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Joanna Kolmas,1 Kamil Pajor,1 Lukasz Pajchel,1 Agata Przekora,2 Grażyna Ginalska,2 Ewa Oledzka,3 Marcin Sobczak3 1Department of Inorganic and Analytical Chemistry, Faculty of Pharmacy with Laboratory Medicine Division, Medical University of Warsaw, Warsaw, 2Department of Biochemistry and Biotechnology, Faculty of Pharmacy with Medical Analytics Division, Medical University of Lublin, Lublin, 3Department of Biomaterials Chemistry, Faculty of Pharmacy with Laboratory Medicine Division, Medical University of Warsaw, Warsaw, Poland Abstract: Nanocrystalline hydroxyapatite containing selenite ions (SeHA; 9.6 wt.% of selenium) was synthesized using wet method and subject to careful physicochemical analysis by powder X-ray diffraction, Fourier transform infrared spectroscopy, transmission electron microscopy, solid-state nuclear magnetic resonance, wavelength dispersive X-ray fluorescence, and inductively coupled plasma optical emission spectrometry. SeHA was then used to develop the selenium-containing hydroxyapatite/alginate (SeHA/ALG) composite granules. Risedronate sodium (RIS) was introduced to the obtained spherical microgranules of a size of about 1.1–1.5mm in 2 ways: during the granules’ preparation (RIS solution added to a suspension of ALG and SeHA), and as a result of SeHA/ALG granules soaking in aqueous RIS solution. The analysis made using 13C and 31P cross-polarization magic angle spinning nuclear magnetic resonance confirmed the presence of RIS and its interaction with calcium ions. Then, the release of selenium (inductively coupled plasma optical emission spectrometry) and RIS (high-performance liquid chromatography) from microgranules was examined. Moreover, cytotoxicity of fabricated granules was assessed by MTT test. Selenium release was biphasic: the first stage was short and ascribed to a “burst release” probably from a hydrated surface layer of SeHA crystals, while the next stage was significantly longer and ascribed to a sustained release of selenium from the crystals’ interior. The study showed that the method of obtaining microgranules containing RIS significantly affects its release profile. Performed cytotoxicity test revealed that fabricated granules had high antitumor activity against osteosarcoma cells. However, because of the “burst release” of selenium during the first 10h, the granules significantly reduced viability of normal osteoblasts as well. Keywords: composites, nanocrystalline hydroxyapatite, drug release, cytotoxicity, antitumor activity, ionic substitutions, biomaterials, bisphosphonates

The need for development of comprehensive therapeutic systems, (e.g., polymer-apatite composites) as a bone substitute material has previously been highlighted in many scientific reports. The aim of this study was to develop a new multifunctional composite based on hydroxyapatite porous granules doped with selenite ions (SeO32−) and a biodegradable branched copolymer-bisphosphonate conjugate as a promising bone substitute material for patients with bone tumours or bone metastasis. A series of biodegradable and branched copolymer matrices, adequate for delivery of bisphosphonate in the bone-deficient area were synthesized and physico-chemically and biologically (cyto- and genotoxicity assays) characterized. Branched copolymers were obtained using a hyperbranched bis-MPA polyester-16-hydroxyl initiator and Sn(Oct)2, a (co)catalyst of the ring-opening polymerization (ROP) of l,l-lactide (LLA) and ε-caprolactone (CL). A new amide bond was formed between the hydroxyl end groups of the synthesized copolymer carriers and an amine group of pamidronate (PAM)—the drug inhibiting bone resorption and osteoclast activity in bone. The dependence of the physico-chemical properties of the copolymer matrices on the kinetic release of PAM from the synthesized branched copolymer conjugate-coated hydroxyapatite granules doped with selenite ions was observed. Moreover, the correlation of these results with the hydrolytic degradation data of the synthesized matrices was evidenced. Therefore, the developed composite porous hydroxyapatite doped with SeO32− ions/biodegradable copolymer-PAM conjugate appears most attractive as a bone substitute material for cancer patients.

