Spray-dried ternary bioactive glass microspheres: Direct and indirect structural effects of copper-doping on acellular degradation behavior.

Silicate-based bioactive glass nano/microspheres hold significant promise for bone substitution by facilitating osteointegration through the release of biologically active ions and the formation of a biomimetic apatite layer. Cu-doping enhances properties such as pro-angiogenic and antibacterial behavior. While sol-gel methods usually yield homogeneous spherical particles for pure silica or binary glasses, synthesizing poorly aggregated Cu-doped ternary glass nano/microparticles without a secondary CuO crystalline phase remains challenging. This article introduces an alternative method for fabricating Cu-doped ternary microparticles using sol-gel chemistry combined with spray-drying. The resulting microspheres exhibit well-defined, poorly aggregated particles with spherical shapes and diameters of a few microns. Copper primarily integrates into the microspheres as Cu0 nanoparticles and as Cu2+ within the amorphous network. This doping affects silica network connectivity, as calcium and phosphorus are preferentially distributed in the glass network (respectively as network modifiers and formers) or involved in amorphous calcium phosphate nano-domains depending on the doping rate. These differences affect the interaction with simulated body fluid. Network depolymerization, ion release (SiO44-, Ca2+, PO43-, Cu2+), and apatite nanocrystal layer formation are impacted, as well as copper release. The latter is mainly provided by the copper involved in the silica network and not from metal nanoparticles, most of which remain in the microspheres after interaction. This understanding holds promising implications for potential therapeutic applications, offering possibilities for both short-term and long-term delivery of a tunable copper dose. STATEMENT OF SIGNIFICANCE: A novel methodology, scalable to industrial levels, enables the synthesis of copper-doped ternary bioactive glass microparticles by combining spray-drying and sol-gel chemistry. It provides precise control over the copper percentage in microspheres. This study explores the influence of synthesis conditions on the copper environment, notably Cu0 and Cu2+ ratios, characterized by EPR spectroscopy, an aspect poorly described for copper-doped bioactive glass. Additionally, copper indirectly affects silica network connectivity and calcium/phosphorus distribution, as revealed by SSNMR. Multiscale characterization illustrates how these features impact acellular degradation in simulated body fluid, highlighting the therapeutic potential for customizable copper dosing to address short- and long-term needs.

α-Aminobisphosphonate Copolymers Based on Poly(ε-caprolactone)s and Poly(ethylene glycol): A New Opportunity for Actinide Complexation.

Original α-aminobisphosphonate-based copolymers were synthesized and successfully used for actinide complexation. For this purpose, poly(α-chloro-ε-caprolactone-co-ε-caprolactone)-b-poly(ethylene glycol)-b-poly(α-chloro-ε-caprolactone-co-ε-caprolactone) copolymers were first prepared by ring-opening copolymerization of ε-caprolactone (εCL) and α-chloro-ε-caprolactone using poly(ethylene glycol) (PEG) as a macro-initiator and tin(II) octanoate as a catalyst. The chloride functions were then converted to azide moieties by chemical modification, and finally α-aminobisphosphonate alkyne ligand (TzBP) was grafted using click chemistry, to afford well-defined poly(αTzBPεCL-co-εCL)-b-PEG-b-poly(αTzBPεCL-co-εCL) copolymers. Three copolymers, showing different α-aminobisphosphonate group ratios, were prepared (7, 18, and 38%), namely, CP8, CP9, and CP10, respectively. They were characterized by 1H and 31P NMR and size exclusion chromatography. Sorption properties of these copolymers were evaluated by isothermal titration calorimetry (ITC) with neodymium [Nd(III)] and cerium [Ce(III)] cations, used as surrogates of actinides, especially uranium and plutonium, respectively. ITC enabled the determination of the full thermodynamic profile and the calculation of the complete set of thermodynamic parameter (ΔH, TΔS, and ΔG), with the Ka constant and the n stoichiometry. The results showed that the number of cations sorbed by the functional copolymers logically increased with the number of bisphosphonate functions borne by the macromolecular chain, independently of the complexed cation. Additionally, CP9 and CP10 copolymers showed higher sorption capacities [21.4 and 34.0 mg·g-1 for Nd(III) and 9.6 and 14.3 mg·g-1 for Ce(III), respectively] than most of the systems previously described in the literature. CP9 also showed a highest binding constant (7000 M-1). These copolymers, based on non-toxic and biocompatible poly(ε-caprolactone) and PEG, are of great interest for external body decontamination of actinides as they combine high number of complexing groups, thus leading to great decontamination efficiency, and limited diffusion through the skin due to their high-molecular weight, thus avoiding additional possible internal contamination.

