Drug Binding Capacity Research Articles

Contrasting the effect of hinge region insertions and non-active site mutations on HIV protease-inhibitor interactions: Insights from altered flap dynamics

HIV-1 protease (PR) enzyme is a viable antiretroviral drug target due to its crucial role in HIV maturation. Over many decades, the HIV-1 PR enzyme has exhibited mutations brought on by drug pressure and error-prone nature of HIV-1 reverse transcriptase. Non-active site mutations have played a pivotal role in drug resistance; however, their mechanism of action has not been fully elucidated. We investigated how non-active site mutations affect the conformational stability and drug binding ability of HIV-1 PR. In light of this, we studied a novel HIV-1 subtype C protease variant containing an insertion of valine (↑V) in the hinge region. We analysed the mutations in the presence and absence of ten background mutations. Molecular dynamics simulations revealed that both with and without the background mutations, the PR exhibited increased flexibility of hinge, flaps and fulcrum regions. This allowed the PR to adopt a wider flap conformation when in complex with several inhibitors. Additionally, the simulations revealed that the protease inhibitors (PIs) could not bring the mutated variant proteases into a stable, closed conformation, resulting in increased solvent exposure of the inhibitors. Together, these results suggest that the mutations decrease the favourability of binding by altering the dynamics of the flap regions. Notably, the insertion mutation increased PR hinge flexibility and the introduction of background mutations compensated for this by stabilising the cantilever and hinge regions. Together, these findings provide insight into how non-active site mutations affect PR conformational dynamics in critical areas of the PR thus impacting on drug binding capacity and potentially contributing to drug resistance.

Reactive oxygen-scavenging polydopamine nanoparticle coated 3D nanofibrous scaffolds for improved osteogenesis: Toward an aging in vivo bone regeneration model.

Tissue engineered scaffolds aimed at the repair of critical-sized bone defects lack adequate consideration for our aging society. Establishing an effective aged in vitro model that translates to animals is a significant unmet challenge. The in vivo aged environment is complex and highly nuanced, making it difficult to model in the context of bone repair. In this work, 3D nanofibrous scaffolds generated by the thermally-induced self-agglomeration (TISA) technique were functionalized with polydopamine nanoparticles (PD NPs) as a tool to improve drug binding capacity and scavenge reactive oxygen species (ROS), an excessive build-up that dampens the healing process in aged tissues. PD NPs were reduced by ascorbic acid (rPD) to further improve hydrogen peroxide (H2O2) scavenging capabilities, where we hypothesized that these functionalized scaffolds could rescue ROS-affected osteoblastic differentiation in vitro and improve new bone formation in an aged mouse model. rPDs demonstrated improved H2O2 scavenging activity compared to neat PD NPs, although both NP groups rescued the alkaline phosphatase activity (ALP) of MC3T3-E1 cells in presence of H2O2. Additionally, BMP2-induced osteogenic differentiation, both ALP and mineralization, was significantly improved in the presence of PD or rPD NPs on TISA scaffolds. While in vitro data showed favorable results aimed at improving osteogenic differentiation by PD or rPD NPs, in vivo studies did not note similar improvements in ectopic bone formation an aged model, suggesting that further nuance in material design is required to effectively translate to improved in vivo results in aged animal models.

Comparison of the Impact of NaIO4-Accelerated, Cu2+/H2O2-Accelerated, and Novel Ion-Accelerated Methods of Poly(l-DOPA) Coating on Collagen-Sealed Vascular Prostheses: Strengths and Weaknesses.

Sensitive biomaterials subjected to surface modification require delicate methods to preserve their structures and key properties. These include collagen-sealed polyester vascular prostheses. For their functionalization, coating with polycatecholamines (PCAs) can be used. PCAs change some important biological properties of biomaterials, e.g., hydrophilicity, bioactivity, antibacterial activity, and drug binding. The coating process can be stimulated by oxidants, organic solvents, or process conditions. However, these factors may change the properties of the PCA layer and the matrix itself. In this work, collagen-sealed vascular grafts were functionalized with a poly(l-DOPA) (PLD) layer using novel seawater-inspired ion combination as an accelerator, compared to the sodium periodate, Cu2+/H2O2 mixture, and accelerator-free reference methods. Then, poly(l-DOPA) was used as the interface for antibiotic binding. The coated prostheses were characterized (SEM, FIB-SEM, FTIR, UV/vis), and their important functional parameters (mechanical, antioxidant, hemolytic, and prothrombotic properties, bioactivity, stability in human blood and simulated body fluid (SBF), antibiotic binding, release, and antibacterial activity) were compared. It was found that although sodium periodate increased the strength and drug-binding capacity of the prosthesis, it also increased the blood hemolysis risk. Cu2+/H2O2 destabilized the mechanical properties of the coating and the graft. The seawater-inspired ion-accelerated method was efficient, stable, and matrix- and human blood-friendly, and it stimulated hydroxyapatite formation on the prosthesis surface. The results lead to the conclusion that selection of the PCA formation accelerator should be based on a careful analysis of the biological properties of medical devices. They also suggest that the ion-accelerated method of PLD coating on medical devices may be highly effective and safer than the oxidant-accelerated coating method.

