Covalent segmented polymer networks composed of poly(2-isopropenyl-2-oxazoline) and selected aliphatic polyesters: designing biocompatible amphiphilic materials containing degradable blocks.

To promote facile and efficient synthesis of segmented covalent networks, we developed a cross-linking process with reactive polymeric components in a system without catalysts or side products. To achieve the direct formation of amphiphilic networks, an addition reaction was performed between the polyesters containing carboxyl terminal groups with pendant groups distributed along poly(2-isopropenyl-2-oxazoline) chains. Covalent cross-linking was achieved from predetermined amounts of components dissolved in DMSO at 140 °C. To tune the properties of the resulting networks, the composition and length of the polyester segments and the degree of cross-linking were changed in the feed. The chemical structure of the networks was characterized using Fourier transform infrared-attenuated total reflection spectroscopy and 13C magic-angle spinning NMR. The swelling ability of the formed networks was investigated in aqueous and organic media. Moreover, mechanical properties were tested during uniaxial compression. The cytocompatibility of the scaffolds was confirmed by MTT assay. Through the results obtained, the first report describing the cross-linking of polyesters on hydrophilic PiPOx was provided to prepare new, biocompatible materials with tuneable properties that are promising for potential biomedical applications.

Functionalization of Polylactide with Multiple Tetraphenyethane Inifer Groups to Form PLA Block Copolymers with Vinyl Monomers.

In the present contribution, a new strategy for preparing block copolymers of polylactide (PLA), a bio-derived polymer of increasing importance, is described. The method should lead to multiblock copolymers of lactide with vinyl monomers (VM), i.e., monomers that polymerize according to different mechanisms, and is based on the introduction of multiple "inifer" (INItiator/transFER agent) groups into PLA's structure. As an "inifer" group, tetraphenylethane (TPE, known to easily thermally dissociate to radicals) was incorporated into PLA chains using diisocyanate. PLA that contained TPE groups (PLA-PU) was characterized, and its ability to form initiating radicals was demonstrated by ESR measurements. PLA-PU was used as a "macroinifer" for the polymerization of acrylonitrile and styrene upon moderate heating (85 °C) of the PLA-PU in the presence of monomers. The formation of block copolymers PLA/PVM was confirmed by 1H NMR, DOSY NMR, and FTIR spectroscopies and the SEC method. The prepared copolymers showed only one glass transition in DSC curves with Tg values higher than those of PLA-PU.

A simple strategy for efficient preparation of networks based on poly(2-isopropenyl-2-oxazoline), poly(ethylene oxide), and selected biologically active compounds: Novel hydrogels with antibacterial properties.

Novel polymer networks composed of biocompatible, hydrophilic poly(2-isopropenyl-2-oxazoline) (PiPOx), poly(ethylene oxide) (PEO), and selected biologically active compounds (cinnamic acid, benzoic acid or eugenol) were developed for potential antimicrobial applications. The applied crosslinking method, based on the addition reaction between oxazoline pendant groups and chosen reagents containing carboxyl functions, is relatively facile, free from by-products, and thus well suited for biomaterial preparation. The one-step synthesis enabled efficient network formation with high gel contents (>90%). The chemical structure of the newly synthesized networks was characterized using Fourier Transform Infrared-attenuated Total Reflection spectroscopy (FTIR-ATR) and 13C Magic-Angle Spinning (MAS) NMR. To evaluate the suitability for biomedical applications, swelling in water and the mechanical properties of the networks were investigated. The antimicrobial efficacy of the prepared hydrogels was tested in neutral medium both by the agar diffusion method and in the liquid culture against Gram-positive and Gram-negative strains: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter cloaceae. All the tested hydrogels showed an antimicrobial effect in the direct contact zone. Moreover, the eugenol loaded hydrogel expressed a broader bacteriostatic effect inhibiting microorganism growth beyond the contact zone. These form-stable hydrogels with antibacterial properties may be of interest for designing materials dedicated to biomedical applications.