Polyester-Polydopamine Copolymers for Intravitreal Drug Delivery: Role of Polydopamine Drug-Binding Properties in Extending Drug Release.

This work reports on a novel polyester copolymer containing poly(dopamine), a synthetic analogue of natural melanin, evaluated in a sustained-release drug delivery system for ocular intravitreal administration of drugs. More specifically, a graft copolymer of poly(ε-caprolactone)-graft-poly(dopamine) (PCL-g-PDA) has been synthesized and was shown to further extend the drug release benefits of state-of-the-art biodegradable intravitreal implants composed of poly(lactide) and poly(lactide-co-glycolide). The innovative biomaterial combines the documented drug-binding properties of melanin naturally present in the eye, with the established ocular tolerability and biodegradation of polyester implants. The PCL-g-PDA copolymer was obtained by a two-step modification of PCL with a final PDA content of around 2-3 wt % and was fully characterized by size exclusion chromatography, NMR, and diffusion ordered NMR spectroscopy. The thermoplastic nature of PCL-g-PDA allowed its simple processing by hot-melt compression molding to prepare small implants. The properties of unmodified PCL and PCL-g-PDA implants were studied and compared in terms of thermal properties (differential scanning calorimetry), thermal stability (thermogravimetry analysis), degradability, and in vitro cytotoxicity. PCL and PCL-g-PDA implants exhibited similar degradation properties in vitro and were both stable under physiological conditions over 110 days. Likewise, both materials were non-cytotoxic toward L929 and ARPE-19 cells. The drug loading and in vitro release properties of the new materials were investigated with dexamethasone (DEX) and ciprofloxacin hydrochloride (CIP) as representative drugs featuring low and high melanin-binding affinities, respectively. In comparison to unmodified PCL, PCL-g-PDA implants showed a significant extension of drug release, most likely because of specific drug-catechol interaction with the PDA moieties of the copolymer. The present study confirms the advantages of designing PDA-containing polyesters as a class of biodegradable and biocompatible thermoplastics that can modulate and remarkably extend the drug release kinetics thanks to their unique drug-binding properties, especially, but not limited to, for ocular applications.

Aliphatic polyesters for medical imaging and theranostic applications.

Medical imaging is a cornerstone of modern medicine. In that context the development of innovative imaging systems combining biomaterials and contrast agents (CAs)/imaging probes (IPs) for improved diagnostic and theranostic applications focuses intense research efforts. In particular, the classical aliphatic (co)polyesters poly(lactide) (PLA), poly(lactide-co-glycolide) (PLGA) and poly(ɛ-caprolactone) (PCL), attract much attention due to their long track record in the medical field. This review aims therefore at providing a state-of-the-art of polyester-based imaging systems. In a first section a rapid description of the various imaging modalities, including magnetic resonance imaging (MRI), optical imaging, computed tomography (CT), ultrasound (US) and radionuclide imaging (SPECT, PET) will be given. Then, the two main strategies used to combine the CAs/IPs and the polyesters will be discussed. In more detail we will first present the strategies relying on CAs/IPs encapsulation in nanoparticles, micelles, dendrimers or capsules. We will then present chemical modifications of polyesters backbones and/or polyester surfaces to yield macromolecular imaging agents. Finally, opportunities offered by these innovative systems will be illustrated with some recent examples in the fields of cell labeling, diagnostic or theranostic applications and medical devices.

