Poly(sebacic acid) microparticles loaded with azithromycin as potential pulmonary drug delivery system: Physicochemical properties, antibacterial behavior, and cytocompatibility studies.

Recurrent bacterial infections are a common cause of death for patients with cystic fibrosis and chronic obstructive pulmonary disease. Herein, we present the development of the degradable poly(sebacic acid) (PSA) microparticles loaded with different concentrations of azithromycin (AZ) as a potential powder formulation to deliver AZ locally to the lungs. We characterized microparticle size, morphology, zeta potential, encapsulation efficiency, interaction PSA with AZ and degradation profile in phosphate buffered saline (PBS). The antibacterial properties were evaluated using the Kirby-Bauer method against Staphylococcus aureus. Potential cytotoxicity was evaluated in BEAS-2B and A549 lung epithelial cells by the resazurin reduction assay and live/dead staining. The results show that microparticles are spherical and their size, being in the range of 1-5 µm, should be optimal for pulmonary delivery. The AZ encapsulation efficiency is nearly 100 % for all types of microparticles. The microparticles degradation rate is relatively fast - after 24 h their mass decreased by around 50 %. The antibacterial test showed that released AZ was able to successfully inhibit bacteria growth. The cytotoxicity test showed that the safe concentration of both unloaded and AZ-loaded microparticles was equal to 50 µg/ml. Thus, appropriate physicochemical properties, controlled degradation and drug release, cytocompatibility, and antibacterial behavior showed that our microparticles may be promising for the local treatment of lung infections.

Stimuli-Responsive Star Polymer as an Admixture for Crystallization of Hollow Crystals.

Polymers are becoming a very popular tool in the crystallization of different compounds. In this work, a new method of crystallization is proposed using stimuli-responsive star polymer in order to obtain hollow structure crystals. In these experiments, amphiphilic copolymer of acrylic acid (AA) and methyl acrylate (MA) were used for isohydric crystallization via they cooling of KCl in deionized water solution. The experiments were realized in quartz cuvette with a magnetic stirrer using a specialized spectrometer with precise temperature control. The crystallization course was monitored by the absorbance readings and analysis of the nucleation energetic effect. It was proved that the moment of the polymer's phase transition occurrence had an important role in the crystal growth process. On the other hand, the occurrence of phase transition did not trigger the nucleation. The supercoolings achieved in the presence of the polymer were significantly higher compared to pure salt crystallization. On the basis of analysis of Particle Size Distribution (PSD) and Critical Aggregation Concentration (CAC) of the polymer, it was proposed that the hydrophobic particles of macromolecules created from polymeric aggregates served as templates for the formation of hollow crystals. Their purity was verified using thermogravimetric analysis (TGA), 1H NMR, and XRD. Only trace amounts of polymer were found in the crystalline product.

Highly Branched Betulin Based Polyanhydrides for Self-Assembled Micellar Nanoparticles Formulation.

Polyanhydrides based on betulin are promising materials for use in controlled drug delivery systems. Due to the broad biological activity of betulin derivatives and lack of toxicity in vitro and in vivo, these polymers can be used both as polymeric prodrug and as carriers of other biologically active compounds. In this study, we develop a novel amphiphilic branched polyanhydrides synthesized by the two-step melt polycondensation of betulin disuccinate (DBB) and a tricarboxylic derivative of poly(ethylene glycol) (PEG_COOH). DBB and PEG_COOH were used as the hydrophobic and hydrophilic segments, respectively. The content of DBB in copolymers was from 10 to 95 wt%. Copolymers were assessed for their cytostatic activity against various cancer cell lines. Compared to linear DBB and PEG-based polyanhydrides, the branched polyanhydrides exhibited higher anticancer activity. The obtained polymers were able to self-assemble in water to form micelles with hydrodynamic diameters from 144.8 to 561.8 nm. and are stable over a concentration range from 12.5 µg/mL to 6.8 mg/mL. The formed micelles were found to be spherical in shape using a scanning electron microscope. It was found that the structure and composition of polyanhydrides affected the hydrodynamic diameter of the micelles. The branched betulin-based polyanhydrides have the potential to serve as biodegradable polymer prodrugs or carriers for other bioactive compounds.