To evaluate the effects of ionic liquids (ILs) on the microstructural features of aliphatic polyesters for biomedical applications, a series of copolymers were synthesized by lipase ring opening polymerization of rac-lactide (rac-LA) and ε-caprolactone (CL). The chemical structures of resulting polymers were characterized by 1H- and 13C-NMR and the average molecular weight (Mn) and dispersity index were characterized by gel permeation chromatography. The structure of the copolymers confirms the presence of linear polymer chains with end-functional hydroxyl groups allowing covalent coupling of the therapeutic agents. Chain microstructure of copolymers indicates the presence of both random and block copolymers depending on the synthesis conditions. Moreover, it was found that CL is the most active co-monomer during copolymerization which enhances the polymerizability of rac-LA and allows to obtain higher Mn of the copolymers. The results demonstrate that ILs could be promising solvents in synthesis of aliphatic esters for biomedical applications.

The paper is a literature review concerning the preparation and biomedical properties of polyurethanes for pharmaceutical applications. The basic uses of polyurethanes in pharmacy comprise modern drug formulations (including therapeutical systems, carriers and conjugates). Clinical studies indicate that the application of polymer—drug conjugates has a beneficial effect on the therapy efficacy. The introduction of such conjugates into the body results in an increase in drug therapeutic index as an effect of increased drug availability in the affected areas,while at the same time reducing systemic exposure to the drug.Owing to the application of polyurethane conjugates, it is also possible to reduce the side effects and toxicity of drugs. It is expected that the studies on macromolecular drug conjugates (including polyurethanes) will stimulate the development of modern forms of drugs and broadly defined medicinal chemistry.

The effective synthesis of citropin–polymer conjugates was described in this paper. The obtained biodegradable polymeric matrices and polymeric conjugates were characterized using 1 H or 13 C NMR and Fourier transform infrared spectroscopies, gel permeation chromatography and scanning electron microscopy. Toxicity of polymers was evaluated with bacterial luminescence test and two protozoan assays. The in vitro release study of citropin from the obtained conjugates was investigated. The preliminary results of antimicrobial activity of the obtained macromolecular conjugates against Bacillus anthracis , Enterococcus hirae and Staphylococcus aureus were also discussed. The peptide had a high level of antimicrobial activity during 3–5 weeks of the degradation process. The development of biodegradable citropin systems should be of a great interest in the delivery systems of antimicrobial agents.

New macromolecular conjugates of camptothecin were prepared. The polymeric matrixes were obtained by the ring-opening polymerization of ϵ-caprolactone, glycolide, rac-lactide or trimethylene carbonate. The synthesized polymers and camptothecin were coupled via 1,6-diisocyanatohexane. The received macromolecular conjugates of camptothecin were characterized by 1H and 13C-NMR or FT-IR spectroscopy. Toxicity of the received polymeric products were evaluated with bacterial luminescence test and two protozoan assays. Furthermore, the in vitro release of camptothecin from the obtained conjugates was investigated.

The past decade has seen growing interest in the investigation of peptides with antimicrobial activity (AMPs). One approach utilized in infection control is incorporation of antimicrobial agents conjugated with the polymers. This review presents the recent developments on polymeric AMP carriers and their potential applications in the biomedical and pharmaceutical fields.

International audience; The study provides detailed information on the differences in the structural, thermal and degradation properties of poly(ε-caprolactone) synthesized in two different ionic liquids, 1-butyl-3-methylimidazolium hexafluorophosphate [bmim][PF6] and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide [bmim][NTf2], regarding its further usage in the pharmaceutical field. The polymer structure confirms the presence of both linear polymer chains with end-functional hydroxyl groups allowing covalent coupling of the therapeutic agents, and cyclic macromolecules, both affecting the degree of crystallinity of polymer. The highest macrocyclic content (64%) after 7 days of polymerization at 80 8C was observed for [bmim][NTf2]. For [bmim][PF6], the macrocyclic content value was not dependent on the reaction time and remained at a similar level (10–14% at 80 8C). The results of degradation test revealed that hydrolytic degradation of ester bonds is more pronounced for PCLs synthesized in [bmim][NTf2], due to their lower degree of crystallinity compared with PCLs obtained in [bmim][PF6]. A high purity, low polydispersity index of the obtained polymers and high yield of the process (ca., 90%) indicate that ionic liquids seem to be promising solvents for the synthesis of biomedical polymers.