Design and Development of Immunomodulatory Antigen Delivery Systems Based on Peptide/PEG-PLA Conjugate for Tuning Immunity.

Cancer vaccines are considered to be a promising tool for cancer immunotherapy. However, a well-designed cancer vaccine should combine a tumor-associated antigen (TAA) with the most effective immunomodulatory agents and/or delivery system to provoke intense immune responses against the TAA. In the present study, we introduced a new approach by conjugating the immunomodulatory molecule LD-indolicidin to the hydrophilic chain end of the polymeric emulsifier poly(ethylene glycol)-polylactide (PEG-PLA), allowing the molecule to be located close to the surface of the resulting emulsion. A peptide/polymer conjugate, named LD-indolicidin-PEG-PLA, was synthesized by conjugation of the amine end-group of LD-indolicidin to the N-hydroxysuccinimide-activated carboxyl end-group of PEG. As an adjuvant for cancer immunotherapeutic use, TAA vaccine candidate formulated with the LD-indolicidin-PEG-PLA-stabilized squalene-in-water emulsion could effectively help to elicit a T helper (Th)1-dominant antigen-specific immune response as well as antitumor ability, using ovalbumin (OVA) protein/EG7 cells as a TAA/tumor cell model. Taken together, these results open up a new approach to the development of immunomodulatory antigen delivery systems for vaccine adjuvants and cancer immunotherapy technologies.

Thermo-responsive drug release from self-assembled micelles of brush-like PLA/PEG analogues block copolymers.

Thermo-responsive brush-like amphiphilic poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate]-b-poly(l-lactide)-b-poly[2-(2-methoxyethoxy) ethyl methacrylate-co-oligo(ethylene glycol) methacrylate] [P(MEO2MA-co-OEGMA)-b-PLLA-b-P(MEO2MA-co-OEGMA)] triblock copolymers were synthesized by atom transfer radical polymerization of MEO2MA and OEGMA co-monomers using a α,ω-Bromopropionyl poly(l-lactide) (Br-PLLA-Br) macroinitiator. The resulting copolymers with MEO2MA/OEGMA molar ratio ranging from 79/21 to 42/58 were characterized by (1)H nuclear magnetic resonance and size exclusion chromatography. Thermo-responsive micelles were obtained by self-assembly of copolymers in aqueous medium. The micelles are spherical in shape with sizes varying from 20.7 to 102.5 nm. A hydrophobic anticancer drug, curcumin, was encapsulated in micelles by using membrane hydration method. The properties of drug loaded micelles were determined by dynamic light scattering, transmission electron microscopy and lower critical solution temperature (LCST) measurements. The micelles size decreases from 102.5 nm for blank micelles to 37.6 nm with 10.8% drug loading, suggesting that the drug plays an important role in the micellization procedure. The LCST decreases from 45.1°C for blank micelles to 40.6 and 38.3°C with 5.9 and 10.8% drug loading, respectively. In vitro drug release was performed in pH 7.4 PBS at different temperatures. Data show that the release rate was significantly enhanced above the LCST comparing with that below the LCST. The amount of released drug at 41°C was ca. 20% higher than that at 37°C. Burst-like release was depressed due to enhanced interaction between drug with hydrophobic PLA and PMA chains.

Thermo-responsive release of curcumin from micelles prepared by self-assembly of amphiphilic P(NIPAAm-co-DMAAm)-b-PLLA-b-P(NIPAAm-co-DMAAm) triblock copolymers.