Chitosan-graphene quantum dot-based molecular imprinted polymer for oxaliplatin release

Molecularly imprinted polymers (MIPs) have garnered the interest of researchers in the drug delivery due to their advantages, such as exceptional durability, stability, and selectivity. In this study, a biocompatible MIP drug adsorption and delivery system with high loading capacity and controlled release, was prepared based on chitosan (CS) and graphene quantum dots (GQDs) as the matrix, and the anticancer drug oxaliplatin (OXAL) as the template. Additionally, samples without the drug (non-imprinted polymers, NIPs) were created for comparison. GQDs were produced using the hydrothermal method, and samples underwent characterization through FTIR, XRD, FESEM, and TGA. Various experiments were conducted to determine the optimal pH for drug adsorption, along with kinetic and isotherm studies, selectivity assessments, in vitro drug release and kinetic evaluations. The highest drug binding capacity was observed at pH 6.5. The results indicated the Lagergren-first-order kinetic model (with rate constant of 0.038 min−1) and the Langmuir isotherm (with maximum adsorption capacity of 17.15 mg g−1) exhibited better alignment with the experimental data. The developed MIPs displayed significant selectivity towards OXAL, by an imprinting factor of 2.88, in comparison to two similar drugs (cisplatin and carboplatin). Furthermore, the analysis of the drug release profile showed a burst release for CS-Drug (87% within 3 h) at pH 7.4, where the release from the CS-GQD-Drug did not occur at pH 7.4 and 10; instead, the release was observed at pH 1.2 in a controlled manner (100% within 28 h). Consequently, this specific OXAL adsorption and delivery system holds promise for cancer treatment.

Poly(amino acid)-based drug delivery nanoparticles eliminate Methicillin resistant Staphylococcus aureus via tunable release of antibiotic

Bacterial infections threaten public health, and novel therapeutic strategies critically demand to be explored. Herein, poly(amino acid) (PAA)-based drug delivery nanoparticles (NPs) were designed for eliminating Methicillin resistant Staphylococcus aureus (MRSA) via tunable release of antibiotic. Using N-acryloyl amino acids (valine, valine methyl ester, aspartic acid, serine) as monomers, four kinds of amphiphilic PAAs were synthesized via photoinduced electron/energy transfer–reversible addition fragmentation chain-transfer (PET-RAFT) polymerization and were further assembled into nano-sized delivery systems. Their assemble behavior was drove mainly by hydrophobic/hydrophilic interaction, which determined the particle size, efficacy of drug loading and release; but numerous hydrogen bonding (HB) interaction also played an important role in regulating morphologies of the NPs and enriching drug-binding capacity. By changing the HB- and hydrophobic-interaction of the PAAs, the particle sizes (240.7 nm-302.7 nm), the drug loading efficiency (9.57%-19.76%), and the Rifampicin (Rif) release rate (49.6%-69.7%) of the PAA-based NPs could be tunable. Specially, the antimicrobial properties of the Rif-loaded NPs are found to be related to the release of Rif, which was determined by its hydrophobic interaction with hydrophobic blocks and HB interaction with hydrophilic blocks. These studies provide a new outlook for the design of delivery systems for the therapy of bacterial infection.

