamage along with reactive oxygen species (ROS) photogeneration was found to trigger autophagy and apoptotic cell death of cancer cells.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Cumarinas/farmacología , Humanos , Mitocondrias/metabolismo , Neoplasias/patología , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/farmacología , Polímeros , Poliuretanos/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Cancer is one of the leading causes of mortality worldwide due, in part, to limited success of some current therapeutic approaches. The clinical potential of many promising drugs is restricted by their systemic toxicity and lack of selectivity towards cancer cells, leading to insufficient drug concentration at the tumor site. To overcome these hurdles, we developed a novel drug delivery system based on polyurea/polyurethane nanocapsules (NCs) showing pH-synchronized amphoteric properties that facilitate their accumulation and selectivity into acidic tissues, such as tumor microenvironment. We have demonstrated that the anticancer drug used in this study, a hydrophobic anionophore named T21, increases its cytotoxic activity in acidic conditions when nanoencapsulated, which correlates with a more efficient cellular internalization. A biodistribution assay performed in mice has shown that the NCs are able to reach the tumor and the observed systemic toxicity of the free drug is significantly reduced in vivo when nanoencapsulated. Additionally, T21 antitumor activity is preserved, accompanied by tumor mass reduction compared to control mice. Altogether, this work shows these NCs as a potential drug delivery system able to reach the tumor microenvironment, reducing the undesired systemic toxic effects. Moreover, these nanosystems are prepared under scalable methodologies and straightforward process, and provide tumor selectivity through a smart mechanism independent of targeting ligands.
RESUMEN
BACKGROUND: During the last decade, polyurethanes and polyureas have emerged as promising alternatives to classical polyacrylate-, polyester- and polyaminoacid-based drug delivery nanosystems. They are not only biocompatible and biodegradable, but also facilitate the manufacture of polymeric nanostructured nanoparticles in quantitative yields. The versatile chemistry reduces the amount of organic solvents used and allows the straightforward multifunctionalization of polymer precursors with the desired targeting molecule at each stage of the process. OBJECTIVES: To highlight the common issues encountered in current drug delivery systems (DDSs) and the state of the art of polyurethane and polyurea polymers that self-assemble in a stratified manner by hydrophobic interactions. Finally, we discuss the importance of taking a holistic view when applying polymer nanotechnologies, in order to enhance their efficiency during preclinical and clinical studies. CONCLUSIONS: Polyurethane-polyurea nanoparticles (PUUa NPs) emerge as suitable platforms to be manufactured in a cost-effective manner at industrial scale and following environmentally friendly synthetic methods. Furthermore, they allow the controlled delivery of a wide range of drugs and can be rapidly adapted to many clinical requirements by means of FDA-approved precursors. Additionally, the ease with which PUUa nanoparticles are biodegraded ensures control over temporal aspects of drug delivery compared to other nanosystems. These advantages make PUUa NPs attractive drug delivery vehicles as long as adequate safety and ethical guidelines for new NP formulations are developed.
Asunto(s)
Sistemas de Liberación de Medicamentos , Nanopartículas/química , Nanotecnología , Polímeros/química , Poliuretanos/química , HumanosRESUMEN
The neuropathological character of copper(II) ions (Cu(2+)) upon interaction with soluble human amyloid-ß(1-42) that subsequently generates senile plaques and/or reactive oxygen species (ROS) is considered as one of the very important features of Alzheimer's disease. The present study carried out by using fluorescence spectroscopy and atomic-force microscopy (AFM) indeed confirms the dual role played by Cu(2+), namely as mediator of protein aggregation and as generator of ROS leading to irreversible protein alteration, which most likely involve two distinct copper-binding sites. The AFM investigations clearly evidence the copper-induced aggregation of Aß oligomers and protofibrils, while comparative fluorescence measurements with copper and zinc reveals the crucial involvement of redox-active copper in the generation of Aß-cross-linked structures.