The overproduction of hydrogen peroxide is an inherent feature of some tumour cells and inflamed tissues. We took advantage of this peculiarity to eliminate cells using chemiluminescent peroxyoxalate ...reaction. We designed dispersions containing polyoxalate and tetramethylhematoporhyrin (TMHP) in dimethylphthalate droplets stabilized with Pluronic L64. The porphyrin plays the dual role. On the one hand, it serves as an activator of the peroxyoxalate reaction of polyoxalate with intracellular hydrogen peroxide and experiences excitation as a result of the reaction. The light emitted in the reaction in the model system without cells was used to optimize the dispersion's composition. On the other hand, TMHP acts as a photosensitizer (PS) causing cell damage. The formation of singlet oxygen led to cell elimination if the dispersions were used in combination with inducers of oxidative stress: hydrogen peroxide, paraquat, antitumour drug doxorubicin, or a nutritional additive menadione. The PS-induced cytotoxicity correlated with the level of intracellular ROS. The developed approach targeted to endogenous ROS is orthogonal to the classical chemotherapy and can be applied to increase its efficiency.
We report here the first evidence for the interaction of poly(ethylene glycol) (PEG) with hyaluronan (HA) in aqueous solutions. PEG–HA complexes (K app = 45,000 ± 8000 M–1) contained about 3.3 ± 0.1 ...of ethylene glycol units per disaccharide of HA. The carboxyl of the D-glucuronic acid and the amide of the N-acetyl-D-glucosamine did not participate in PEG binding. Similar experiments performed with dextran and monosaccharides showed that multiple free primary hydroxyls regularly distributed along the polysaccharide chain are necessary for PEG binding. Another novelty of our study is contraction of HA upon PEG binding. The effect was observed with HA in solution or adsorbed on positively charged liposomes. The thickness of the HA layer on the liposomes decreased 2-fold upon PEG addition. HA compaction induced by PEG may underlie the changes in the plasma membrane properties and resealing of mechanical injuries induced by Pluronics.
A facile technique for the preparation of mixed polylactide micelles from amorphous poly-D,L-lactide-block-polyethyleneglycol and crystalline amino-terminated poly-L-lactide is described. In ...comparison to the classical routine solvent substitution method, the ultrasonication assisted formation of polymer micelles allows shortening of the preparation time from several days to 15–20 min. The structure and morphology of mixed micelles were analyzed with the assistance of electron microscopy, dynamic and static light scattering and differential scanning calorimetery. The resulting polymer micelles have a hydrodynamic radius of about 150 nm and a narrow size distribution. The average molecular weight of micelles was found to be 2.1 × 107 and the aggregation number was calculated to be 6000. The obtained biocompatible particles were shown to possess low cytotoxicity, high colloid stability and high stability towards enzymatic hydrolysis. The possible application of mixed polylactide micelles as drug delivery vehicles was studied for the antitumor hydrophobic drug paclitaxel. The lethal concentration (LC50) of paclitaxel encapsulated in polylactide micelles was found to be 42 ± 4 µg/mL—a value equal to the LC50 of paclitaxel in the commercial drug Paclitaxel-Teva.
Here, we report on the evaluation of critical packing parameters, P
C
, of
l
-tyrosine and ethylene glycol (PEG) amphiphilic block copolymers. The copolymers were synthesized via
l
-tyrosine-
N
...-carboxyanhydride ring-opening polymerization using different amino-terminated PEGs as macroinitiators. The size and shape of their associates formed in water were investigated by transmission electron microscopy and dynamic and static light scatterings. The copolymers containing 20–30 wt. % of Tyr formed rod-like micelles. The copolymers with 30–50 wt. % of Tyr formed spherical vesicles, while those with 50–80 wt. % Tyr formed irregularly shaped polymeric nanoparticles. P
C
of the copolymers was estimated as the ratio of the van der Waals volume of the hydrophobic block (V) to its length (L) and the cross-sectional area of the polar block (S
H
). The values of S
H
for each copolymer were calculated according to the equation obtained from the correlation analysis of the published data. The hydrophobic block length L was calculated in three ways, i.e., assuming that polytyrosine adopts (1) stretched, (2) amyloid hairpin, or (3) Gaussian coil conformation. In the latter case, the best match of the calculated P
C
values with the morphology of the copolymer assemblies was observed.