PH-responsive release of ciprofloxacin hydrochloride from micro-, nano-, and functionalized nanocellulose

This research evaluated pH-responsive release characteristics for the drug (ciprofloxacin hydrochloride) from micro-, nano-, and functionalized cellulose forms. Nanocrystalline cellulose (NCC) was prepared from microcrystalline cellulose (MCC) by sulfuric acid hydrolysis. The aldehyde (–CHO) groups were introduced at the carbon-2 (C-2) and carbon-3 (C-3) positions of glucose moiety of the cellulose network by selective oxidation to form di-aldehyde nanocellulose (DANC). The conversion was validated by chemical, spectroscopic, morphological, and crystallographic analysis. Drug binding capacity (mg/g) of DANC was higher (200.8 mg/g) compared to NCC (138.3 mg/g) and MCC (120.2 mg/g), respectively. The increase in pH from 2.5 to 8.5 enhanced drug release for all the excipients. At pH 2.5, slow release of the drugs was observed. In 6 h, DANC released 44.7 % of the loaded drug at pH 2.5. However, drug release reached equilibrium (84.8 % of loaded drug) within 10 min at pH 8.5. The release kinetics at acidic pH were validated using zero-order, first-order, Higuchi, and Korsmeyer-Peppas kinetics models. Higuchi and Korsmeyer–Peppas' kinetic models interpreted drug release phenomena with a good fit. This implies that diffusion, dissolution, swelling, and slight erosion contribute to drug release. The results suggest that selective functionalization can be applied to cellulose for its potential applications in pH-responsive drug delivery, and therefore, the functionalized cellulose deserves immediate attention.

Large-scale and cost-effective production of recombinant human serum albumin (rHSA) in transgenic Bombyx mori cocoons

HSA is considered a versatile natural cargo carrier with multiple bio-functions and applications. However, insufficient supply of HSA has limited widespread use. Although various recombinant expression systems had been applied to produce the rHSA to overcome the limited resource, cost-effective and large scale production of rHSA remains a challenge. Herein, we provide a strategy for the large-scale and cost-effective production of rHSA in cocoons of transgenic silkworms, achieving a final 13.54 ± 1.34 g/kg of rHSA yield in cocoons. rHSA was efficiently synthesized and stable over the long-term in the cocoons at room temperature. Artificial control of silk crystal structure during silk spinning significantly facilitated rHSA extraction and purification, with 99.69 ± 0.33 % purity and a productivity of 8.06 ± 0.17 g rHSA from 1 kg cocoons. The rHSA had the same secondary structure to natural HSA, along with effective drug binding capacity, biocompatibility, and bio-safe. The rHSA was successfully evaluated as a potential substitute in serum-free cell culture. These findings suggest the silkworm bioreactor is promising for large-scale and cost-effective production of high quality rHSA to meet the increased worldwide demand.

Design of molecularly imprinted hydrogels with thermoresponsive drug binding sites.

Drug delivery systems (DDS) regulate the spatiotemporal distribution of drugs in vivo to maximize efficacy and minimize side effects. Stimuli-responsive hydrogels, which exhibit a drastic change in volume in response to external stimuli such as temperature and pH, have attracted considerable interest as drug reservoirs for self-regulating DDS, as stimuli-responsive changes in the network size can regulate drug diffusion. However, such hydrogels have the disadvantage of leaking drugs even in the absence of stimulation. Proteins such as hemoglobin have dynamic molecular binding sites that modify their binding capacities by their conformational changes induced when an effector molecule binds to allosteric sites. Such dynamic binding sites are useful for loading drugs into reservoirs because their conformational changes can be used to control drug loading and release. In this study, we prepared thermoresponsive hydrogels with a controlled drug binding capacity to design drug reservoirs capable of both suppressing drug leakage below the transition temperature and accelerating drug release above it. Dynamic molecular binding sites were created by molecular imprinting that used 4,4'-diaminodiphenyl sulfone (dapsone) as the model drug, β-cyclodextrin (CD) as the ligand, and N-isopropylacrylamide as the primary monomer. The molecularly imprinted (MIP) and nonimprinted (NIP) hydrogels with CD ligands, as well as the poly(N-isopropylacrylamide) (PNIPAAm) hydrogels without CD ligands, drastically shrunk above their transition temperature because of the PNIPAAm major chains changing conformation from a hydrophilic random coil to a hydrophobic globule as temperature increased. Because the MIP hydrogel has dynamic molecular binding sites, it absorbs a larger amount of dapsone than the NIP hydrogels in an aqueous solution below the transition temperature. The amount of dapsone adsorbed into the MIP hydrogel significantly decreased with increasing temperatures above 37 °C, despite the fact that the hydrophobic interaction between the polymer chains and dapsone became strong. The decrease in dapsone adsorption capability of the MIP hydrogel is due to a conformational change from a swollen to a shrunken state as temperature increases. The MIP hydrogel suppressed drug leakage below its transition temperature due to the high binding capacity of dynamic binding sites, but accelerated the drug release above its transition temperature due to the collapse of dynamic molecular binding sites, in contrast to the drug release behavior of general PNIPAAm-based hydrogels. Thus, the thermoresponsive MIP hydrogels with dynamic molecular binding sites regulated drug release in response to a change in temperature.

