Charged polymersomes are attractive for advanced material applications due to their versatile encapsulation capabilities and charge-induced functionality. Although desirable, the pH-sensitivity of ...charged block copolymers adds complexity to its self-assembly process, making it challenging to produce charged polymersomes in a reliable manner. In this work, a flow approach to control and strike a delicate balance between solvent composition and pH for self-assembly is used. This allows for the identification of a phase window to reliably produce of charged polymersomes. The utility of this approach to streamline downstream processes, such as morphological transformation or in-line purification is further demonstrated. As proof-of-concept, it is shown that the processed polymersomes can be used for surface modifications facilitated by charge complexation.
Drug delivery carriers are now widely established because they can increase the therapeutic efficiency of drugs. In general, the aim in this field is to create effective carriers that have large ...amounts of drugs loaded to minimize drug carrier material that needs to be disposed of. However, there has been little attention so far in the literature on the effect of the amount of loaded drugs on the biological activity. In this paper, we are trying to answer the question of how the drug-loading content will affect the in vitro activity. We use two methods to load paclitaxel (PTX) into micelles based on the glycopolymer, poly(1- O-methacryloyl-β-d-fructopyranose)- block-poly(methyl methacylate) (Poly(1- O-MAFru)
- b-PMMA
). In the one-step method, the drug is loaded into the particles during the self-assembly process. However, the size of nanoparticle increased with the PTX content from 26 to 50 nm, triggering enhanced cellular uptake by MCF-7 and MDA-MB-231, which was caused by changes in diameter size and not by changes in drug concentration. To keep the nanoparticle size constant, preformed micelles were loaded with PTX (two-step process). The increasing amount of loaded drug led to decreased cellular uptake and reduced cytotoxicity by the cancer cell lines. Small-angle neutron scattering and small-angle X-ray scattering, supported by transmission electron microscopy and dynamic light scattering, exposed the PTX location in the shell. This caused shrinkage of the shell and lower levels of shell hydration, resulting in lower cellular uptake and lower cytotoxicity. Upon the release of PTX, the shell regained its original level of hydration. We could show that because drug loading causes morphology changes, in either the shell or the size, it is impossible to separate the parameters that will influence the biological activity. Although the same phenomenon may not apply to every drug delivery system, it needs to be considered that except for the well-known parameters that affect cell uptake-size, shape, surface chemistry, type of nanoparticle, and presence of bioactive groups-the amount of loaded drugs might change the physicochemical parameters of the nanoparticle and thus the in vitro and potentially the in vivo outcomes.
Low serum albumin and low serum cholesterol levels are among the most consistent predictors of mortality in patients with end-stage renal disease (ESRD) undergoing hemodialysis. Hypoalbuminemia is ...often interpreted as a marker of poor nutrition, but serum albumin and cholesterol levels can also be low as part of a cytokine-mediated acute- phase reaction to acute or chronic inflammation. Here we report the results from a 900-day prospective study designed to determine whether tumor necrosis factor-alfa (TNF-alpha) and interleukin-6 (IL-6) predict serum albumin and cholesterol levels and mortality in a group of 90 ambulatory, adult hemodialysis patients with no acute infection, hospitalization or surgery, and no known acquired immunodeficiency syndrome (AIDS), malignancy, or liver disease. Measurable levels of TNF- alpha and/or IL-6 were found in 89 of 90 patients. Significant relationships were found between TNF-alpha and IL-6 and the degree of hypoalbuminemia and dyslipoproteinemia. IL-6 was the strongest predictor of mortality in univariate and multivariate analysis, followed by age, albumin level, and body mass index (BMI). Although the cause of hypercytokinemia was not addressed in this study, the data support the view that hypoalbuminemia and hypocholesterolemia are negative acute-phase responses to inflammatory stimuli. These results suggest that efforts to identify the nature of the stimuli for cytokine production and to lower cytokine levels in hemodialysis patients might be effective in improving the survival of patients undergoing hemodialysis. (Am J Kidney Dis 1998 Jul;32(1):107-14)
The present feature article provides an overview on the use of state-of-the-art mass spectrometry techniques such as matrix assisted laser desorption and ionization time of flight (MALDI-TOF) mass ...spectrometry as well as electrospray ionization mass spectrometry (ESI-MS) for probing the mechanism of free radical polymerization processes. The article features representative examples of the application of mass spectrometry techniques to conventional free radical polymerization, nitroxide mediated polymerization (NMP), atom transfer radical polymerization (ATRP), reversible addition fragmentation chain transfer (RAFT) as well as catalytic chain transfer (CCT) processes.
Biocompatible nanoparticles as drug carriers can improve the therapeutic efficiency of hydrophobic drugs. However, the synthesis of biocompatible and biodegradable polymeric nanoparticles can be ...time-consuming and often involves toxic solvents. Here, a simple method for protein-based stable drug-loaded particles with a narrow polydispersity is introduced. In this process, lysozyme is mixed with hydrophobic drugs (curcumin, ellipticine, and dasatinib) and fructose to prepare lysozyme-based drug particles of around 150 nm in size. Fructose is mixed with the drug to generate nanoparticles that serve as templates for the lysozyme coating. The effect of lysozyme on the physicochemical properties of these nanoparticles is studied by transmission electron microscopy (TEM) and scattering techniques (e.g., dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS)). We observed that lysozyme significantly stabilized the curcumin fructose particles for 7 days. Moreover, additional drugs, such as ellipticine and dasatinib, can be loaded to form dual-drug particles with narrow polydispersity and spherical morphology. The results also reveal that lysozyme dual ellipticine/dasatinib curcumin particles enhance the cytotoxicity and uptake on MCF-7 cells, RAW 264.7 cells, and U-87 MG cells due to the larger and rigid hydrophobic core. In summary, lysozyme in combination with fructose and curcumin can serve as a powerful combination to form protein-based stable particles for the delivery of hydrophobic drugs.
