This finding opens an intriguing possibility of intranuclear delivery by merely tailoring the size of polymeric carriers, thus promising a new approach for cancer therapies.
Nanoparticles (NPs) produced from amphiphilic derivatives of poly-N-vinylpyrrolidone (Amph-PVP), composed of various molecular weight polymeric hydrophilic fragments linked into hydrophobic n-alkyl chains of varying lengths, were previously shown to exert excellent biocompatibility. Although routes of administration can be different, finally, most nanosystems enter the blood circulation or lymphatic vessels, and by this, they establish direct contact with endothelial cells. In this study, Amph-PVP NPs and fluorescently labeled Amph-PVP-based NPs, namely "PVP" NPs (Amph-PVP-NPs (6000 Da) unloaded) and "F"-NPs (Amph-PVP-NPs (6000 Da) loaded with fluorescent FITC), were synthesized to study Amph-PVP NPs interactions with HMEC-1 endothelial cells. PVP NPs were readily uptaken by HMEC-1 cells in a concentration-dependent manner, as demonstrated by immunofluorescence imaging. Upon uptake, the FITC dye was localized to the perinuclear region and cytoplasm of treated cells. The generation of lipopolysaccharide (LPS)-induced activated endothelium model revealed an increased uptake of PVPNPs, as shown by confocal microscopy. Both unloaded PVP NPs and F-NPs did not affect EC viability in the 0.01 to 0.066 mg/mL range. Furthermore, we focused on the potential immunological activation of HMEC-1 endothelial cells upon PVPNPs treatment by assessing the expression of their E-Selectin, ICAM-1, and VCAM-1 adhesion receptors. None of the adhesion molecules were affected by NP treatments of both activated by LPS and nonactivated HMEC-1 cells, at the utilized concentrations (p = NS). In this study, PVP (6000 Da) NPs were used to encapsulate indomethacin, a widely used anti-inflammatory drug. The synthesized drug carrier complex did not affect HMEC-1 cell growth and expression of E-selectin, ICAM-1, and VCAM-1 adhesion receptors. In summary, PVP-based NPs are safe for use on both basal and activated endothelium, which more accurately mimics pathological conditions. Amph-PVP NPs are a promising drug delivery system.
Nanoparticles can experience numerous impacts during storage or after intravenous administration resulting in disassembly and/or drug leakage and affecting their efficiency as drug delivery systems. In this study, this crucial issue was addressed by investigating the stability of amphiphilic poly-N-vinylpyrrolidone derivative nanocarriers in blood serum, against destabilizing agents and during long-term storage. All amphiphilic poly-N-vinylpyrrolidone derivative nanoparticles prepared in this study were found to possess sizes less than 150 nm, narrow size distribution, spherical morphology, and a slightly negative surface charge. These nanoparticles could efficiently entrap hydrophobic substances (pyrene and curcumin) while retaining excellent compatibility with red blood cells. Moreover, our studies demonstrate the stability of the nanoparticles during long-term storage and upon dilution with body liquids enhancing their potential as stable in vivo carriers, which is critically important for intravenous drug delivery applications. All properties were found to strongly depend on the ratio between the hydrophobic and the hydrophilic moiety of the polymers under study.
The blood-retina barrier (BRB), analogous to the blood-brain barrier, is a major hurdle for the passage of drugs from the blood to the central nervous system. Here, we designed polymeric nanoparticles from amphiphilic poly-/V-vinylpyrrolidone (Amph-PVP NPs) as a new carrier-system and
investigated their ability to pass the BRB using a live In-Vivo neuroimaging system for the retina in rats and ex-vivo wholemounted retinae preparation. Amph-PVP NPs were loaded with hydrophobic fluorescent markers as a surrogate for hydrophobic drugs. Linking these NPs with
the hydrophobic fluorescence marker Carboxyfluorescein-succinimidyl-ester (CFSE) to the surface, induced the passage of the cargo into the retina tissue. In particular, we observed a substantial internalization of the CFSE-linked NPs into blood cells. We propose surface- modified Amph-PVP
NPs as a potential new nano-carrier platform to target posterior eye and potentially brain diseases while camouflaged by blood cells.
Development of nanocarrier-based drug delivery systems is a major breakthrough in pharmacology, promising targeted delivery and reduction in drug toxicity. On the cellular level, encapsulation of a drug substantially affects the endocytic processes due to nanocarrier–membrane interaction. In this study we synthesized and characterized nanocarriers assembled from amphiphilic oligomers of N-vinyl-2-pyrrolidone with a terminal thiooctadecyl group (PVP-OD). It was found that the dissolution free energy of PVP-OD depends linearly on the molecular mass of its hydrophilic part up to M¯n = 2 × 104, leading to an exponential dependence of critical aggregation concentration (CAC) on the molar mass. A model hydrophobic compound (DiI dye) was loaded into the nanocarriers and exhibited slow release into the aqueous phase on a scale of 18 h. Cellular uptake of the loaded nanocarriers and that of free DiI were compared in vitro using glioblastoma (U87) and fibroblast (CRL2429) cells. While the uptake of both DiI/PVP-OD nanocarriers and free DiI was inhibited by dynasore, indicating a dynamin-dependent endocytic pathway as a major mechanism, a decrease in the uptake rate of free DiI was observed in the presence of wortmannin. This suggests that while macropinocytosis plays a role in the uptake of low-molecular components, this pathway might be circumvented by incorporation of DiI into nanocarriers.
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