Comparative Pharmaceutical and Analytical Study of Chapal Shodhan (Purification Process) with Special Reference to Bismuth and Selenium

Rasashastra is the branch of science which deals with alchemic preparation or metal and mineral medicinal formulation explained in ancient texts of Ayurved. Rasashastra explained group of drugs in different names on the basis their therapeutic application and binding capacity of drug with Mercury. Chapal one among the group of Maharasa which is having potent therapeutic properties like immune modulator, analgesic, rejuvenator and aphrodisiac. Due to lack of identification, difficulty in procurement and confusion in synonyms and vernacular names, Chapal placed in controversial drugs. Some opines Chapal as Bismuth and some says Selenium. To overcome from these controversies to confirm the type of drug this comparative study is undertaken. Comparative study given nearer conclusion that Chapal can be Selenium, after observing organoleptic properties and symptoms experienced by the person during the purificatory process.

MO799IS COMBINATION OF MAINTENANCE HEMODIALYSIS WITH HEMOPERFUSION AN EFFECTIVE METHOD IN MANAGEMENT OF RENAL OSTEODYSTROPHY AND INFLAMMATION IN HEMODIALYSIS PATIENTS?

Abstract Background and Aims Some of the conditions which occur in maintenance hemodialysis (MHD) patients with a high incidence resulting in a decline in their quality of life, include malnutrition, renal osteodystrophy, refractory hypertension and chronic systemic inflammation. In developing countries, due to the low level of economic development, low-flux dialysis is the main means of extracorporeal blood purification therapy. But it can hardly remove the middle and large molecule uremic toxins and protein-bound toxins; as a result, the patients suffer from long-term complications and poor quality of life. In this study, we attempted to investigate whether the combination of maintenance hemodialysis (MHD) with hemoperfusion (HP) could improve the clearance rate of middle and large molecule uremic toxins so as to improve their uremic complications. Method A total of 54 patients, who underwent routine hemodialysis, were assessed in this study. Those patients were randomly divided into two groups: Group 1 (27 patients) received combined treatment of HD with hemoperfusion (HP) in this regimen: HD 2 times a week with HD+HP once a week two times in a row, then after two weeks, and afterwards once a month as a maintenance treatment. Group 2 (27 patients) was only undergoing maintenance HD 3 times a week. The clinical and laboratory properties of both groups were followed up for 18 months, whereas the primary outcomes included normal clinical data, high sensitive C-reactive protein (hsCRP), immunoreactive parathyroid hormone (iPTH), phosphorus (P04), calcium (Ca), albumin, iron (Fe), total iron binding capacity (TIBC), hemoglobin, Epo doses and types of hypertensive drugs. Results At the end of the 18-month observation, the serum concentration of albumin, P04, hsCRP, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were lower with Group 1 than with Group 2 (p<0.05). Whereas, higher levels of iPTH were noticed in group 1, but when the laboratory and clinical data are analysed of the group 1 alone a statistically significant lower values after the observational period are noticed especially in the serum values of iPTH (p<0.05), P04 (p<0.001), CRP (p<0.011), SBP and DBP (p<0.05). Conclusion HD+HP was superior to HD in regularly eliminating middle and large molecule uremic toxins accumulated in the body which is mostly shown through reducing the values of iPTH and hsCRP. These findings suggest a potential role for HD+HP in the treatment of inflammation and renal osteodystrophy as well, because lowering these values of iPTH leads to a normalization of other minerals which is expected and therefore leads to a stabilization of this long-term uremic complications, which can improve the overall general condition of the MHD patient.