Thermo-responsive micelles are prepared by self-assembly of amphiphilic triblock copolymers composed of a poly(l-lactide) (PLLA) central block and two poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) lateral blocks, using solvent evaporation/film hydration method. The resulting micelles exhibit very low critical micelle concentration (CMC) which slightly increases from 0.0113 to 0.0144 mg mL(-1) while the DMAAm content increases from 31.8 to 39.4% in the hydrophilic P(NIPAAm-co-DMAAm) blocks. The lower critical solution temperatures (LCST) of copolymers varies from 44.7 °C to 49.4 °C in water as determined by UV spectroscopy, and decreases by ca. 3.5 °C in phosphate buffered saline (PBS). Curcumin was encapsulated in the core of micelles. High drug loading up to 20% is obtained with high loading efficiency (>94%). The LCST of drug loaded micelles ranges from 37.5 to 38.0 °C with drug loading increasing from 6.0 to 20%. The micelles with diameters ranging from 47.5 to 88.2 nm remain stable over one month due to the negative surface charge as determined by zeta potential (-12.4 to -18.7 mV). Drug release studies were performed under in vitro conditions at 37 °C and 40 °C, i.e. below and above the LCST, respectively. Initial burst release is observed in all cases, followed by a slower release. The release rate is higher at 40 °C than that at 37 °C due to thermo-responsive release across the LCST. On the other hand, micelles with lower drug loading exhibit higher release rate than those with higher drug loading, which is assigned to the solubility effect. Peppas' theory was applied to describe the release behaviors. Moreover, the in vitro cytotoxicity of copolymers was evaluated using MTT assay. The results show that the copolymers present good cytocompatibility. Therefore, the nano-scale size, low CMC, high drug loading and stability, as well as good biocompatibility indicate that these thermo-responsive triblock copolymer micelles present a good potential as carrier for targeted delivery of anticancer drugs.

Tunable thermo-responsive P(NIPAAm-co-DMAAm)-b-PLLA-b-P(NIPAAm-co-DMAAm) triblock copolymer micelles as drug carriers.

Thermo-responsive triblock copolymers were synthesized by atom transfer radical polymerization of N-isopropyl acrylamide (NIPAAm) and N,N-dimethyl acrylamide (DMAAm) using α,ω-bromopropionyl poly(l-lactide) as the macro-initiator and a CuCl/tris(2-dimethylaminoethyl) amine (Me6TREN) complex as the catalyst. The polymerization was realized at 25 °C in a DMF-water mixture. DMAAm was incorporated in the copolymer as a hydrophilic comonomer in order to tune the lower critical solution temperature (LCST). The LCST linearly increases from 32.2 to 39.1 °C upon increasing the DMAAm content from 0 to 24%. The phase transition of polymeric micelles at the LCST occurs in a narrow temperature interval below 0.5 °C. Reversible size changes are observed when the temperature increases from 25 to 45 °C and then decreases down to 25 °C. Nano-size micelles (37 to 54 nm) with narrow distribution were obtained by self-assembly of amphiphilic copolymers in aqueous medium. The critical micelle concentration (CMC) ranges from 0.010 to 0.015 mg mL-1. In vitro drug release studies show a much faster release at temperatures above the LCST. The MTT assay was conducted to evaluate the cytotoxicity of copolymers. Therefore, the nano-scale size, low CMC, rapid phase transition, LCST slightly above body temperature and thermo-responsive drug release indicate that these copolymers could be potential candidates for applications in targeted delivery of drugs.

Drug delivery systems based on pharmaceutically active ionic liquids and biocompatible poly(lactic acid).

Poly(l-lactic acid) (PLLA) membranes containing pharmaceutically active ionic liquids (API-ILs) have been prepared by using a simple film casting from solvent evaporation method. Several sets of membranes were prepared from two different ionic liquids namely 1-methyl-3-butyl-imidazolium ibuprofenate (C4MImIbu) and lidocainium ibuprofenate (LidIbu) with different API-IL contents. Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Wide-Angle and Small-Angle X-ray Scattering (WAXS and SAXS) revealed the strong influence of both the IL nature and content on the morphology and the crystallinity of the resulting PLLA. At 20 weight%, LidIbu was shown to act as a plasticizer for PLLA and homogeneous membranes were obtained. In contrast, at the same IL content, phase separation occurred using C4MImIbu, resulting in the formation of porous PLLA. An increase of LidIbu content to 50 weight% results also in phase separation. 1H and 1H-13C CP-MAS NMR measurements evidenced the influence of different morphologies and crystallinities on IL mobility. C4MImIbu was found to be highly mobile whereas the mobility of LidIbu was content dependent. At low percent, low mobility was observed while at higher content, two populations with respectively high and low mobility were observed. These PLLA-IL membranes were further tested as drug delivery systems. In accordance with the morphology and mobility obtained, we demonstrated that release kinetics from PLLA membranes can be tuned by the nature and the content of API-ILs. Sustainable release kinetics were obtained with API-IL acting as a plasticizer while the fastest release was obtained with API-IL acting as a porogenic agent.