Biodegradable and Bioactive Carriers Based on Poly(betulin disuccinate-co-sebacic Acid) for Rifampicin Delivery.

This paper describes the preparation and characterization of polymer-drug systems based on polymeric microspheres obtained from poly(betulin disuccinate-co-sebacic acid). The active compound that was coupled to the betulin-based carriers was rifampicin (RIF), an ansamycin drug used in the treatment of tuberculosis. Poly(betulin disuccinate-co-sebacic acid) microspheres were prepared using a solvent evaporation technique from copolymers obtained by polycondensation of betulin disuccinate (DBB) and sebacic acid (SEB). The content of sebacic acid in the copolymers was 20, 40, 60 and 80 wt%, respectively. Small and large rifampicin-loaded microspheres were obtained for each of the copolymers. The initial amount of drug was 10, 30 or 50 wt%, based on the weight of the polymer. Particles obtained in this study were round in shape with diameter in the range of 2-21 µm and of orange to red colour originating from rifampicin. The RIF encapsulation efficacy varied from 7% to 33%. Drug loading varied from 2% to 13% and increased at a higher RIF ratio. The highest degree of drug loading was observed for large particles, in which the initial amount of drug (at the particle preparation stage) was 50 wt%. Microspheres prepared from betulin-based polyanhydrides may have significant applications in drug delivery systems. The concentration of loaded drug was enough to obtain bactericidal effects against reference S. Aureus ATCC 25923 bacteria.

Bioactive Betulin and PEG Based Polyanhydrides for Use in Drug Delivery Systems.

In the course of this study, a series of novel, biodegradable polyanhydrides based on betulin disuccinate and dicarboxylic derivatives of poly(ethylene glycol) were prepared by two-step polycondensation. These copolymers can be used as carriers in drug delivery systems, in the form of microspheres. Betulin and its derivatives exhibit a broad spectrum of biological activity, including cytotoxic activity, which makes them promising substances for use as therapeutic agents. Microspheres that were prepared from betulin based polyanhydrides show promising properties for use in application in drug delivery systems, including inhalation systems. The obtained copolymers release the active substance-betulin disuccinate-as a result of hydrolysis under physiological conditions. The use of a poly(ethylene glycol) derivative as a co-monomer increases the solubility and bioavailability of the obtained compounds. Microspheres with diameters in the range of 0.5-25 µm were prepared by emulsion solvent evaporation method and their physicochemical and aerodynamic properties were analyzed. The morphological characteristics of the microspheres depended on the presence of poly(ethylene glycol) (PEG) segment within the structure of polyanhydrides. The porosity of the particles depended on the amount and molecular weight of the PEG used and also on the speed of homogenization. The most porous particles were obtained from polyanhydrides containing 20% wt. of PEG 600 by using a homogenization speed of 18,000 rpm.

Novel polymeric derivatives of betulin with anticancer activity.

In order to provide novel polymeric biomaterials for chemotherapeutic purposes, in this paper we described the synthesis and the characterization of the physicochemical properties of a betulin-based polyanhydride exhibiting anti-cancer effects. The polyanhydride was obtained by a melt polycondensation of a disuccinate betulin (3,28-di-O-succinyl betulin), and was thoroughly characterized through 1H NMR and 13C NMR spectroscopies, correlation spectroscopy, heteronuclear single quantum correlation, size exclusion chromatography, differential scanning calorimetry and FT-IR spectroscopy. It was confirmed, that the obtained polyanhydride undergoes hydrolytic degradation, releasing disuccinate betulin as a degradation product. Polyanhydride of a disuccinate betulin was tested for cytostatic activity against a wide range of cancer cell lines (HeLa, MCF-7, A-549, U-87MG, KB and HepG2), proving its efficiency in inhibiting the growth of selected cancer cells. To realize the concept of an easily administrated drug release system, polyanhydride was fabricated in a form of micro- (1-30 µm) and nanospheres (∼400 nm) by using an emulsion solvent evaporation method. The micro- and nanospheres were characterized by SEM.