Natural creatine and arginine-6-oligomer have been effectively engaged as ring-opening polymerization initiators of poly(L-lactide) (PLLA) and poly(ɛ-caprolactone) (PCL) in bulk. The nonlinear structure and thermal properties of the resulted polymers were further elucidated by 1H, 13C nuclear magnetic resonance, and a modulated differencial scanning calorimetry (MDSC). Thermal analysis indicated that the synthesized polymers had lower melting points, glass-transition temperatures, fusion enthalpy, and crystallization temperature than those of linear PCL or PLLA due to the presence of the arginine-6-oligomer in the macromolecule and crystalline imperfections caused by the branched structure. This study provides an efficient and metal-free method for the synthesis of branched biodegradable polymers with incorporated compounds, which exhibit therapeutic properties, adequate for the drug carrier applications. Open image in new window

A series of novel star-shaped poly(ϵ-caprolactone) (PCL) biodegradable polyesters were synthesized through ring-opening polymerization of ϵ-caprolactone in the presence of a poly(amidoamine) (PAMAM) dendrimer initiator. The polymers (PAMAM/PCLs) were obtained with a high yield (92%) and a number-average molecular weight of up to 14 000 g/mol. The nonlinear structure of PAMAM/PCLs was confirmed by nuclear magnetic resonance, gel-permeation chromatography, thermogravimetric analysis and differential scanning calorimetry. Thermal analysis indicated that the star-shaped PAMAM/PCLs had a melting point, degree of crystallinity, glass transition temperature and maximum decomposition temperature all lower than those of linear PCL. Ibuprofen (IBU), a popular non-steroidal anti-inflammatory drug, was co-valently (ester) bonded to the PAMAM/PCL molecules using the DCC/DMAP coupling method (DCC, N,N'-dicyclohexylcarbodiimide; DMAP, 4-(dimethylamino)pyridine). A high drug content (33.1 mol%) in the conjugate was obtained. The in-vitro drug-release profiles of IBU from the PAMAM/PCL/IBU conjugate were examined and found adequate for drug-carrier applications of our star-shaped polymers.

The controlled release of 5-fluorouracil (5FU) from aliphatic poly(amide urethane)s (PURs) was studied in vitro. Linear PUR conjugates were prepared by the reaction between oligo(ɛ-caprolactone) (PCL), oligolactide (PLA), copolymers of ɛ-caprolactone (CL) and rac-lactide (rac-LA), dihydroxy(polyethylene adipate) (OEDA) with 1,6-diisocyanatohexane (HDI). Release of 5FU from PURs was found to depend on the nature of oligoester units and consist of soft and hard segments.

Biodegradable polymers/oligomers were successfully synthesized through a ring-opening polymerization of e-caprolactone and L,L-lactide, initiated by L-arginine and L-citrulline. The α-amino acid initiators are natural, operationally simple, inexpensive, environmentally friendly and safe for human health. The polymerizations were performed with no solvents and without introducing any metal impurities. The chemical structures of the polymers obtained were elucidated using 1H NMR, 13C NMR and Fourier transform infrared spectroscopies. In addition, incorporation of α-amino acid molecules into the polymer chain was confirmed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Due to the significant biological activity of L-arginine and L-citrulline, these α-amino acid initiators may open a new route for the synthesis of functional polymers especially for pharmaceutical applications. Copyright © 2011 Society of Chemical Industry