MRI-visible poly(ε-caprolactone) with controlled contrast agent ratios for enhanced visualization in temporary imaging applications.

Hydrophobic macromolecular contrast agents (MMCAs) are highly desirable to provide safe and efficient magnetic resonance (MR) visibility to implantable medical devices. In this study, we report on the synthesis and evaluation of novel biodegradable poly(ε-caprolactone)-based MMCAs. Poly(α-propargyl-ε-caprolactone-co-ε-caprolactone)s containing 2, 5, and 10 mol % of propargyl groups have been prepared by ring-opening copolymerization of ε-caprolactone and the corresponding propargylated lactone. In parallel, a diazido derivative of the clinically used diethylenetriaminepentaacetic acid (DTPA)/Gd(3+) complex has been synthesized. Finally, MRI-visible poly(ε-caprolactone)s (PCLs) were obtained by the efficient click ligation of these compounds via a Cu(I)-catalyzed [3 + 2] cycloaddition. ICP-MS analyses confirmed the efficient coupling of the complex on the PCL backbone with the MRI-visible PCLs containing 1.0, 2.6, and 3.6 wt % of Gd(3+). The influence of the Gd(3+) grafting density on the T1 relaxation times and on the MRI visibility of the novel biodegradable MMCAs was evaluated. Finally, their stability and cytocompatibility were assessed with regard to their potential as innovative MRI-visible biomaterials for biomedical applications.

Modeling and self-assembly behavior of PEG-PLA-PEG triblock copolymers in aqueous solution.

A series of poly(ethylene glycol)-polylactide-poly(ethylene glycol) (PEG-PLA-PEG) triblock copolymers with symmetric or asymmetric chain structures were synthesized by combination of ring-opening polymerization and copper-catalyzed click chemistry. The resulting copolymers were used to prepare self-assembled aggregates by dialysis. Various architectures such as nanotubes, polymersomes and spherical micelles were observed from transmission electron microscopy (TEM), cryo-TEM and atomic force microscopy (AFM) measurements. The formation of diverse aggregates is explained by modeling from the angle of both geometry and thermodynamics. From the angle of geometry, a "blob" model based on the Daoud-Cotton model for star polymers is proposed to describe the aggregate structures and structural changes with copolymer composition and molar mass. In fact, the copolymer chains extend in aqueous medium to form single layer polymersomes to minimize the system's free energy if one of the two PEG blocks is short enough. The curvature of polymersomes is dependent on the chain structure of copolymers, especially on the length of PLA blocks. A constant branch number of aggregates (f) is thus required to preserve the morphology of polymersomes. Meanwhile, the aggregation number (N(agg)) determined from the thermodynamics of self-assembly is roughly proportional to the total length of polymer chains. Comparing f to N(agg), the aggregates take the form of polymersomes if N(agg) ≈ f, and change to nanotubes if N(agg) > f to conform to the limits from both curvature and aggregation number. The length of nanotubes is mainly determined by the difference between N(agg) and f. However, the hollow structure becomes unstable when both PEG segments are too long, and the aggregates eventually collapse to yield spherical micelles. Therefore, this work gives new insights into the self-assembly behavior of PEG-PLA-PEG triblock copolymers in aqueous solution which present great interest for biomedical and pharmaceutical applications.

Toward potent antibiofilm degradable medical devices: a generic method for the antibacterial surface modification of polylactide.

