Potential Use In Drug Delivery Research Articles

Exploring the Versatility of Exosomes: A Review on Isolation, Characterization, Detection Methods, and Diverse Applications.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication and can be classified based on their physical properties, biomolecular structure, and origin. Among EVs, exosomes have garnered significant attention due to their potential as therapeutic and diagnostic tools. Exosomes are released via fusion of multivesicular bodies on plasma membranes and can be isolated from various biofluids using methods such as differential ultracentrifugation, immune affinity capture, ultrafiltration, and size exclusion chromatography. Herein, an overview of different techniques for exosome characterization and isolation, as well as the diverse applications of exosome detection, including their potential use in drug delivery and disease diagnosis, is provided. Additionally, we discuss the emerging field of exosome detection by sensors, which offers an up-and-coming avenue for point-of-care diagnostic tools development. Overall, this review aims to provide a exhaustive and up-to-date summary of the current state of exosome research.

Silica particles convert thiol-containing molecules to disulfides

Synthetic amorphous silica is a common food additive and a popular cosmetic ingredient. Mesoporous silica particles are also widely studied for their potential use in drug delivery and imaging applications because of their unique properties, such as tunable pore sizes, large surfaces areas, and assumed biocompatibility. Such a nanomaterial, when consisting of pure silicon dioxide, is generally considered to be chemically inert, but in this study, we showed that oxidation yields for different compounds were facilitated by simply incubating aqueous solutions with pure silica particles. Three thiol-containing molecules, L-cysteine, glutathione, and D-penicillamine, were studied separately, and it was found that more than 95% of oxidation happened after incubating any of these compounds with mesoporous silica particles in the dark for a day at room temperature. Oxidation increased over incubation time, and more oxidation was found for particles having larger surface areas. For nonporous silica particles at submicron ranges, yields of oxidation were different based on the structures of molecules, correlating with steric hindrance while accessing surfaces. We propose that the silyloxy radical (SiO•) on silica surfaces is what facilitates oxidation. Density functional theory calculations were conducted for total energy changes for reactions between different aqueous species and silicon dioxide surfaces. These calculations identified two most plausible pathways of the lowest energy to generate SiO• radicals from water radical cations H2O•+ and hydroxyl radicals •OH, previously known to exist at water interfaces.

Magnetic Nanoparticle Coating Decreases the Senescence and Increases the Targeting Potential of Fibroblasts and Adipose-Derived Mesenchymal Stem Cells.

Magnetic nanoparticles (MNPs) are intensely scrutinized for applications in emerging biomedical fields. Their potential use for drug delivery, tracking, and targeting agents or for cell handling is tested for regenerative medicine and tissue engineering applications. The large majority of MNPs tested for biomedical use are coated with different lipids and natural or synthetic polymers in order to decrease their degradation process and to increase the ability to transport drugs or bioactive molecules. Our previous studies highlighted the fact that the as-prepared MNP-loaded cells can display increased resistance to culture-induced senescence as well as ability to target pathological tissues; however, this effect tends to be dependent on the cell type. Here, we assessed comparatively the effect of two types of commonly used lipid coatings, oleic acid (OA) and palmitic acid (PA), on normal human dermal fibroblasts and adipose-derived mesenchymal cells with culture-induced senescence and cell motility in vitro. OA and PA coatings improved MNPs stability and dispersibility. We found good viability for cells loaded with all types of MNPs; however, a significant increase was obtained with the as-prepared MNPs and OA-MNPs. The coating decreases iron uptake in both cell types. Fibroblasts (Fb) integrate MNPs at a slower rate compared to adipose-derived mesenchymal stem cells (ADSCs). The as-prepared MNPs induced a significant decrease in beta-galactosidase (B-Gal) activity with a nonsignificant one observed for OA-MNPs and PA-MNPs in ADSCs and Fb. The as-prepared MNPs significantly decrease senescence-associated B-Gal enzymatic activity in ADSCs but not in Fb. Remarkably, a significant increase in cell mobility could be detected in ADSCs loaded with OA-MNPscompared to controls. The OA-MNPs uptake significantly increases ADSCs mobility in a wound healing model in vitro compared to nonloaded counterparts, while these observations need to be validated in vivo. The present findings provide evidence that support applications of OA-MNPs in wound healing and cell therapy involving reparative processes as well as organ and tissue targeting.

