New type of carriers based on grafted poly(ionic liquid)s was designed for delivery of ionically attached salicylates (Sal). Choline derived ionic liquid monomeric units were successfully introduced with various content in the side chains by the controlled radical polymerization. Properly high amounts of ionic pharmaceutics in the polymer systems were achieved by the well-fitted length and grafting degree of the side chains. In aqueous solution the graft copolymers were self-assembled into the spherical superstructures with sizes up to 73 nm. Delivery studies showed “burst” release within 4 h, after that it was slower yielding ~70% of released drug within 80 h. Proposed nanocarriers supported low toxicity against human cells (NHDF and BEAS-2B), anti-inflammation activity evaluated with the use of pro-inflammatory interleukins (IL-6 and IL-8) and antibacterial activities towards E. coli. Adjustment of ionic drug content by structural parameters of graft copolymers, including grafting degree and graft length, are advantageous to tailor nanocarriers with self-assembly properties in aqueous media. Effective release process by ionic exchange and biological activity with low toxicity are promising for further development of this type of drug delivery (DDS).

Copolymers of [2-(methacryloyloxy)ethyl]trimethylammonium chloride, salicylate or bis(trifluoromethanesulfonate)imide (Cl − , Sal − or Tf 2 N − ), and methyl methacrylate (MMA) were synthesized by atom transfer radical polymerization (ATRP). The effect of different molar fractions of ionic monomer (0.05−1.0) on physicochemical properties was investigated. The relative reactivity ratios of MMA and ionic monomer with the chloride anion (0.88 and 1.13, respectively) were determined by the linearization Jaacks method. The particles formed in water by copolymers with trimethylammonium chloride (≥50 mol %) reached sizes below 10 nm, whereas salicylate-containing copolymers supported strong self-assembly, yielding 200 nm superstructures. The copolymers, after modification by the exchange of Cl − and Sal − with Tf 2 N − , demonstrated the influence of the anion on solubility, glass transition temperature, and morphology. The anionmodified trimethylammonium copolymers, compared with those directly synthesized from Tf 2 N-containing monomer, indicated different properties. Both the chloride monomer (Cl − replaced by Sal − or Tf 2 N − ) and its copolymers are able to exchange anions, including biologically active ones, which extends their future applications as poly(ionic liquid)s with therapeutic properties for controlled drug delivery.

The synthesis of acetal‐derived d‐glucopyranosides with a various number of hydroxyl groups (the first step, acetalization) and their modified forms with bromoester groups (the second step, esterification) are presented here. The latter, due to the type of functional groups, can be used to initiate the controlled atom transfer radical polymerization. The copolymerizations of equimolar feed of methacrylate monomers, namely, methyl methacrylate and glycidyl methacrylate, were initiated by prepared new glycoinitiators, based on methyl α‐d‐glucopyranoside (MeαdGlu) or 2‐(hydroxymethyl)phenyl‐β‐d‐glucopyranoside (salicin), in the presence of the catalyst system CuCl/dNbpy in anisole at 30 °C. The conditions were sufficient for successful synthesis of well‐defined copolymers with sugar cores sheltered by two‐, three‐, four‐, or six‐polymethacrylate segments with various polymerization degrees (DParm = 15 – 70) and low dispersity indices (Ð = 1.15–1.30). Because of the presence of oxirane groups, the star‐copolymers can be functionalized in further steps by biologically active compounds or modified to amphipilics. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 2483–2494

The new polymeric systems for delivery in cosmetology applications were prepared using self-assembling amphiphilic graft copolymers. The synthesis based on “click” chemistry reaction included grafting of azide-functionalized polyethylene glycol (PEG-N3) onto multifunctional polymethacrylates containing alkyne units. The latter ones were obtained via atom transfer radical polymerization (ATRP) of alkyne-functionalized monomers, e.g., ester of hexynoic acid and 2-hydroxyethyl methacrylate (AlHEMA) with methyl methacrylate (MMA), using bromoester-modified retinol (RETBr) as the initiator. Varying the content of alkyne moieties adjusted by initial monomer ratios of AlHEMA/MMA was advantageous for the achievement of a well-defined grafting degree. The designed amphiphilic graft copolymers P((HEMA-graft-PEG)-co-MMA), showing tendency to micellization in aqueous solution at room temperature, were encapsulated with arbutin (ARB) or vitamin C (VitC) with high efficiencies (>50%). In vitro experiments carried out in the phosphate-buffered saline solution (PBS) at pH 7.4 indicated the maximum release of ARB after at least 20 min and VitC within 10 min. The fast release of the selected antioxidants and skin-lightening agents by these micellar systems is satisfactory for applications in cosmetology, where they can be used as the components of masks, creams, and wraps.

