Polypeptide-Based Systems: From Synthesis to Application in Drug Delivery.

Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in the physicochemical and biological properties of polypeptide-containing materials. In this review article, we summarize the advances in the synthesis of polypeptides and their copolymers and the application of these systems for drug delivery in the form of (nano)particles or hydrogels. The issues, such as the diversity of polypeptide-containing (nano)particle types, the methods for their preparation and drug loading, as well as the influence of physicochemical characteristics on stability, degradability, cellular uptake, cytotoxicity, hemolysis, and immunogenicity of polypeptide-containing nanoparticles and their drug formulations, are comprehensively discussed. Finally, recent advances in the development of certain drug nanoformulations for peptides, proteins, gene delivery, cancer therapy, and antimicrobial and anti-inflammatory systems are summarized.

Drug Loaded 3D-Printed Poly(ε-Caprolactone) Scaffolds for Local Antibacterial or Anti-Inflammatory Treatment in Bone Regeneration.

Annual bone grafting surgeries due to bone fractures, resections of affected bones, skeletal anomalies, osteoporosis, etc. exceed two million worldwide. In this regard, the creation of new materials for bone tissue repair is one of the urgent tasks of modern medicine. Additive manufacturing, or 3D printing, offers great opportunities for the development of materials with diverse properties and designs. In this study, the one-pot technique for the production of 3D scaffolds based on poly(ε-caprolactone) (PCL) loaded with an antibiotic or anti-inflammatory drug was proposed. In contrast to previously described methods to prepare drug-containing scaffolds, drug-loaded PCL scaffolds were prepared by direct 3D printing from a polymer/drug blend. An investigation of the mechanical properties of 3D-printed scaffolds containing 0.5-5 wt% ciprofloxacin (CIP) or dexamethasone (DEX) showed almost no effect of the drug (compression modulus ~70-90 MPa) compared to unfilled PCL (74 MPa). At the same time, introducing the drug and increasing its content in the PCL matrix contributed to a 1.8-6.8-fold decrease in the specific surface area of the scaffold, depending on composition. The release of CIP and DEX in phosphate buffer solution and in the same buffer containing lipase revealed a faster release in enzyme-containing medium within 45 days. Furthermore, drug release was more intensive from scaffolds with a low drug load. Analysis of the release profiles using a number of mathematical dissolution models led to the conclusion that diffusion dominates over other probable factors. In vitro biological evaluation of the scaffolds containing DEX showed moderate toxicity against osteoblast-like and leukemia monocytic cells. Being 3D-printed together with PCL both drugs retain their biological activity. PCL/CIP and PCL/DEX scaffolds demonstrated antibacterial properties against Pseudomonas aeruginosa (a total inhibition after 48 h) and anti-inflammatory activity in experiments on TNFα-activated monocyte cells (a 4-time reduction in CD-54 expression relative to control), respectively.

Composites Based on Poly(ε-caprolactone) and Graphene Oxide Modified with Oligo/Poly(Glutamic Acid) as Biomaterials with Osteoconductive Properties.

The development of new biodegradable biomaterials with osteoconductive properties for bone tissue regeneration is one of the urgent tasks of modern medicine. In this study, we proposed the pathway for graphene oxide (GO) modification with oligo/poly(glutamic acid) (oligo/poly(Glu)) possessing osteoconductive properties. The modification was confirmed by a number of methods such as Fourier-transform infrared spectroscopy, quantitative amino acid HPLC analysis, thermogravimetric analysis, scanning electron microscopy, and dynamic and electrophoretic light scattering. Modified GO was used as a filler for poly(ε-caprolactone) (PCL) in the fabrication of composite films. The mechanical properties of the biocomposites were compared with those obtained for the PCL/GO composites. An 18-27% increase in elastic modulus was found for all composites containing modified GO. No significant cytotoxicity of the GO and its derivatives in human osteosarcoma cells (MG-63) was revealed. Moreover, the developed composites stimulated the proliferation of human mesenchymal stem cells (hMSCs) adhered to the surface of the films in comparison with unfilled PCL material. The osteoconductive properties of the PCL-based composites filled with GO modified with oligo/poly(Glu) were confirmed via alkaline phosphatase assay as well as calcein and alizarin red S staining after osteogenic differentiation of hMSC in vitro.

Design, Fabrication and Characterization of Biodegradable Composites Containing Closo-Borates as Potential Materials for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) has been recognized as a very promising approach for cancer treatment. In the case of osteosarcoma, boron-containing scaffolds can be a powerful tool to combine boron delivery to the tumor cells and the repair of postoperative bone defects. Here we describe the fabrication and characterization of novel biodegradable polymer composites as films and 3D-printed matrices based on aliphatic polyesters containing closo-borates (CB) for BNCT. Different approaches to the fabrication of composites have been applied, and the mechanical properties of these composites, kinetics of their degradation, and the release of closo-borate have been studied. The most complex scaffold was a 3D-printed poly(ε-caprolactone) matrix filled with CB-containing alginate/gelatin hydrogel to enhance biocompatibility. The results obtained allowed us to confirm the high potential of the developed composite materials for application in BNCT and bone tissue regeneration.