Green Biodegradable Polylactide-Based Polyurethane Triblock Copolymers Reinforced with Cellulose Nanowhiskers

A novel series of biodegradable polylactide-based triblock polyurethane (TBPU) copolymers covering a wide range of molecular weights and compositions were synthesized for potential use in biomedical applications. This new class of copolymers showed tailored mechanical properties, improved degradation rates, and enhanced cell attachment potential compared to polylactide homopolymer. Triblock copolymers, (TB) PL-PEG-PL, of different compositions were first synthesized from lactide and polyethylene glycol (PEG) via ring-opening polymerization in the presence of tin octoate as the catalyst. After which, polycaprolactone diol (PCL-diol) reacted with TB copolymers using 1,4-butane diisocyanate (BDI) as a nontoxic chain extender to form the final TBPUs. The final composition, molecular weight, thermal properties, hydrophilicity, and biodegradation rates of the obtained TB copolymers, and the corresponding TBPUs were characterized using 1H-NMR, GPC, FTIR, DSC, and SEM, and contact angle measurements. Results obtained from the lower molecular weight series of TBPUs demonstrated potential use in drug delivery and imaging contrast agents due to their high hydrophilicity and degradation rates. On the other hand, the higher molecular weight series of TBPUs exhibited improved hydrophilicity and degradation rates compared to PL-homopolymer. Moreover, they displayed improved tailored mechanical properties suitable for utilization as bone cement, or in regeneration medicinal applications of cartilage, trabecular, and cancellous bone implants. Furthermore, the polymer nanocomposites obtained by reinforcing the TBPU3 matrix with 7% (w/w) bacterial cellulose nanowhiskers (BCNW) displayed a ~16% increase in tensile strength, and 330% in % elongation compared with PL-homo polymer.

New chromatographic insights on drug:cyclodextrin inclusion complexes and their potential use in drug delivery

ABSTRACT Objectives Cyclodextrins (CDs) play a pivotal role in the controlled release of drugs; however, their ability to gradually release drugs is here interrogated: can cyclodextrins, even those that form strong inclusion complexes, sustain a prolonged release of drugs? Methods An original chromatographic approach was developed and accordingly we classified and determined drugs that form the most stable inclusion complexes with cyclodextrins. β-CD and hydroxypropyl-β-CD (HP-β-CD) were coupled to pullulan (Pul) microspheres and packed into a chromatographic column. Then, different drugs or model compounds were eluted, and values of the retention time (RT) were determined. In vitro release studies were performed for drugs that form the most stable inclusion complexes. Results The drugs with the longest RT value form the most stable inclusion complexes with Pul/β-CD and Pul/HP-β-CD microspheres. Pul/β-CD microspheres form more stable inclusion complexes than Pul/HP-β-CD microspheres. However, in spite of their high stability, they were not able to gradually release the included drug (15 min release time). The cross-chromatographic experiments confirmed the hypothesis that in aqueous solution, drug/cyclodextrin complexes are continuously associated and dissociated. Conclusions If the dissociation of the guest molecule is very rapid, why is it expected that these complexes gradually release the drug?

Synthesis of 6-Methyluracilpentylviologen Resorcinarene Cavitand

Resorcinarenes, as macrocyclic compounds, are widely used to recognize substrates and create supramolecular assemblies. Their bowl-like form organizes functional groups at the upper and lower rims, which has a substantial impact on the molecular recognition of various substrates. As a result, resorcinarenes make good drug nanocarrier candidates. This paper presents the synthesis of a new resorcinarene cavitand functionalized along the upper rim with methyluracil and viologen fragments for its potential use in drug delivery. Methyluracils and viologens are well-known receptor-targeted compounds capable of facilitating the vector transfer of drugs and increasing the effectiveness of their action on cells. The paper describes the synthesis of resorcinarene modified with methyluracil and viologen groups along with its structure determined by 1H-, 13C-NMR and IR spectroscopy.

