Nanomaterials are now well-established components of many sectors of science and technology. Their sizes, structures, and chemical properties allow for the exploration of a vast range of potential applications and novel approaches in basic research. Biomedical applications, such as drug or gene delivery, often require the release of nanoparticles into the bloodstream, which is populated by blood cells and a plethora of small peptides, proteins, sugars, lipids, and complexes of all these molecules. Generally, in biological fluids, a nanoparticle’s surface is covered by different biomolecules, which regulate the interactions of nanoparticles with tissues and, eventually, their fate. The adsorption of molecules onto the nanomaterial is described as “corona” formation. Every blood particulate component can contribute to the creation of the corona, although small proteins represent the majority of the adsorbed chemical moieties. The precise rules of surface-protein adsorption remain unknown, although the surface charge and topography of the nanoparticle seem to discriminate the different coronas. We will describe examples of adsorption of specific biomolecules onto nanoparticles as one of the methods for natural surface functionalization, and highlight advantages and limitations. Our critical review of these topics may help to design appropriate nanomaterials for specific drug delivery.
5-FU is a chemotherapy drug commonly used for the treatment of human cancers; however drug resistance represents a major challenge for its clinical application. In the present study, we reporte that rpL3 induced by 5-FU treatment in Calu-6 cells represses CBS transcription and reduces CBS protein stability leading to a decrease of CBS protein levels. rpL3 also regulates negatively the activation of NFκB by preventing NFκB nuclear translocation through IκB-α up-regulation. Furthermore, we demonstrate that rpL3 significantly enhances the apoptosis of 5-FU treated Calu-6 cells promoting the overexpression of the pro-apoptotic proteins Bax and the inhibition of the anti-apoptotic protein Bcl-2. We finally demonstrate that rpL3 potentiates 5-FU efficacy inhibiting cell migration and invasion. Our results suggest that combination of rpL3 and 5-FU is a promising strategy for chemotherapy of lung cancers lacking functional p53 that are resistant to 5-FU.
The innate immune system consists of several complex cellular and molecular mechanisms. During inflammatory responses, blood-circulating monocytes are driven to the sites of inflammation, where they differentiate into tissue macrophages. The research of novel nanomaterials applied to biomedical sciences is often limited by their toxicity or dangerous interactions with the immune cell functions. Platinum nanoparticles (PtNPs) have shown efficient antioxidant properties within several cells, but information on their potential harmful role in the monocyte-to-macrophage differentiation process is still unknown. Here, we studied the morphology and the release of cytokines in PMA-differentiated THP-1 pre-treated with 5 nm PtNPs. Although NP endocytosis was evident, we did not find differences in the cellular structure or in the release of inflammatory cytokines and chemokines compared to cells differentiated in PtNP-free medium. However, the administration of PtNPs to previously differentiated THP-1 induced massive phagocytosis of the PtNPs and a slight metabolism decrease at higher doses. Further investigation using undifferentiated and differentiated neutrophil-like HL60 confirmed the harmlessness of PtNPs with non-adherent innate immune cells. Our results demonstrate that citrate-coated PtNPs are not toxic with these immune cell lines, and do not affect the PMA-stimulated THP-1 macrophage differentiation process in vitro.
The development of new strategies for enhancing drug delivery to the brain represents a major challenge in treating cerebral diseases. In this paper, we report on the synthesis and structural characterization of a biocompatible nanoparticle (NP) made up of poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) co-polymer (namely PELGA) functionalized with the membranotropic peptide gH625 (gH) and the iron-mimicking peptide CRTIGPSVC (CRT) for transport across the blood-brain barrier (BBB). gH possesses a high translocation potency of the cell membrane. Conversely, CRT selectively recognizes the brain endothelium, which interacts with transferrin (Tf) and its receptor (TfR) through a non-canonical ligand-directed mechanism. We hypothesize that the delivery across the BBB of PELGA NPs should be efficiently enhanced by the NP functionalization with both gH and CRT. Synthesis of peptides and their conjugation to the PLGA as well as NP physical-chemical characterization are performed. Moreover, NP uptake, co-localization, adhesion under dynamic conditions, and permeation across in vitro BBB model are evaluated as a function of gH/CRT functionalization ratio. Results establish that the cooperative effect of CRT and gH may change the intra-cellular distribution of NPs and strengthen NP delivery across the BBB at the functionalization ratio 33% gH–66% CRT.
Driving nanomaterials to specific cell populations is still a major challenge for different biomedical applications. Several strategies to improve cell binding and uptake have been tried thus far by intrinsic material modifications or decoration with active molecules onto their surface. In the present work, we covalently bound the chemokine CXCL5 on fluorescently labeled amino-functionalized SiO2 nanoparticles to precisely targeting CXCR2+ immune cells. We synthesized and precisely characterized the physicochemical features of the modified particles. The presence of CXCL5 on the surface was detected by z-potential variation and CXCL5-specific electron microscopy immunogold labeling. CXCL5-amino SiO2 nanoparticle cell binding and internalization performances were analyzed in CXCR2+ THP-1 cells by flow cytometry and confocal microscopy. We showed improved internalization of the chemokine modified particles in the absence or the presence of serum. This internalization was reduced by cell pre-treatment with free CXCL5. Furthermore, we demonstrated CXCR2+ cell preferential targeting by comparing particle uptake in THP-1 vs. low-CXCR2 expressing HeLa cells. Our results provide the proof of principle that chemokine decorated nanomaterials enhance uptake and allow precise cell subset localization. The possibility to aim at selective chemokine receptor-expressing cells can be beneficial for the diverse pathological conditions involving immune reactions.
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