A molecular dynamics study on the binding of gemcitabine to human serum albumin

Human Serum Albumin (HSA) is introduced as one of the ideal protein-based nanoparticles for drug delivery due to some of its unique performances such as non-toxic, non-immunogenic, biocompatible, and biodegradable. Besides, the HSA has gained considerable attention owing to high compatibility without any severe side effects and extraordinary binding capacity of various drugs on its Sudlow sites (Ⅰ and Ⅱ). Hence, this study tries to explore and discuss the interactions between two Sudlow sites of HSA as the drug delivery agent and Gemcitabine (GEM), a drug used for treating cancerous tissues and cells, employing molecular dynamics. To investigate the adsorption phenomenon and the binding process of GEM on the Sudlow sites of HSA, the dynamics of GEM molecule, radial distribution function, radius of gyration, solvent-accessible surface area, hydrogen bonding, vdw energy, and free binding energy results are analyzed. The simulation results reveal that the binding of GEM molecules to the Sudlow sites of HSA induced slight conformational changes in the HSA structure. The results also illustrate that the GEM could strongly bind to the subdomain IIIA of HSA, and its stability on the site Ⅱ is higher than site Ⅰ. Hydrogen bonding as a non-bond interaction is the primary force in the stability of the GEM-HSA complex.

When Albumin Meets Liposomes: A Feasible Drug Carrier for Biomedical Applications.

Albumin, the most abundant protein in plasma, possesses some inherent beneficial structural and physiological characteristics that make it suitable for use as a drug delivery agent, such as an extraordinary drug-binding capacity and long blood retention, with a high biocompatibility. The use of these characteristics as a nanoparticle drug delivery system (DDS) offers several advantages, including a longer circulation time, lower toxicity, and more significant drug loading. To date, many innovative liposome preparations have been developed in which albumin is involved as a DDS. These novel albumin-containing liposome preparations show superior deliverability for genes, hydrophilic/hydrophobic substances and proteins/peptides to the targeting area compared to original liposomes by virtue of their high biocompatibility, stability, effective loading content, and the capacity for targeting. This review summarizes the current status of albumin applications in liposome-based DDS, focusing on albumin-coated liposomes and albumin-encapsulated liposomes as a DDS carrier for potential medical applications.

Glutathione-responsive hydrogel and molecularly imprinted polymer nanospheres: New aspect on cisplatin delivery

In this study, Glutathione-responsive hydrogel, MIPs and their related NIPs were synthesized by precipitation polymerization method. Effect of HEMA/MAA and EGDMA/TRIM as functional monomer and crosslinking agents on size, morphology, drug loading and releasing were studied. BACy as a disulfide cross-linking agent was used in praparation of Glutathione-responsive hydrogel. The size and morphology of MIPs and NIPs were examined by FE-SEM technique. Results showed EGDMA-synthesized MIPs had the smaller size than TRIM-prepared MIPs. In order to measure the capacity of MIPs or NIPs for binding to cisplatin, static and dynamic adsorption experiments were done. The amounts of cisplatin were measured by HPLC method. The binding capacity of drug by MIPs is observed to be higher than NIPs. The EGDMA-synthesized polymers showed a high percentage of adsorption. NIPs were saturated much sooner than MIPs. In vitro release assays of cisplatin were done in PBS at pH=7.4 and temperature of 37°C. The results showed that increase of the amount of GSH cause to increase release of the drug from hydrogel.

Controlled Release of Doxorubicin from the Drug Delivery Formulation Composed of Single-Walled Carbon Nanotubes and Congo Red: A Molecular Dynamics Study and Dynamic Light Scattering Analysis.

The controlled delivery and release of drug molecules at specific targets increases the therapeutic efficacy of treatment. This paper presents a triple complex which is a new potential drug delivery system. Triple complex contains single-walled carbon nanotubes, Congo red, and doxorubicin. Nanotubes are built of a folded graphene layer providing a large surface for binding Congo red via “face-to-face” stacking which markedly increases the binding capacity of the carrier. Congo red is a compound that self-associates to form supramolecular ribbon-like structures, which are able to bind some drugs by intercalation. The nanotube–Congo red complex can bind the model drug doxorubicin. Thus, a new triple carrier system was obtained. The aim of this paper is to present studies on the controlled release of a model anticancer drug from a triple carrier system through pH changes. The specific aim of the study was to model the structure of the obtained experimental systems and to compare the changes in the average energy of interaction between its components induced by pH changes. The studies also aimed to compare the intensity of pH-dependent changes in hydrodynamic diameters of individual components of the triple carrier system. The effect of pH changes on the stability of the analyzed systems was examined using the molecular modeling method and dynamic light scattering. The decrease in pH influenced the structure and stability of the analyzed triple systems and ensured efficient drug release. The changes in hydrodynamic diameters of the obtained fractions were examined with the use of dynamic light scattering and were confirmed by computer simulation methods. The formulation presented in this paper shows potential for a therapeutic application owing to its high drug binding capacity and pH-dependent release. This ensures prolonged local action of the drug. The results reveal that the studied complex fulfills the basic requirements for its potential use as drug carrier, thus reducing side effects and enhancing pharmacological efficacy of drugs.