Chitosan hydrogels chemically crosslinked with L-glutamic acid and their potential use in drug delivery

Chitosan hydrogels chemically crosslinked with L-glutamic acid and their potential use in drug delivery

Triggering the nanophase separation of albumin through multivalent binding to glycogen for drug delivery in 2D and 3D multicellular constructs.

Engineered nanoparticles for the encapsulation of bioactive agents hold promise to improve disease diagnosis, prevention and therapy. To advance this field and enable clinical translation, the rational design of nanoparticles with controlled functionalities and a robust understanding of nanoparticle-cell interactions in the complex biological milieu are of paramount importance. Herein, a simple platform obtained through the nanocomplexation of glycogen nanoparticles and albumin is introduced for the delivery of chemotherapeutics in complex multicellular 2D and 3D systems. We found that the dendrimer-like structure of aminated glycogen nanoparticles is key to controlling the multivalent coordination and phase separation of albumin molecules to form stable glycogen-albumin nanocomplexes. The pH-responsive glycogen scaffold conferred the nanocomplexes the ability to undergo partial endosomal escape in tumour, stromal and immune cells while albumin enabled nanocomplexes to cross endothelial cells and carry therapeutic agents. Limited interactions of nanocomplexes with T cells, B cells and natural killer cells derived from human blood were observed. The nanocomplexes can accommodate chemotherapeutic drugs and release them in multicellular 2D and 3D constructs. The drugs loaded on the nanocomplexes retained their cytotoxic activity, which is comparable with the activity of the free drugs. Cancer cells were found to be more sensitive to the drugs in the presence of stromal and immune cells. Penetration and cytotoxicity of the drug-loaded nanocomplexes in tumour mimicking tissues were validated using a 3D multicellular-collagen construct in a perfusion bioreactor. The results highlight a simple and potentially scalable strategy for engineering nanocomplexes made entirely of biological macromolecules with potential use for drug delivery.

Neutrally charged self-assembling peptide hydrogel recapitulates in vitro mechanisms of breast cancer progression

Self-assembling peptide hydrogels (SAPH) are a popular biomaterial due to their biocompatibility with a wide range of cell types, synthetic design, structural properties that provide a more accurate 3D microenvironment, and potential for cell- and/or drug-delivery system. Mimicking solid tumors in vitro using hydrogels is one method of testing anti-cancer drug efficacy and observing cancerous cell-ECM interactions within a 3D system. In this study, a SAPH, PeptiGel®Alpha1, was used to model in vitro the 3D breast tumor microenvironment. PeptiGel®Alpha1 is composed of entangled nanofibers with consistent diameter and mechanical properties similar to breast cancer that more accurately mimic the stiffness of breast tumor tissue than Matrigel® or collagen type I. PeptiGel®Alpha1 supported the viability and growth of the breast cancer cell lines MCF-7 and MDA-MB-231 and recapitulated key features of solid tumors such as hypoxia and invasion. MCF-7 cells in the hydrogels formed large spheroids resembling acini, while MDA-MB-231 remained dispersed. When treated with tamoxifen, PeptiGel®Alpha1 acted as a barrier, providing drug penetration geometry similar to that in vivo, providing better prediction of the drug effect. Finally, it was observed that MCF-7 cells engulfed the peptide matrix after 14 days, highlighting a potential use in drug delivery. PeptiGel®Alpha1 is a suitable platform for in vitro modeling of breast cancer.

Trimodal attributes within acidic mesostructured bioactive glass nanoparticles

This study reports the synthesis of multicomponent 80SiO2-15CaO-5P2O5 bioactive glass having a spherical morphology with an ordered mesoporous structure comprising of uniformly grown nanocrystals of apatite embedded within it. These nanospheres were synthesized through a centrifugation-assisted two step acid-catalyzed sol–gel method and were found to have a size range of 200–250 nm. The bulk crystallographic analysis together with microstructural characterizations reveals that the inorganic amorphous glass matrix is composed of nanocrystalline apatite domains. These nanoapatite domains those are dispersed throughout the matrix are found to influence the textural properties since the crystal growth of apatite interrupts the mesoporous structuring. Alongside the mesoporous ordering is observed to have a short range order. These particles find its potential use in drug delivery since spherical and also due to the apatite nanocrystals that can act as temporary barrier to prevent rapid release of drugs.

