Abstract
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.
Highlights
Conventional chemotherapy cannot act on cancer cells in a targeted manner, which results in damage to healthy tissues and considerable secondary adverse effects.This is why new therapeutic approaches are focused on targeted therapies and novel tumor-targeted delivery systems.Nanomedicine, the application of nanotechnology in medicine and healthcare, is understood to be a key enabling instrument for personalized medicine by delivering generation therapies
We focused on the design of a multi-sensitive drug delivery system that could lead to a preferential uptake of the chemotherapeutic drugs by tumor cells, an increase of drug tolerability, and a minimization of undesired cytotoxic side effects
We encapsulated the antitumor drug tambjamine 21 (T21) into amphoteric GSH-sensitive NCs, taking advantage of the pH shift that occurs between healthy cells and the tumor microenvironment
Summary
Conventional chemotherapy cannot act on cancer cells in a targeted manner, which results in damage to healthy tissues and considerable secondary adverse effects.This is why new therapeutic approaches are focused on targeted therapies and novel tumor-targeted delivery systems.Nanomedicine, the application of nanotechnology in medicine and healthcare, is understood to be a key enabling instrument for personalized medicine by delivering generation therapies. Conventional chemotherapy cannot act on cancer cells in a targeted manner, which results in damage to healthy tissues and considerable secondary adverse effects. This is why new therapeutic approaches are focused on targeted therapies and novel tumor-targeted delivery systems. Nanomedicine, the application of nanotechnology in medicine and healthcare, is understood to be a key enabling instrument for personalized medicine by delivering generation therapies In this sense, nanomedicines have the potential to overcome current limitations of conventional therapies providing, among others, selectivity to target tissues, controlled drug release and protection against premature inactivation [1]. According to this, adjusting surface and the physicochemical properties of the nanoparticles results in differentiated behaviors in vitro and in vivo They can be modulated in terms of size, material, surface charge, nature, and biofunctionalization, among others. Such a cellular uptake does not occur exclusively in tumor cells, since both tumor and healthy cells can internalize cationic nanoparticles
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