Graphical abstract
Here we report formation of gold nanoparticles (GNPs) in micelles of polytyrosine-PEG copolymers that combine the properties of a reducer and a stabilizer. The size and properties of the GNPs were ...tailored by the excess chloroaurate over the copolymer. The latter quickly formed non-covalent complexes with HAuCl
4
and then slowly reduced it to form GNPs. 3 Tyr residues are consumed by reduction of one mole of chloroaurate. The size of the GNPs was controlled by the Tyr/Au(
iii
) molar ratio. Small GNPs with
D
≅ 8 nm were formed at Tyr/Au(
iii
) = 0.5-1.5. 90% of these small GNPs remained bound to the copolymer and could be stored in a lyophilized state. Such polypeptide-gold hybrid materials produced at Tyr/Au(
iii
) = 0.5 demonstrated high activity in the catalytic reduction of 4-nitrophenol by sodium borohydride. Tyr/Au(
iii
) = 5 led to the formation of large nanoplates (
D
≅ 30-60 nm). Thus, in the polymer-based system the GNP size grew in line with the excess of the reducing agent in contrast to Turkevich synthesis of GNPs with citric acid, which also combines the functions of a stabilizer and a reducer. The difference results from the reduction of HAuCl
4
in solution according to the Turkevich method and in the micelles of the amphiphilic polymer where the seed growth is limited by the amount of neighboring reducer.
Here we report formation of gold nanoparticles (GNPs) in micelles of polytyrosine-PEG copolymers that combine the properties of a reducer and a stabilizer.
All polymeric chemosensitizers proposed thus far have a linear poly(ethylene glycol) (PEG) hydrophilic block. To testify whether precisely this chemical structure and architecture of the hydrophilic ...block is a prerequisite for chemosensitization, we tested a series of novel block copolymers containing a hyperbranched polyglycerol segment as a hydrophilic block (PPO-NG copolymers) on multi-drug-resistant (MDR) tumor cells in culture. PPO-NG copolymers inhibited MDR of three cell lines, indicating that the linear PEG can be substituted for a hyperbranched polyglycerol block without loss of the polymers’ chemosensitizing activity. The extent of MDR reversal increased with the polymers affinity toward the cells and the expression level of P-glycoprotein. In contrast with Pluronic L61, which increases viability of tumor cells in the absence of drugs, PPO-NG chemosensitizers are completely devoid of this property undesired in cancer therapy, making them promising candidates for application as novel MDR reversal agents.
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Detonation nanodiamonds, being a good sorbent, were shown to affect considerably cytotoxicity of cationic surfactants and to possess the significant binding efficiency.
To elucidate factors stirring the manifestation of different biological effects of Pluronics, we exposed multidrug resistant NCI/ADR-RES cells to various concentrations of polymers in the absence or ...presence of 5 μg/mL of doxorubicin. This method of analysis showed that each Pluronic exhibits chemosensitizing, cell supporting, and cytotoxic properties depending on its concentration. The effects developed in certain concentration ranges specific to each polymer. The free energies of Pluronics interaction with the lipids of cell membrane determined from the concentration dependencies of MDR suppression were close to the free energies of Pluronics partitioning between water and lipid bilayer of liposomes, indicating that PPO–lipid interaction underlies MDR suppression. Free energies corresponding to the increase in cell viability correlated with Pluronic’s binding to cells. It follows that cell support by Pluronics results from their attachment to the cell surface. The presented data are feasible for predicting the biological properties of PEG-containing block copolymers.
•Amino groups in the core of nanogel particles are inaccessible for ion pairing.•Increase in the cross-linking elevates the fraction of inaccessible amino groups.•Elevation of the cross-linking ...favours endosomolytic properties in cell cultures.
The comparison study of interaction of linear poly(2-dimethyl amino)ethyl methacrylate and its cationic nanogels of various cross-linking with both DNA and sodium poly(styrene sulfonate) has been performed. Although all amino groups of the nanogels proved to be susceptible for protonation, their accessibility for ion pairing with the polyanions was controlled and impaired with the cross-linking. The investigation of nanogels complexes with cells in culture that was accomplished by using of calcein pH-sensitive probe revealed a successive increase in the cytoplasmic fluorescence upon the growth in the cross-linking due to calceine leakage from acidic compartments to cytosol. This regularity implies that amino groups which are buried presumably inside the nanogel are protected against the ion-pairing with polyanions of plasma membrane and hence are able to manifest buffer properties while captured into acidic endosomes, i.e. possess lyso/endosomolytic capacity. These findings suggest that network architecture makes an important contribution to proton sponge properties of weak polycations.
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