Human induced pluripotent stem cells (BIONi010-C) generate tight cell monolayers with blood-brain barrier traits and functional expression of large neutral amino acid transporter 1 (SLC7A5)

The barrier properties of the brain capillary endothelium, the blood-brain barrier (BBB) restricts uptake of most small and all large molecule drug compounds to the CNS. There is a need for predictive human in vitro models of the BBB to enable studies of brain drug delivery. Here, we investigated whether human induced pluripotent stem cell (hiPSC) line (BIONi010-C) could be differentiated to brain capillary endothelial- like cells (BCEC) and evaluated their potential use in drug delivery studies.BIONi010-C hIPSCs were differentiated according to established protocols. BCEC monolayers displayed transendothelial electrical resistance (TEER) values of 5,829±354 Ω∙cm2, a Papp,mannitol of 1.09±0.15 ∙ 10−6 cm∙s−1 and a Papp,diazepam of 85.7 ± 5.9 ∙ 10−6 cm ∙s−1. The Pdiazepam/Pmannitol ratio of ~80, indicated a large dynamic passive permeability range. Monolayers maintained their integrity after medium exchange. Claudin-5, Occludin, Zonulae Occludens 1 and VE-Cadherin were expressed at the cell-cell contact zones. Efflux transporters were present at the mRNA level, but functional efflux of substrates was not detected. Transferrin-receptor (TFR), Low density lipoprotein receptor-related protein 1 (LRP1) and Basigin receptors were expressed at the mRNA-level. The presence and localization of TFR and LRP1 were verified at the protein level. A wide range of BBB-expressed solute carriers (SLC's) were detected at the mRNA level. The presence and localization of SLC transporters GLUT1 and LAT1 was verified at the protein level. Functional studies revealed transport of the LAT1 substrate [3H]-L-Leucine and the LRP1 substrate angiopep-2.In conclusion, we have demonstrated that BIONi010-C-derived BCEC monolayers exhibited, BBB properties including barrier tightness and integrity, a high dynamic range, expression of some of the BBB receptor and transporter expression, as well as functional transport of LAT1 and LRP1 substrates. This suggests that BIONi010-C-derived BCEC monolayers may be useful for studying the roles of LAT-1 and LRP1 in brain drug delivery.

Noninvasive characterization (EPR, μCT, NMR) of 3D PLA electrospun fiber sponges for controlled drug delivery

Highly porous 3D-scaffolds, made from cut, electrospun PLA fibers, are relatively new and promising systems for controlled drug-delivery applications. Because knowledge concerning fundamental processes of drug delivery from those scaffolds is limited, we noninvasively characterized drug-loading and drug-release mechanisms of these polymer-fiber sponges (PFS). We screened simplified PFS-implantation scenarios with EPR and μCT to quantify and 3D-visualize the absorption of model-biofluids and an oil, a possible drug-loading liquid. Saturation of PFS (6 × 8 mm, h x d) is governed by the high hydrophobicity of the material and air-entrapment. It required up to 45 weeks for phosphate-buffered saline and 11 weeks for a more physiological, surface-active protein-solution, indicating the slow fluid-uptake of PFS as an effective mechanism to substantially prolong the release of a drug incorporated within the scaffold. Medium-chain triglycerides, as a good wetting liquid, saturated PFS within seconds, suggesting PFS potential to serve as carrier-vessels for immobilizing hydrophobic drug-solutions to define a liquid's 3D-interface. Oil-retention under mechanical stress was therefore investigated. 1H NMR permitted insights into PFS-oil interaction, confirming surface-relaxation and restricted diffusion; both did not influence drug release from oil-loaded PFS. Results facilitate better understanding of PFS and their potential use in drug delivery.