Environmentally friendly organocatalytic synthesis of aliphatic polyesters was studied. The catalysis investigated is novel, and lends itself well to the potential production of valuable biodegradable products. The reactions were based on an organic acids-catalyzed ring-opening polymerization of e-caprolactone with fatty acid derivatives as the initiator and were performed in the absence of solvents. The chemical structures of the functionalized polymers were confirmed by 1H and 13C-NMR spectra. Polymers with different molecular weights, in the range 10,900–15,200 were obtained in the presence of fumaric acid as catalyst. The thermal properties of the functionalized PCLs were determined by modulated differential scanning calorimetry and thermogravimetric analysis. The MDSC results verified that the crystallinity and the melting point of the lipid-functionalized polymers were lower than that of the unfunctionalized poly(e-caprolactone). The hydrolytic degradation of the functionalized polymer was also investigated. The result shows the degradation rate was affected by the presence of oleic acid derivatives in the polymer molecule. The lipid-functionalized polymers synthesized by the metal-free polymerization systems seem to be suitable biodegradable polyesters for use in biomedical and pharmacological applications. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Antimicrobial peptides (AMPs) are prospective therapeutic options for treating multiple-strain infections. However, clinical and commercial development of AMPs has some limitations due to their limited stability, low bioavailability, and potential hemotoxicity. The purpose of this study was to develop new polymeric carriers as highly controlled release devices for amphibian peptides citropin 1.1 (CIT) and temporin A (TEMP). The release rate of the active pharmaceutical ingredients (APIs) was strongly dependent on the API characteristics and the matrix microstructure. In the current work, we investigated the effect of the polymer microstructure on in vitro release kinetics of AMPs. Non-contact laser profilometry, scanning electron microscopy (SEM), and differential scanning calorimetry (DSC) were used to determine the structural changes during matrix degradation. Moreover, geno- and cytotoxicity of the synthesized new carriers were evaluated. The in vitro release study of AMPs from the obtained non-toxic matrices shows that peptides were released with near-zero-order kinetics. The peptide “burst release” effect was not observed. New devices have reached the therapeutic concentration of AMPs within 24 h and maintained it for 28 days. Hence, our results suggest that these polymeric devices could be potentially used as therapeutic options for the treatment of local infections.

The low-molecular weight poly(ϵ -caprolactone) and polylactide were obtained by the polymerization of cyclic esters in the presence of amino acid initiators. The polymer structures were elucidated by means of MALDI TOF, NMR and IR studies. Effects of temperature, reaction time and initiator dosage on the polymerization process were examined.

Novel nickelocene based catalysts were used for polymerization of 2-butyne, 1-phenyl-1-propyne, bis(trimethylsilyl)acetylene and trimethylsilylacetylene. The catalyst prepared in the reaction of nickelocene with organolithium compounds in the presence of alkyne was previously isolated and fully characterized. It enabled us to explain the mechanism of the polymerization. Polymerization of alkynes proceeds according to coordination-insertion mechanism. Coordinated acetylene molecule inserts into Ni C bond. An active catalytic species of polymerization appeared to be {CpNiR} stabilized by alkyne molecule. Cyclization is catalyzed by {CpNiH} species.

Results of the reactions of nickelocene with phenyl- and methyllithium in the presence of bis(trimethylsilyl)acetylene have been reported. It was found that in the reaction of nickelocene with phenyllithium and bis(trimethylsilyl)acetylene three products were formed: di(cyclopentadienylnickel) complex with bis(trimethylsilyl)acetylene (NiCp)2(μ–η2–η2-Me3SiCCSiMe3) (1); di(cyclopentadienylnickel) complex with phenyl(trimethylsilyl)acetylene (NiCp)2(μ–η2–η2-PhCCSiMe3) (2) and tetra(cyclopentadienylnickel) complex with 1,4-bis(trimethylsilyl)-1,3-butadiyne (NiCp)4(μ,μ–η2–η2–η2–η2-Me3SiCCCCSiMe3) (3). Phenyl(trimethylsilyl)acetylene and 1,4-bis(trimethylsilyl)-1,3-butadiyne were the products of coupling and cross-coupling of {CpNiPh} and {CpNiCCSiMe3} formed as intermediate products of the reactions. All products were characterized by spectroscopic methods and crystal and molecular structures of compounds 1 and 3 were determined by single crystal X-ray measurements.

Camptothecin-polylactide conjugates (CMPT-PLA) were synthesized by covalent incorporation of CMPT into PLA of different microstructure, i.e., atactic PLA and atactic-block-isotactically enriched PLA (Pm = 0.79) via urethane bonds. The kinetic release of CPMT from CMPT-PLA conjugates, tested in vitro under different conditions, is possible in both cases and notably, strongly dependent on PLA microstructure. It shows that release properties of drug-PLA conjugates can be tailored by controlled design of the PLA microstructure, and allow in the case of CMPT-PLA conjugates for the development of highly controlled biodegradable CMPT systems—important delivery systems for anti-cancer agents.