Biocompatible Polymers Combined with Cyclodextrins: Fascinating Materials for Drug Delivery Applications.

Cyclodextrins (CD) are a group of cyclic oligosaccharides with a cavity/specific structure that enables to form inclusion complexes (IC) with a variety of molecules through non-covalent host-guest interactions. By an elegant combination of CD with biocompatible, synthetic and natural polymers, different types of universal drug delivery systems with dynamic/reversible properties have been generated. This review presents the design of nano- and micro-carriers, hydrogels, and fibres based on the polymer/CD supramolecular systems highlighting their possible biomedical applications. Application of the most prominent hydrophobic aliphatic polyesters that exhibit biodegradability, represented by polylactide and polycaprolactone, is described first. Subsequently, particular attention is focused on materials obtained from hydrophilic polyethylene oxide. Moreover, examples are also presented for grafting of CD on polysaccharides. In summary, we show the application of host-guest interactions in multi-component functional biomaterials for controlled drug delivery.

Stereocomplexed microparticles loaded with Salvia cadmica Boiss. extracts for enhancement of immune response towards Helicobacter pylori.

Controlled delivery of therapeutic substance gives numerous advantages (prevents degradation, improves uptake, sustains concentration, lowers side effects). To encapsulate Salvia cadmica extracts (root or aerial part), enriched with polyphenols with immunomodulatory activity, in stereocomplexed microparticles (sc-PLA), for using them to enhance the immune response towards gastric pathogen Helicobacter pylori. Microparticles were made of biodegradable poly(lactic acid) (PLA) and poly(D-lactic acid) (PDLA). Their stereocomplexation was used to form microspheres and enhance the stability of the obtained particles in acidic/basic pH. The release of Salvia cadmica extracts was done in different pH (5.5, 7.4 and 8.0). The obtained polymers are safe in vitro and in vivo (guinea pig model). The sc-PLA microparticles release of S. cadmica extracts in pH 5.5, 7.4, and 8.0. S. cadmica extracts enhanced the phagocytic activity of guinea pig bone marrow-derived macrophages, which was diminished by H. pylori, and neutralized H. pylori driven enhanced production of tumor necrosis factor (TNF)-α and interleukin (IL)-10. The sc-PLA encapsulated S. cadmica extracts can be recommended for further in vivo study in guinea pigs infected with H. pylori to confirm their ability to improve an immune response towards this pathogen.

Synthesis and Characterization of Functionalized Polylactides Containing Acetal Units.

New functionalized lactide copolymers containing acetal units were prepared for the first time in a controlled manner that enabled the regulation of the number of reactive groups introduced into the polyester chain. The presence of functional groups in the copolymer backbone provided chemical modification sites, and the nature of the acetal unit affected the material degradability. First, paraformaldehyde was reacted with selected diols containing reactive pendant groups (3-allyloxypropane-1,2-diol and 3-chloropropane-1,2-diol), which was catalyzed by p-toluenesulfonic acid, to synthesize new cyclic acetals with different functionalities (allyl- or chloro-). In addition, using butane-1,4-diol, a nonfunctionalized seven-membered cyclic acetal (dioxepane) was obtained for comparative studies. In the next step, the prepared cyclic acetals were used for cationic copolymerization with lactide in the presence of glycol as an initiator and triflic acid as a catalyst. Different temperatures (-15, 2, and 30 °C) and copolymerization times (24, 48, 72, and 192 h) were investigated to produce copolyesters with variable contents of acetal units in the range of 5-27%. The copolymers' structure and molar masses were carefully investigated using 1H, 13C NMR, 2D NMR, and size-exclusion chromatography. Moreover, the ability of functionalized copolymers to perform post modifications was also proven by the reaction with sodium azide and propanethiol. Finally, we speculate that structurally diverse groups can be attached to the copolyester chain, fine-tuning the on-demand properties, which could rapidly expand the library of polylactide-based materials.