Host–guest inclusion systems of nedaplatin with cucurbit[7]uril for improved in vitro antitumour activity

Encapsulation of platinum-based anticancer drugs inside cucurbit[n]urils provides a steric hindrance to drug degradation. This study describes an alternative strategy for the enhancement of in vitro antitumor activity of nedaplatin (NDP) by encapsulating it in the cavity of cucurbit[7]uril (CB[7]). The complexation stoichiometry, binding affinity and geometry were studied via reliable spectroscopic and physicochemical techniques. The stoichiometry of the inclusion complex was 1:1 and the stability constant (KS) value was found to be (2.89 ± 0.26) × 106 M−1 at 293 K, which suggested a favorable inclusion complexation system has been formed. In vitro cytotoxicity of the free NDP and complexed NDP (NDP@CB[7]) was examined by MTT assay using three human cancer cell lines: A549, HCT116, MCF-7. Interestingly, more cytotoxicity on MCF-7 was observed for NDP@CB[7] as compared with free drugs. In addition, NDP@CB[7] showed significantly improved cytotoxicity against A549 and HCT116 cells with up to almost threefold and twofold higher cytotoxicity than that of free NDP, indicating that the encapsulation of NDP in CB[7] can enhance the cytotoxicity of NDP in tested cancer cell lines. The formed species are shown to be stabilized in solution and the host–guest complexation between NDP and CB[7] may allow this strategy to be effective for potential use in drug delivery.

Self-assembled DNA hollow spheres from microsponges

We report a novel approach for generating nanosized DNA hollow spheres (HSs) using enzymatically produced DNA microsponges in a self-templating manner. In previous studies, preparation of DNA nanostructures with specified functions required multiple complicated steps. In this study, however, a simple treatment with the nucleophilic agent 4-dimethylaminopyridine (DMAP) enabled a gradual disentanglement of DNA in microsponges by electrostatic interactions between DMAP and DNA, and the DNA underwent a reassembly process to generate hollow shell structures without denaturation/annealing by thermal cycling. In addition, this synthetic process was conducted in a water-based system without organic solvents, enabling the synthesis of biologically and environmentally friendly products. Based on the benefits of hollow shell structures, which include their high surface-to-volume ratio and ability to encapsulate small molecules, we envision that this simple approach for synthesizing DNA HSs will provide a new platform for maximizing their potential use in drug delivery and bio-imaging.

Drug-Induced Micelle-to-Vesicle Transition of a Cationic Gemini Surfactant: Potential Applications in Drug Delivery.

An impetus for the sustained interest in the formation of vesicles is their potential application as efficient drug-delivery systems. A simple approach for ionic surfactants is to add a vesicle-inducing drug of opposite charge. In ionic gemini surfactants (GSs) two molecules are covalently linked by a spacer. Regarding drug delivery, GSs are more attractive candidates than their single-chain counterparts because of their high surface activity and the effect on the physicochemical properties of their solutions caused by changing the length of the spacer and inclusion of heteroatoms therein. Herein, the effect of the (anionic) anti-inflammatory drug diclofenac sodium (DS) on the morphology of aqueous micellar aggregates of gemini surfactant hexamethylene-1,6-bis (dodecyldimethylammonium) dibromide (12-6-12) at 25 °C is reported. Several independent techniques are used to demonstrate drug-induced micelle-to-vesicle transition. These include UV/Vis spectrophotometry, dynamic light scattering, TEM, and small-angle neutron scattering. The micelles are transformed into vesicles with increasing [DS]/[12-6-12] molar ratio; precipitation of the catanionic (DS-GS) complex then occurred, followed by partial resuspension of the weakly anionic precipitate. The stability of some of the prepared vesicles at human body temperature shows their potential use in drug delivery.