3D-Printed composite scaffolds based on poly(ε-caprolactone) filled with poly(glutamic acid)-modified cellulose nanocrystals for improved bone tissue regeneration.

The manufacturing of modern scaffolds with customized geometry and personalization has become possible due to the three-dimensional (3D) printing technique. A novel type of 3D-printed scaffolds for bone tissue regeneration based on poly(ε-caprolactone) (PCL) filled with nanocrystalline cellulose modified by poly(glutamic acid) (PGlu-NCC) has been proposed in this study. The 3D printing set-ups were optimized in order to obtain homogeneous porous scaffolds. Both polymer composites and manufactured 3D scaffolds have demonstrated mechanical properties suitable for a human trabecular bone. Compression moduli were in the range of 334-396 MPa for non-porous PCL and PCL-based composites, and 101-122 MPa for porous scaffolds made of the same materials. In vitro mineralization study with the use of human mesenchymal stem cells (hMSCs) revealed the larger Ca deposits on the surface of PCL/PGlu-NCC composite scaffolds. Implantation of the developed 3D scaffolds into femur of the rabbits was carried out to observe close and delayed effects. The histological analysis showed the lowest content of immune cells and thin fibrous capsule, revealing low toxicity of the PCL/PGlu-NCC scaffolds seeded with rabbit MSCs (rMSCs) to the surrounding tissues. The most pronounced result on the generation of new bone tissue after implantation of PCL/PGlu-NCC + rMSCs scaffolds was detected by both microcomputed tomography and histological analysis. Around 33% and 55% of bone coverage were detected for composite 3D scaffolds with adhered rMSCs after 1 and 3 months of implantation, respectively. This achievement can be a result of synergistic effect of PGlu, which attracts calcium ions, and stem cells with osteogenic potential.

Magneto-Luminescent Nanocomposites Based on Carbon Dots and Ferrite with Potential for Bioapplication.

Multifunctional nanocomposites that combine both magnetic and photoluminescent (PL) properties provide significant advantages for nanomedical applications. In this work, a one-stage synthesis of magneto-luminescent nanocomposites (MLNC) with subsequent stabilization is proposed. Microwave synthesis of magnetic carbon dots (M-CDs) was carried out using precursors of carbon dots and magnetic nanoparticles. The effect of stabilization on the morphological and optical properties of nanocomposites has been evaluated. Both types of nanocomposites demonstrate magnetic and PL properties simultaneously. The resulting MLNCs demonstrated excellent solubility in water, tunable PL with a quantum yield of up to 28%, high photostability, and good cytocompatibility. Meanwhile, confocal fluorescence imaging showed that M-CDs were localized in the cell nuclei. Consequently, the multifunctional nanocomposites M-CDs are promising candidates for bioimaging and therapy.

Modification of Cellulose Micro- and Nanomaterials to Improve Properties of Aliphatic Polyesters/Cellulose Composites: A Review.

Aliphatic polyesters/cellulose composites have attracted a lot attention due to the perspectives of their application in biomedicine and the production of disposable materials, food packaging, etc. Both aliphatic polyesters and cellulose are biocompatible and biodegradable polymers, which makes them highly promising for the production of "green" composite materials. However, the main challenge in obtaining composites with favorable properties is the poor compatibility of these polymers. Unlike cellulose, which is very hydrophilic, aliphatic polyesters exhibit strong hydrophobic properties. In recent times, the modification of cellulose micro- and nanomaterials is widely considered as a tool to enhance interfacial biocompatibility with aliphatic polyesters and, consequently, improve the properties of composites. This review summarizes the main types and properties of cellulose micro- and nanomaterials as well as aliphatic polyesters used to produce composites with cellulose. In addition, the methods for noncovalent and covalent modification of cellulose materials with small molecules, polymers and nanoparticles have been comprehensively overviewed and discussed. Composite fabrication techniques, as well as the effect of cellulose modification on the mechanical and thermal properties, rate of degradation, and biological compatibility have been also analyzed.

Detection of Topological Spin Textures via Nonlinear Magnetic Responses.

Topologically nontrivial spin textures, such as skyrmions and dislocations, display emergent electrodynamics and can be moved by spin currents over macroscopic distances. These unique properties and their nanoscale size make them excellent candidates for the development of next-generation race-track memory and unconventional computing. A major challenge for these applications and the investigation of nanoscale magnetic structures in general is the realization of suitable detection schemes. We study magnetic disclinations, dislocations, and domain walls in FeGe and reveal pronounced responses that distinguish them from the helimagnetic background. A combination of magnetic force microscopy (MFM) and micromagnetic simulations links the response to the local magnetic susceptibility, that is, characteristic changes in the spin texture driven by the MFM tip. On the basis of the findings, which we explain using nonlinear response theory, we propose a read-out scheme using superconducting microcoils, presenting an innovative approach for detecting topological spin textures and domain walls in device-relevant geometries.