A New Approach to The Synthesis of Polylactide/Polyacrylonitrile Block Copolymers.

As a result of the search for alternatives to the known methods for the synthesis of PLA/vinyl polymer block copolymers, a new approach based on the "iniferter" concept was demonstrated in this article. In this approach, the introduction of a group that was capable of forming radicals and initiating radical polymerization into the polylactide (PLA) chain was conducted. Then, the obtained functional PLA was heated in the presence of a radically polymerizable monomer. The tetraphenylethane (TPE) group was chosen as a group that could dissociate to radicals. PLA with a TPE group in the middle of the chain was prepared in several steps as follows: (1) the synthesis of 4-(2-hydroxyethoxy)benzophenone (HBP-ET); (2) the polymerization of lactide, which was initiated with HBP-ET; and (3) the coupling of HBP-ET chains under UV radiation to form TPE-diET_PLA. A "macroiniferter", i.e., TPE-diET_PLA, was used to initiate the polymerization of acrylonitrile (AN) by heating substrates at 85 °C. 1H and 13C NMR and SEC analyses of the products indicated that the triblock copolymer PLA-PAN-PLA formed and thus confirmed the assumed mechanism of the initiation of AN polymerization, which relied on the addition of the radical that formed from TPE (linked with the PLA chain) to the monomer molecule. Copolymerizations were performed with the application of prepared TPE-diET_PLA with three different Mn's (1400, 2200, and 3300) and with different AN/PLA ratios, producing copolymers with varied compositions, i.e., with AN/LA ratios in the range of 2.3-11.1 and Mn's in the range of 5100-9400. It was shown that the AN/LA ratio in the copolymer was increasable by the applied excess of AN with respect to the PLA macroiniferter in the feed and that more AN monomer was able to be introduced to PLA with shorter chains.

Microfluidic preparation of antimicrobial microparticles composed of l-lactide/1,3-dioxolane (co)polymers loaded with quercetin.

The resistance of microorganisms against commonly used antibiotics is becoming an increasingly important problem in the food and pharmaceutical industries. Therefore, the development of novel bactericidal agents, as well as the design of drug delivery systems based on materials composed of biocompatible and biodegradable building blocks, has attracted increasing attention. To address this challenge, microparticles composed of l-lactide homopolymer and l-lactide/1,3-dioxolane (co)polymers loaded with quercetin (Q) were fabricated by using a microfluidic technique. This method enables the preparation of homogeneous particles with sizes ranging from 60 to 80 µm, composed of degradable semicrystalline or amorphous (co)polyesters. The microencapsulation of Q in a (co)polymeric matrix enables prolonged release of the antimicrobial agent. The antibacterial properties of the obtained biocompatible microparticles are confirmed by the agar diffusion plate method for various bacterial strains. Therefore, Q-loaded microparticles can have important applications in food preservation as a novel antimicrobial system.

Microfluidic-assisted nanoprecipitation of biodegradable nanoparticles composed of PTMC/PCL (co)polymers, tannic acid and doxorubicin for cancer treatment.

This study was aimed towards the development of a novel microfluidic approach for the preparation of (co)polymeric and hybrid nanoparticles (NPs) composed of (co)polymers/tannic acid (TA) in the microfluidic flow-focusing glass-capillary device. The MiliQ water was used as water phase, whereas the organic phase was composed of poly(ε-caprolactone) (PCL) and poly(trimethylene carbonate) (PTMC) homopolymers and (co)polymers with different proportion of comonomers which were prepared via enzymatic polymerization that allows avoiding the usage of potentially toxic catalyst. To prepare hybrid NPs, TA was additionally added to the organic phase. Subsequently, as a result of mixing between these distinct phases in microfluidic channels, the nanoprecipitation in the form of spherical NPs occurs. The size of NPs was tuned over the range of 140-230 nm by controlling phase flow rates and the composition of NPs. Moreover, the release studies of the encapsulated anticancer drug doxorubicin (DOX) demonstrated that the drug release is greatly influenced by the (co)polymers composition, their molecular weight, NPs size, and the presence of TA. The antitumor activities of the (co)polymeric and hybrid NPs toward breast cancer cells (MCF-7) were tested in vitro. Among all tested formulation, the NPs composed of PCL/TA most efficiently inhibit the cell proliferation of MCF-7 cells, most importantly, their efficiency was higher than free DOX. The proposed strategy may provide an efficient alternative for the construction of nanocarriers with great potential in anticancer therapy.