The effects of biomaterials on their environment must be carefully modulated in most biomedical applications. Among other approaches, this modulation can be obtained through the modification of the biomaterial surface. This paper proposes a simple and versatile strategy to produce non-leaching antibacterial polylactide (PLA) surfaces without any degradation of the polyester chains. The method is based on a one-pot procedure that provides a "clickable" PLA surface via anionic activation which is then functionalized with an antibacterial quaternized poly(2-(dimethylamino)ethyl methacrylate) (QPDMAEMA) by covalent immobilization on the surface. The anti-adherence and antibiofilm activities of modified PLA surfaces are assessed for different QPDMAEMA molecular weights and different quaternization agents. Antibacterial PLA surfaces are shown to be very active against Gram-negative and Gram-positive strains, with adherence reduction factors superior to 99.999% and a marked reduction in biofilm on the most potent surfaces. In addition to this substantial antibacterial activity, the proposed PLA surfaces are also cytocompatible, as demonstrated through the proliferation of L929 fibroblasts.

Synthesis and evaluation of triazole-linked poly(ε-caprolactone)-graft-poly(2-methyl-2-oxazoline) copolymers as potential drug carriers.

Well-defined graft copolymers were obtained using a copper-catalysed azide-alkyne Huisgen's cycloaddition click reaction from both biocompatible and non-toxic poly(ε-caprolactone) and poly(2-methyl-2-oxazoline) homopolymers. Resulting amphiphilic copolymers proved to form micelles that could be used as potential drug carriers.

Poly(DL-lactic acid) film surface modification with heparin for improving hemocompatibility of blood-contacting bioresorbable devices.

This work describes a simple method to immobilize heparin by covalent bonding to the surface of poly(lactic acid) film with the aim of showing improved hemocompatibility. Carboxyl groups present in heparin molecules were activated by reaction with N-hydroxy-succinimide and allowed to react with free amino groups created at the surface of poly(DL-lactic acid) films by controlled aminolysis. Contact angle measurements and XPS analysis confirmed the binding. Quantification was determined by radioactivity using heparin labeled with tritium. The surface exhibited anti factor Xa activity, thus confirming the presence of bounded heparin that kept some biological activity. Finally platelets adhesion showed less platelet adhesion on heparin modified films as well as preserved morphology.

Synthesis and Ring Opening Polymerization of a New Functional Lactone, α-Iodo-ε-caprolactone: A Novel Route to Functionalized Aliphatic Polyesters.

A new functional lactone, α-iodo-ε-caprolactone (αIεCL), was synthesized from ε-caprolactone by anionic activation using a non-nucleophilic strong base (lithium diisopropylamide) followed by an electrophilic substitution with iodine chloride. Ring-opening (co)polymerizations of the resulting monomer with ε-caprolactone were carried out using tin 2-ethylhexanoate as a catalyst in toluene at 100 °C. Homopolymerization of αIεCL was achieved, and poly(αIεCL) was fully characterized by SEC, (1) H NMR and elemental analysis. Random copolymerizations of αIεCL with εCL were controlled with experimental molecular weights close to the theoretical values, narrow molecular weight distributions and a good agreement between experimental and theoretical molar compositions of αIεCL.

Synthesis of hybrid dendrimer-star polymers by the RAFT process.

A first generation phosphorus-containing dendrimer with twelve terminal benzyl dithiobenzoate functions was designed and subsequently used as a multifunctional agent to derive hybrid star copolymers consisting of a dendritic core surrounded by twelve polystyrene branches by reversible addition-fragmentation chain transfer (RAFT).

Supramolecular control of [2 + 2] photodimerization via hydrogen bonding.

The use of supramolecular catalysis to control the photoinduced dimerization of styrene, cinnamate, and stilbene chromophores is reported. The strategy employs the formation of a 2:1 supramolecular assembly in the presence of 5,5-dihexylbarbituric acid (DHB). A 3- to 10-fold increase in dimerization efficiency is observed in its presence, concomitant with accrued selectivity for the syn photodimers. The origin of the regioselectivity in the presence of DHB is discussed in terms of topochemical control within the supramolecular architecture.