Dislocation-Driven Relaxation Processes at the Conical to Helical Phase Transition in FeGe.

The formation of topological spin textures at the nanoscale has a significant impact on the long-range order and dynamical response of magnetic materials. We study the relaxation mechanisms at the conical-to-helical phase transition in the chiral magnet FeGe. By combining macroscopic ac susceptibility measurement, surface-sensitive magnetic force microscopy, and micromagnetic simulations, we demonstrate how the motion of magnetic topological defects, here edge dislocations, impacts the local formation of a stable helimagnetic spin structure. Although the simulations show that the edge dislocations can move with a velocity up to 100 m/s through the helimagnetic background, their dynamics are observed to disturb the magnetic order on the time scale of minutes due to randomly distributed pinning sites. The results corroborate the substantial impact of dislocation motions on the nanoscale spin structure in chiral magnets, revealing previously hidden effects on the formation of helimagnetic domains and domain walls.

Aminated Graphene-Graft-Oligo(Glutamic Acid) /Poly(ε-Caprolactone) Composites: Preparation, Characterization and Biological Evaluation.

Biodegradable and biocompatible composites are of great interest as biomedical materials for various regeneration processes such as the regeneration of bones, cartilage and soft tissues. Modification of the filler surface can improve its compatibility with the polymer matrix, and, as a result, the characteristics and properties of composite materials. This work is devoted to the synthesis and modification of aminated graphene with oligomers of glutamic acid and their use for the preparation of composite materials based on poly(ε-caprolactone). Ring-opening polymerization of N-carboxyanhydride of glutamic acid γ-benzyl ester was used to graft oligomers of glutamic acid from the surface of aminated graphene. The success of the modification was confirmed by Fourier-transform infrared and X-ray photoelectron spectroscopy as well as thermogravimetric analysis. In addition, the dispersions of neat and modified aminated graphene were analyzed by dynamic and electrophoretic light scattering to monitor changes in the characteristics due to modification. The poly(ε-caprolactone) films filled with neat and modified aminated graphene were manufactured and carefully characterized for their mechanical and biological properties. Grafting of glutamic acid oligomers from the surface of aminated graphene improved the distribution of the filler in the polymer matrix that, in turn, positively affected the mechanical properties of composite materials in comparison to ones containing the unmodified filler. Moreover, the modification improved the biocompatibility of the filler with human MG-63 osteoblast-like cells.

PGlu-Modified Nanocrystalline Cellulose Improves Mechanical Properties, Biocompatibility, and Mineralization of Polyester-Based Composites.

The development of biocompatible composite materials is in high demand in many fields such as biomedicine, bioengineering, and biotechnology. In this study, two series of poly (D,L-lactide) and poly (ε-caprolactone)-based films filled with neat and modified with poly (glutamic acid) (PGlu) nanocrystalline cellulose (NCC) were prepared. An analysis of scanning electron and atomic force microscopies' results shows that the modification of NCC with poly (glutamic acid) favored the better distribution of the nanofiller in the polymer matrix. Investigating the ability of the developed materials to attract and retain calcium ions led to the conclusion that composites containing NCC modified with PGlu induced better mineralization from model solutions than composites containing neat NCC. Moreover, compared to unmodified NCC, functionalization with PGlu improved the mechanical properties of composite films. The subcutaneous implantation of these composite materials into the backs of rats and the further histological investigation of neighboring tissues revealed the better biocompatibility of polyester materials filled with NCC-PGlu.

Cholesterol-imprinted macroporous monoliths: Preparation and characterization.

The development of sorbents for selective binding of cholesterol, which is a risk factor for cardiovascular disease, has a great importance for analytical science and medicine. In this work, two series of macroporous cholesterol-imprinted monolithic sorbents differing in the composition of functional monomers (methacrylic acid, butyl methacrylate, 2-hydroxyethyl methacrylate and ethylene dimethacrylate), amount of a template (4, 6 and 8 mol%) used for molecular imprinting, as well as mean pore size were synthesized by in situ free-radical process in stainless steel housing of 50 mm × 4.6 mm i.d. All prepared materials were characterized regarding to their hydrodynamic permeability and porous properties, as well as examined by BET and SEM methods. Imprinting factors, apparent dynamic dissociation constants, the maximum binding capacity, the number of theoretical plates and the height equivalent to a theoretical palate of MIP monoliths at different mobile phase flow rates were determined. The separation of a mixture of structural analogues, namely, cholesterol and prednisolone, was demonstrated. Additionally, the possibility of using the developed monoliths for cholesterol solid-phase extraction from simulated biological solution was shown.