PLA/ß-CD-based fibres loaded with quercetin as potential antibacterial dressing materials.

Microbial infections lead to elevated inflammatory responses, which usually result in prolonged and incomplete wound healing. Therefore, there is an increasing demand for biodegradable fibres that are effective against a different range of microorganisms, especially those with antibiotic resistance. Herein, quercetin-(Q)-loaded polylactide-based fibres were developed using the electrospinning technique. Since Q exhibits low chemical stability, we used star-shaped polylactides (PLAs) with a ß-CD core to host Q by inclusion complexation. To enhance the stability of the fibres and additionally entrap the Q between polymeric chains, we adapted supramolecular cross-linking by the stereocomplexation of PLAs with opposite configurations. As a control, we prepared an additional formulation of star-shaped/commercial PLA/Q for the preparation of nonwovens in which the ß-CD moiety was not present. All developed fibres were smooth and continuous, with an average diameter of 37 µm. Although nonwovens did not possess diffusible activity, good antibacterial effects against Staphylococcus aureus (S. aureus), Escherichia coli (E.coli) and Klebsiella pneumoniae (K. pneumoniae) were observed. All these features validate the proposed approach, in which different supramolecular interactions were used to modify the properties of PLA-based fibres and, most importantly, show their great potential usefulness against microbial infections.

Hydrophilic Polyhedral Oligomeric Silsesquioxane, POSS(OH)32, as a Complexing Nanocarrier for Doxorubicin and Daunorubicin.

A novel strategy, recently developed by us, to use polyhedral oligomeric silsesquioxanes (POSS) as an anti-cancer drug carrier is presented. Anthracycline:POSS complexes were prepared by simple co-addition of doxorubicin (DOX) or daunorubicin (DAU) with hydrophilic POSS(OH)32. Co-delivery of POSS and anthracyclines led to higher anti-cancer activity towards HeLa (cervical cancer endothelial) and MCF-7 (human breast adenocarcinoma) cell lines. The obtained supramolecular hybrid complexes were characterised by nuclear magnetic resonance (NMR) spectroscopy (nuclear Overhauser effect spectroscopy [NOESY] and homonuclear correlation spectroscopy [COSY]), Fourier transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS). The two-dimensional (2D) NOESY spectra of the complexes showed the cross-correlation peaks for hydroxyl groups of POSS (~4.3-4.8 ppm) with OH groups of DOX and DAU. FTIR showed that hydroxyl group of POSS can interact with amine and hydroxyl groups of DOX and DAU. The viability of HeLa and MCF-7 was analysed with the MTT assay to evaluate the cytotoxicity of free DOX and DAU and the relevant complexes with POSS at different molar ratios. At a low DOX concentration (2.5 µM), for molar ratios 1:1, 1:4, and 1:8 (POSS:DOX), the complexes showed two and three times higher cytotoxicity towards HeLa and MCF-7 cells, respectively, than DOX itself after both 24- and 48-h incubation. The 1 µM concentration for a 1:4 POSS:DOX molecular ratio and the 2.5 µM concentration for all complexes were more toxic towards MCF-7 cells than free DOX after 48-h incubation. In the case of POSS:DAU complexes, there was higher toxicity than that of free drug after 48-h incubation. It can be concluded that the formation of non-covalent complexes increases toxicity of anthracycline drugs towards Hela and MCF-7 cells. The novel complexes are inexpensive to prepare and more effective than free drugs at low systemic toxicity.