Recently the role of protein absorption in nanoparticle drug delivery has gathered significant attention as the protein corona can significantly decide on the fate of nanoparticles in the body. ...Although it is known that the surface chemistry will significantly influence the amount and type of bound protein, there is little known about the effect of surface roughness and surface topography on the interaction. In this work, we show how patchy nanoparticles can noticeably reduce the adsorption of proteins compared to spherical nanoparticles with a smooth surface as demonstrated using six ABC triblock terpolymers based on glucose, mannose and galactose. To obtain patchy nanoparticles, poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-poly(4-vinyl pyridine) (PSugEA-b-PBuA-b-P4VP) was prepared by reversible addition-fragmentation chain-transfer (RAFT) polymerization and assembled into nanoparticles with a patch-like appearance and a hydrodynamic diameter of around 130-160 nm. As control, smooth nanoparticles were prepared from poly(2-d-sugar ethyl acrylate)-b-poly (n-butyl acrylate)-b-polystyrene (PSugEA-b-PBuA-b-PS). The patchy nanoparticles displayed significantly reduced protein absorption when exposed to serum-supplemented cell culture media, as observed using dynamic light scattering. The smooth particles, however, supported the formation of a large protein corona. Additionally, an enrichment of haemoglobin was observed in the corona compared to the serum protein in solution. The amount of albumin on the surface was observed to be dependent on the type of sugar with glucose resulting in the highest absorption. The protein corona led to cellular uptake that was unrelated to the underlying sugar, which was supposed to help targeting specific cell lines. This example demonstrated how the protein corona can override any attempts to target receptor expressing cells.
Synthetic carbohydrate ligands - also widely known as glycopolymers - are known to undergo numerous recognition events when interacting with their corresponding lectins. Interactions are greatly ...enhanced due to the multivalent character displayed by the large number of repeating carbohydrate units along the polymers (pendant glycopolymers); therefore, resulting what is called the "glycocluster effect". Moreover, the strength and the availability of these multivalent recognitions can be tuned
via
the architecture of the glycopolymers. Hence, understanding the mechanistic interactions between the types of lectins (plant, animal, toxin and bacteria) with their synthetic ligands is crucial. This review focuses on the synthesis of pendant glycopolymers
via
various synthetic pathways (free radical polymerization, NMP, RAFT, ATRP, cyanoxyl mediated polymerization, ROP, ROMP and post-polymerization modification) and their interactions with their respectively lectins.
Glycopolymers are known to undergo numerous recognition events when interacted with their corresponding lectins. This review focuses on the synthesis of pendant glycopolymers and their interaction with lectins.
Morphologies, that resemble viruses, were created using a single ABC triblock terpolymer poly(2-acryloylethyl-α-d-mannopyranoside)-b-poly(n-butyl acrylate)-b-poly(4-vinylpyridine) ...(PAcManA70-b-PBA369-b-PVP370). Morphologies ranging from flower-like micelles, cylindrical micelles, raspberry-like morphologies to nanocaterpillars were obtained by adjusting the pH value during the self-assembly process. The resulting nanoparticles had an abundance of mannose on the surface, which were recognized by the mannose receptors of RAW264.7, a macrophage cell line that can be used as a model for virus entry.
Building nanostructures using RAFT polymerization Boyer, Cyrille; Stenzel, Martina H.; Davis, Thomas P.
Journal of polymer science. Part A, Polymer chemistry,
1 February 2011, Letnik:
49, Številka:
3
Journal Article
Although a range of polymer–protein polyion complex (PIC) micelle systems have been developed in the literature, relatively little attention has been paid to the influence of polymer structure on the ...assembly, or to the mechanism of disassembly. In this work, Förster resonance energy transfer is used in combination with light sheet fluorescence microscopy and isothermal calorimetry to monitor the formation and stability of PIC micelles with various carboxylic‐acid‐based binding blocks in MCF‐7 cancer spheroid models. All micelles are stable in the presence of free protein, but are unstable in solutions with an ionic strength >200 mm and prone to disassembly at reduced pH. Introducing carbon spacers between the backbone and the binding carboxylic acid results in improved PIC micelle stability at physiological pH, but also increases the pKa of the binding moiety, resulting in improved protein release upon cell uptake. These results give important insights into how to tune PIC micelle stability for controlled protein release in biological environments.
Proteins suffer from low stability and often for biomedical applications unfavorable surface charge. Protecting proteins using polyion complex micelles can be a fast and efficient way to allow better transport into 3D cancer spheroids. In this work, the effect of a hydrophobic flexible spacer between polymer and the negative charge on the stability of the complex is investigated
.
PDF