Characterization of the mechanism of interaction between α1 -acid glycoprotein and lipid membranes by vacuum-ultraviolet circular-dichroism spectroscopy.

α1 -Acid glycoprotein (AGP) interacts with lipid membranes as a peripheral membrane protein so as to decrease the drug-binding capacity accompanying the β→α conformational change that is considered a protein-mediated uptake mechanism for releasing drugs into membranes or cells. This study characterized the mechanism of interaction between AGP and lipid membranes by measuring the vacuum-ultraviolet circular-dichroism (VUVCD) spectra of AGP down to 170 nm using synchrotron radiation in the presence of five types of liposomes whose constituent phospholipid molecules have different molecular characteristics in the head groups (e.g., different net charges). The VUVCD analysis showed that the α-helix and β-strand contents and the numbers of segments of AGP varied with the constituent phospholipid molecules of liposomes, while combining VUVCD data with a neural-network method predicted that these membrane-bound conformations comprised several common long helix and small strand segments. The amino-acid composition of each helical segment of the conformations indicated that amphiphilic and positively charged helices formed at the N- and C-terminal regions of AGP, respectively, were candidate sites for the membrane interaction. The addition of 1 M sodium chloride shortened the C-terminal helix while having no effect on the length of the N-terminal one. These results suggest that the N- and C-terminal helices can interact with the membrane via hydrophobic and electrostatic interactions, respectively, demonstrating that the liposome-dependent conformations of AGP analyzed using VUVCD spectroscopy provide useful information for characterizing the mechanism of interaction between AGP and lipid membranes.

Solvent Mapping Approach for Uncovering Cryptic Pockets in Membrane-Bound Proteins

Flaviviruses are vector-borne human pathogens which include viruses such as dengue, Zika, yellow fever virus or the West Nile virus. Dengue virus is associated with 390 million clinical cases worldwide and the research into a safe and effective neutralizing antibody or a drug molecule is still ongoing, with a particular focus being placed on a viral envelope consisting of a protein and a membrane component. Molecular dynamics simulations with small organic probes added to the solvent are being used as a method to efficiently reveal cryptic pockets usually hidden from the water environment. We have designed a benzene-mapping method which relies on a modified force-field with added repulsive forces between the membrane and the benzene molecules, enabling effective cryptic pocket discovery even with a membrane present in the system. Repulsion parameters were optimized using a system containing a heterogeneous membrane. The method was tested on a dengue envelope and subsequently applied to six viral strains with a goal of finding a cryptic pocket conserved within the flaviviral family and with a potential to be a drug-binding site. Cryptic pocket which experimentally binds n-octyl-β-D-glucoside was consistently revealed in all simulations with benzene probes in the solvent. The addition of benzene also enhanced the flexibility and hydrophobic exposure of pockets within the domain III across all simulated systems, suggesting the drug-binding capacity of the envelope protein and the potential to modify or obstruct the interactions between the virus and the host receptors.

Nanoclay-functionalized 3D nanofibrous scaffolds promote bone regeneration.

Developing a biomaterial that can promote osteoblastic differentiation, thereby reducing the needs of exogenous osteogenic factors for large bone repair, has been a significant and long-term technical hurdle. In this study, we developed an innovative nanoclay (nanosilicate, NS)-functionalized 3D gelatin nanofibrous scaffold (GF/NS) through a thermally induced phase separation method together with the particle leaching technique (TIPS&P). In addition to the significantly higher mechanical strength, the composite scaffolds (GF/NS) demonstrated a significantly stronger ability to promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs) in vitro compared to the GF scaffold. Our data further revealed that this intriguing pro-osteoblastic functionality was largely because of the unique features of NS, particularly, the strong binding ability to pro-osteoblastic factors (e.g., BMP2) as well as the intrinsic osteoinductivity of its bioactive degradation products. Most importantly, our in vivo studies indicated that GF/NS scaffolds significantly improved low-dose BMP2-induced ectopic bone regeneration in mice.

