Modular Multimodal Iron Oxide-Based Nanocarriers for Image-Guided dsRNA Immunostimulation and Platinum Anticancer Drug Design

237 p.El objetivo de este proyecto se centra en la síntesis de nanopartículas inorgánicas de óxido de hierro con una composición, superficie y tamaño especialmente diseñados para activar el sistema inmune y tener capacidad anticancerígena y/o para su utilización como agente de imagen multimodal.Para la activación del sistema inmune se ha biofuncionalizado el sistema con un patrón molecular asociado a patógeno (PAMPs) de interés clínico, llamado poly (I:C) (Polyinosinic:polycytidylic acid). Este PAMP es capaz de activar un receptor tipo Toll (TLR3) presente en las células del sistema inmune.La capacidad anticancerígena, se consigue mediante a la incorporación en el sistema de un complejo de Pt (IV) inerte que actúa como profármaco de cisplatino y que junto con el poly (I:C) como agente inmunoestimulador se usan para combinar los efectos de dos terapias complementarias para matar células tumorales in vitro e in vivo.La incorporación de fluorescencia en el sistema mediante un fosfolípido modificado con rodamina B disponible en el mercado, así como el uso del agente radioactivo fac-[99mTc(OH2)3(CO)3]+ y las propiedades magnéticas intrínsecas del sistema, permitieron la visualización del mismo in vitro e in vivo mediante diferentes técnicas de imagen molecular

Safer by design strategies

Throughout the EU funded FP7 project GUIDENano, we are trying to control and monitor the evolution of nano-enable products during their lifecycle. Small alterations of the nanoparticle (NP) state may have critical consequences on the NP behaviour and performance. For this reason it is important to highlight the importance of an extensive and proper characterization to define the NP physico-chemical characteristics under several environmental conditions. Furthermore, this characterization is necessary to ensure that obtained results are reproducible and allow understanding the behaviour of the NP on biological systems. In this paper different strategies reported in the literature regarding the safety-by-design concept are summarized. Several strategies from the synthetic point of view that help us to modulate the main factors which determine the safety of nanomaterials are proposed

Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles

Chemotherapeutic agents have limited efficacy and resistance to them limits today and will limit tomorrow our capabilities of cure. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours. In front of this, multimodality has appeared as a promising strategy to overcome resistance. In this context, the use of nanoparticle-based platforms enables many possibilities to address cancer resistance mechanisms. Nanoparticles can act as carriers and substrates for different ligands and biologically active molecules, antennas for imaging, thermal and radiotherapy and, at the same time, they can be effectors by themselves. This enables their use in multimodal therapies to overcome the wall of resistance where conventional medicine crash as ageing of the population advance. In this work, we review the cancer resistance mechanisms and the advantages of inorganic nanomaterials to enable multimodality against them. In addition, we comment on the need of a profound understanding of what happens to the nanoparticle-based platforms in the biological environment for those possibilities to become a reality

Modular Multimodal Iron Oxide-Based Nanocarriers for Image-Guided dsRNA Immunostimulation and Platinum Anticancer Drug Design

237 p.El objetivo de este proyecto se centra en la síntesis de nanopartículas inorgánicas de óxido de hierro con una composición, superficie y tamaño especialmente diseñados para activar el sistema inmune y tener capacidad anticancerígena y/o para su utilización como agente de imagen multimodal.Para la activación del sistema inmune se ha biofuncionalizado el sistema con un patrón molecular asociado a patógeno (PAMPs) de interés clínico, llamado poly (I:C) (Polyinosinic:polycytidylic acid). Este PAMP es capaz de activar un receptor tipo Toll (TLR3) presente en las células del sistema inmune.La capacidad anticancerígena, se consigue mediante a la incorporación en el sistema de un complejo de Pt (IV) inerte que actúa como profármaco de cisplatino y que junto con el poly (I:C) como agente inmunoestimulador se usan para combinar los efectos de dos terapias complementarias para matar células tumorales in vitro e in vivo.La incorporación de fluorescencia en el sistema mediante un fosfolípido modificado con rodamina B disponible en el mercado, así como el uso del agente radioactivo fac-[99mTc(OH2)3(CO)3]+ y las propiedades magnéticas intrínsecas del sistema, permitieron la visualización del mismo in vitro e in vivo mediante diferentes técnicas de imagen molecular