In this study, new composite bisphosphonate delivery systems were obtained from polyurethanes (PUs) and nanocrystalline hydroxyapatite (HA). The biodegradable PUs were first synthesized from poly(ε-caprolactone) diols (PCL diols), poly(ethylene adipate) diol, 1,6-hexamethylene diisocyanate, 1,4-butanediol and HA. Moreover, the PCL diols were synthesized by the ring-opening polymerization catalysed by the lipase from Candida antarctica. Next, composite drug delivery systems for clodronate were prepared. The mechanical properties of the obtained biomaterials were determined. The cytotoxicity of the synthesized polymers was tested. The preliminary results show that the obtained composites are perspective biomaterials and they can be potentially applied in the technology of implantation drug delivery systems.

The development and characterization of novel macromolecular conjugates of ampicillin using branched biodegradable polymers has been described in this study. The conjugates have been prepared coupling the β-lactam antibiotic with branched polymer matrices based on the natural oligopeptide core. The cyto- and genotoxicity of the synthesized polymers were evaluated with a bacterial luminescence test, two protozoan assays and Salmonella typhimurium TA1535. The presence of a newly formed covalent bond between the drug and the polymer matrices was confirmed by 1H-NMR and FTIR studies. A drug content (15.6 and 10.2 mole %) in the macromolecular conjugates has been determined. The obtained macromolecular products have been subjected to further in vitro release studies. The total percentage of ampicillin released after 21 days of incubation was nearly 60% and 14% and this resulted from the different physicochemical properties of the polymeric matrices. This is the first report on the application of branched biodegradable polymeric matrices for the covalent conjugation of ampicillin. The obtained results showed that the synthesized macromolecular drug-conjugates might slowly release the active drug molecule and improve the pharmacokinetics of ampicillin.

Recently, particular interest of scientists has been focused on biomedical polymers, especially those used for drug delivery systems, therapeutic systems and macromolecular prodrugs. The aforementioned applications have opened new exciting prospects for medicine, because specially designed polymers are capable of delivering medicinal substances to the target diseased tissues and cells together with dosing those drugs according to controlled specified pharmacodynamics. Particular attention has recently been paid to chemistry of biocompatiable and biodegradable polymers, because they have an advantage of being readily hydrolyzed into removable and non-toxic products, which can be subsequently eliminated by metabolic pathways. Furthermore, the biomedical polymers have to be synthesized now using friendly for the environment and safe for human health, effective natural initiators, co-initiators and/or catalysts.

Two-, three- and four-arm, star-shaped poly(epsilon-caprolactone) and poly(D,L-lactide) homopolymers, and copolymers of epsilon-caprolactone with D,L-lactide were synthesized via ring-opening polymerization of cyclic esters in the presence of glycerol, penthaerythritol and poly(ethylene glycol) as initiators and stannous octoate as a catalyst. Thus obtained oligomers were successfully used in the synthesis of novel macromolecular prodrugs of norfloxacin. The structures of the polymers and prodrugs were elucidated by means of MALDI-TOF MS, NMR and IR studies.

A novel initiator, naturally occurring in soy, has been developed for a direct synthesis of aliphatic star-shaped homo- and copolyesters. The synthesis is based on one of several known isoflavones, genistein, which has been employed as an initiator of homopolymerization of poly(l-Lactide) or co-initiator of copolymerization of e-caprolactone and l-Lactide with Sn(Oct)2 as a catalyst. The non-toxic chemicals used allow for an inexpensive and safe for human body facile synthesis of biocompatible functionalized polymers suitable for medical and pharmaceutical applications. The obtained polymers were characterized by 1H, 13C NMR, FT-IR, SEC–MALLS and MALDI-TOF MS analysis.

The pharmacy is one of the most important areas in which the macromolecular compounds are applied. They are used as pharmacological substances, blood substitutes, various auxiliary materials or excipients as well as in the production of macromolecular prodrugs, polymeric drug delivery systems, therapeutic systems, etc. (Table 1 and 2). The prodrugs, polymeric drug delivery systems and therapeutic systems are characterized with unique pharmacokinetics, ability to distribute precisely the drugs in the organism as well as pharmacological efficiency. In this paper the natural, modified and synthetic polymers and examples of their applications were described.