Well-defined star-shaped copolymers consisting of acetal derivatives of methyl a-D-glucopyranoside cores and polymethacrylate arms containing oxirane pendant groups have been modified with ethylenediamine (EDA) to form amphiphilic and water soluble polycations (positive zeta potential). Normal human dermal fibroblasts (NHDF) and human colon cancer cells (HCT-116) were employed to investigate the cellular uptake and cytotoxicity of diamine-functionalized star copolymers. Star-shaped polymers exhibited low cytotoxicity in NHDF cells, whereas in the case of HCT-116 cell line MTS assay resulted in the decrease of cell proliferation, which was also confirmed by Annexin-V assay indicating the increased rate of HCT-116 cell apoptosis. In the next step, the incorporated amine groups were applied for covalent conjugation of fluorescein isothiocyanate (FITC) with an efficiency of 60-85% estimated by 1 H NMR. The additional conjugation experiments were performed by isothermal titration calorimetry (ITC) yielding 45-100% of polymer labeling by fluorescent FITC. The confocal laser scanning microscopy proved cell internalization of the fluorescein-conjugated star copolymers was successful. The model studies showed that this type of star copolymers can be promising carriers for the delivery of drugs.

In this study, the phase transition phenomena of linear poly(acrylic acid) (PAA) and linear or star-shaped poly(acrylic acid-co-methyl acrylate) (P(AA-co-MA)) in highly concentrated KCl solutions were investigated. The effects of polymer molecular weight, topology, and composition on their phase transition behavior in solution were investigated. The cloud point temperature (TCP) of polymers drastically increased as the KCl concentration (CKCl) and solution pH increased. CKCl strongly influenced the temperature range at which the phase transition of PAA occurred: CKCl of 1.0–2.2 M allowed the phase transition to occur between 30 and 75 °C. Unfortunately, at CKCl above 2.6 M, the TCP of PAA was too high to theoretically trigger the crystallization of KCl. The addition of hydrophobic methyl acrylate moieties decreased the TCP into a temperature region where KCl crystallization could occur. Additionally, the hydrodynamic diameters (Dh) and zeta potentials of commercial PAA samples were examined at room temperature and at their TCP using dynamic light scattering. The salt concentration (from 1 to 3 M) did not impact the hydrodynamic diameter of the molecules. Dh values were 1500 and 15 nm at room temperature and at TCP, respectively.

V-shaped and star-shaped hydroxylamine-functionalized polymethacrylates designed as nanosized conjugates (<120 nm) with anticancer agent, namely, doxorubicin (DOX), were evaluated in vitro toward their potential usage as drug delivery systems in breast cancer (MCF-7) treatment. Statistical analysis of MTS assay results showed that the 4-arm conjugate (n(DOX) = 16) was the most effective polymeric system against MCF-7/W (wild type) and MCF-7/R (DOX resistant) cell lines. Apoptosis assay analysis showed that MCF-7/R cells cultured with nonlinear copolymers died due to necrosis and late apoptotis, whereas MCF-7/W cells were in early and late apoptosis. Among all tested conjugates, the most promising results with induction of apoptosis without inducing necrosis in both MCF-7 cell lines were obtained for conjugate based on 4-arm stars with low content of DOX. The cell cycle assay revealed that increase of MMA units in 4-arm copolymers induced MCF-7/R cell arrest in the SubG1 phase. In the same cell line, the corresponding conjugates triggered S and G2/M arrest. Gradual internalization of the chosen conjugate by MCF-7/R cells was monitored via fluorescence microscopy showing its main localization in the cytoplasm.

Amphiphilic ethylenediamine (EDA)-functionalized V-shape and star copolymers with centrally placed methyl-α,D-glucopyranoside were designed as nanocarriers. Anticancer doxorubicin (DOX) was conjugated in water via amine groups in copolymers to form ketimine linkers. Variations of arm length and number (40-65 units per arm and 2 vs 3 vs 4 arms), DOX feed amount, and conjugation site content (50-160 units of EDA groups), as responsible for efficiency of drug attachment (10-60 units of conjugated DOX) and its release at various pH (5.0 vs 7.4), were studied to demonstrate potential for drug delivery. Size of conjugate particles (10-195 nm) formed in aqueous solution was strongly dependent on the polymer composition and topology. The broad range of drug amounts (25-95%) were detected by the precipitation method, showing pH sensitivity by some polymeric conjugates with faster DOX release in acidic conditions.