Safer by design strategies

Throughout the EU funded FP7 project GUIDENano, we are trying to control and monitor the evolution of nano-enable products during their lifecycle. Small alterations of the nanoparticle (NP) state may have critical consequences on the NP behaviour and performance. For this reason it is important to highlight the importance of an extensive and proper characterization to define the NP physico-chemical characteristics under several environmental conditions. Furthermore, this characterization is necessary to ensure that obtained results are reproducible and allow understanding the behaviour of the NP on biological systems. In this paper different strategies reported in the literature regarding the safety-by-design concept are summarized. Several strategies from the synthetic point of view that help us to modulate the main factors which determine the safety of nanomaterials are proposed

Cancer resistance to treatment and antiresistance tools offered by multimodal multifunctional nanoparticles

Chemotherapeutic agents have limited efficacy and resistance to them limits today and will limit tomorrow our capabilities of cure. Resistance to treatment with anticancer drugs results from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours. In front of this, multimodality has appeared as a promising strategy to overcome resistance. In this context, the use of nanoparticle-based platforms enables many possibilities to address cancer resistance mechanisms. Nanoparticles can act as carriers and substrates for different ligands and biologically active molecules, antennas for imaging, thermal and radiotherapy and, at the same time, they can be effectors by themselves. This enables their use in multimodal therapies to overcome the wall of resistance where conventional medicine crash as ageing of the population advance. In this work, we review the cancer resistance mechanisms and the advantages of inorganic nanomaterials to enable multimodality against them. In addition, we comment on the need of a profound understanding of what happens to the nanoparticle-based platforms in the biological environment for those possibilities to become a reality

Iron oxide-filled micelles as ligands for fac-[M(CO)3]+ (M = 99mTc, Re)

Magnetite-filled micelles capture fac-[M(OH2)(3)(CO)(3)](+) complexes (M = Tc-99m, Re), creating versatile self-assembled constructs for multimodal SPECT/MR/optical imaging and radiopharmaceutical guided delivery

Bacterial endotoxin (lipopolysaccharide) binds to the surface of gold nanoparticles, interferes with biocorona formation and induces human monocyte inflammatory activation

Nanoparticles (NPs) are easily contaminated by bacterial endotoxin (lipopolysaccharide [LPS]). The presence of LPS can be responsible for many immune/inflammatory effects attributed to NPs. In this study, we examined the effects of LPS adsorption on the NP surface on the formation of a biocorona in biological fluids and on the subsequent inflammation-inducing activity of NPs. Different gold (Au) NPs with sizes ranging from 10 to 80 nm and with different surface functionalization (sodium citrate, lipoic acid, and branched polyethyleneimine (BPEI), or polyethylene glycol (PEG)) were exposed to E. coli LPS under different conditions. The binding capacity of LPS to the surface of AuNPs was dose- and time-dependent. LPS attached to sodium citrate and lipoic acid coatings, but did not adhere to BPEI- or PEG-coated NPs. By computational simulation, the binding of LPS to AuNPs seems to follow the Langmuir absorption isotherm. The presence of LPS on AuNP surface interfered and caused a decrease in the formation of the expected biomolecular corona upon incubation in human plasma. LPS-coated AuNPs, but not the LPS-free NPs, induced significant inflammatory responses in vitro. Notably, while free LPS did also induce an anti-inflammatory response, LPS bound to NPs appeared unable to do so. In conclusion, the unintentional adsorption of LPS onto the NP surface can affect the biocorona formation and the inflammatory properties of NPs. Thus, for an accurate interpretation of NP interactions with cells, it is extremely important to be able to distinguish the intrinsic NP biological effects from those caused by biologically active contaminants such as endotoxin