Development and Characterization of Composites Consisting of Calcium Phosphate Cements and Mesoporous Bioactive Glass for Extrusion-Based Fabrication.

Calcium phosphate cements (CPC) and mesoporous bioactive glasses (MBG) are two degradable biomaterial groups widely under investigation concerning their applicability to treat bone defects. MBG-CPC composites were recently shown to possess enhanced degradation properties in comparison to pure CPC. In addition, modification of MBG allows an easy incorporation of therapeutically effective ions. Additive manufacturing of such composites enables the fabrication of patient-specific geometries with further improved degradation behavior due to control over macroporosity. In this study, we developed composites prepared from a non-aqueous carrier-liquid (cl) based CPC paste and MBG particles suitable for extrusion-based additive manufacturing (3D plotting). CPC with the addition of up to 10 wt % MBG were processible by adjusting the amount of cl. Scaffolds consisting of a 4, 6 and 8%-MBG-CPC composite were successfully manufactured by 3D plotting. While mechanically characterization of the scaffolds showed an influence of the MBG, no changes of microstructure were observed. During degradation of the composite, the release of Ca2+ and Sr2+ ions could be controlled by the MBG composition and plotted scaffolds with macropores showed a significant higher release than bulk samples of comparable mass. These findings demonstrate a high flexibility regarding ion release of the developed composites and suggest utilizing the drug binding capacities of MBG as a prospective delivery system for biologically active proteins.

Whey protein: A functional and promising material for drug delivery systems recent developments and future prospects

Natural polymers have been extensively utilized in the past decades due to their outstanding features. Among these natural excipients, protein‐based polymers have superb features owing to their high drug binding capacity and biodegradability. Whey protein is a versatile protein‐based vehicle for drug delivery systems. It has been shown to be nontoxic, biocompatible, and biodegradable. Therefore, it has been considered as an ideal biomaterial for the design of advanced drug delivery systems. Protein‐based cargo acts as synthetic polymers counterpart for innovative delivery systems. The current review is mainly focused on application of whey proteins as an emerging carrier in drug delivery systems, achieved during the past.

On the way to precision formulation additives: 2D-screening to select solubilizers with tailored host and release capabilities

A 2-dimensional high-throughput screening method is presented to select peptide sequences from large peptide libraries for precision formulation additives, having a high capacity to specifically host a drug of interest and provide tailored drug release properties. The identified sequences are conjugated with poly(ethylene glycol) (PEG) to obtain peptide-PEG conjugates that proved to be valuable as solubilizers for small organic molecule drugs to overcome limitations of poor water-solubility and low bio-availability. The 2D-screening method selects peptide sequences on both (i) high loading capacities and (ii) preferred drug-release capabilities as demonstrated on an experimental Tau-protein aggregation inhibitor/Tau- deaggregator with potentials for an anti-Alzheimer disease drug (BB17). To enable 2D-screening, a one-bead one-compound (OBOC) peptide library was immobilized on a glass slide, allocating individual beads to permanent positions. While the first screening step involved incubation of the supported OBOC library with BB17 to identify beads with high drug binding capacities by fluorescence scanner readouts, the second step reveals release properties of the high capacity binders by incubation with blood plasma protein model solutions. Efficiently peptides with high BB17 capacities and either keeper or medium or fast releaser properties can be identified by direct sequence readouts from the glass slide supported resin beads via matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry. Four peptides are synthesized as peptide-PEG solubilizers representing strong, medium, weak releasers and non-binders. Loading capacities reached up to 1:3.4 (mol drug per mol carrier) and release kinetics (fast/medium/slow) are in agreement with the selection process as investigated by fluorescence anisotropy and fluorescence correlation spectroscopy. The ability of BB17/conjugate complexes to inhibit the aggregation of Tau4RDΔK (four repeat Tau ((M)Q244-E372 with deletion of K280), 129 residues) in N2a cells is studied by a Tau-pelleting assay showing the modulation of cellular Tau aggregation. Promising effects such as the reduction of 55% of total Tau load are observed for the strong releaser additive. Studies of in vitro Thioflavin S Tau-aggregation assays show half-maximal inhibitory activities (IC50 values) of BB17/conjugates in the low micro-molar range.