Investigation of the host-guest complexation between 4-sulfocalix[4]arene and nedaplatin for potential use in drug delivery

Macromolecules including macrocyclic species have been reported to have the potential to encapsulate biologically active compounds such as drugs through host-guest complexation to increase their solubility, stability and bioavailability. In this paper the first experimental and theoretical investigation of the complexation between nedaplatin, a second generation antineoplastic drug, and p-4-sulfocalix[4]arene, a macromolecule possessing a bipolar amphiphilic structure with good biocompatibility and relatively low haemolytic toxicity for potential use as a drug delivery system is presented. Data from 1H NMR, UV, Job's plot analysis, HPLC and DFT calculations are detailed and suggest the formation of a 1:1 complex. The stability constant of the complex was experimentally estimated to be 3.6×104M−1 and 2.1×104M−1 which correspond to values of −6.2 and −5.9kcalmol−1, respectively for the free energy of complexation while the interaction free energy is calculated to be −4.9kcalmol−1. The formed species is shown to be stabilised in solution through hydrogen bonding between the host and the guest which may allow for this strategy to be effective for potential use in drug delivery.

The effects of the thiolation with thioglycolic acid and l-cysteine on the mucoadhesion properties of the starch-graft-poly(acrylic acid)

The aim of this study is to investigate the effects of the thiolation on the mucoadhesion characteristics of the gelatinized and crosslinked wheat starch-graft-poly(acrylic acid) [(WS-g-PAA)gc] for potential use in drug delivery via vaginal route. Thiolation of (WS-g-PAA)gc was first time realized using l-cysteine hydrochloride monohydrate (CyS) and thioglycolic acid (TGA). These conjugates [(WS-g-PAA)gcth] were characterized using FTIR. The free SH group, mucoadhesion, cytotoxicity characteristics and the mechanism of the thiolation were also evaluated. To obtain fundamental data for possible application such as drug carrier, in vitro and in vivo progesterone release profiles from the mucoadhesive tablet formulations were also determined. The results showed that, vaginal tablet containing (WS-g-PAA)gc-TGA, which has not contain free SH groups in its structure, displays higher mucoadhesion than (WS-g-PAA)gc and (WS-g-PAA)gc-CyS. This tablet formulation can also be used as a drug carrier in vaginal applications.

Drug induced micelle-to-vesicle transition in aqueous solutions of cationic surfactants

Solubilization of the drug diclofenac sodium (DS) in micellar aggregates of ionic liquid-based surfactants and cetyltrimethylammonium bromide at 25 °C induces changes to worm-like micelles and vesicles, with potential use in drug delivery.

Lithography-based methods to manufacture biomaterials at small scales

Along with the search for new therapeutic agents, advanced formulation and fabrication of drug carriers are required for better targeting, sensing, and responding to environmental stimuli as well as maximizing treatment efficiency. The emergence of intelligent therapeutics involves the use of functional biomaterials to mimic biological system for prolonged circulation and to work harmoniously with the body. One of the main concerns lies in the feasibility of creating systems with well-defined architectures including size, shape, components, and functionality. This review provides an overview regarding current challenges and potential of manufacturing and fabrication of biomaterials at small scales for various biomedical applications. Accordingly, novel lithography-based fabrication approaches are introduced together with their remarkable applications. Besides being popular in microelectronics, lithography techniques have demonstrated a great potential use for drug delivery, tissue engineering, and diagnostic tools.

Accessing Three-Dimensional Crystals with Incorporated Guests through Metal-Directed Coiled-Coil Peptide Assembly.

Obtaining three-dimensional (3D) protein and peptide crystals on demand requires a precisely orchestrated hierarchical assembly of biopolymer building blocks. In this work, we disclose a metal-ion-mediated strategy to assemble trimeric coiled-coil peptides in a head-to-tail fashion into linear strands with interstrand interactions. This design led to hexagonal 3D peptide crystal formation within 30 min in the presence of divalent metal ions. The crystal morphology could be controlled by varying the metal ion/peptide ratio, resulting in hexagonal discs to rods. Diffraction studies elucidated the head-to-tail arrangement of the coiled-coil linear strands and their hexagonal, antiparallel packing within the crystal. Unsatisfied ligands at the hexagonal ends of the crystals were harnessed as a powerful means to direct His-tagged fluorophores to distinct locations within the crystals. Overall, the designed hierarchical assembly provides a facile means to obtain 3D peptide crystals and incorporate His-tag-based cargoes and may have potential use in drug delivery and sensor design.