Search Results (7)

Low dose methotrexate (MTX) is known to effectively decrease type I collagen production in dermal fibroblasts, while increasing the matrix metalloproteinase-1 (MMP-1) production in vitro. For in vivo use as an antifibrotic agent on wounds, a linear and extended controlled release formulation of MTX is required. The objective of this study was to optimize the fabrication of MTX-loaded polymeric microspheres with such properties, and to test the efficacy for the prevention of fibrosis in vivo. Poly lactic-co-glycolic acid (PLGA), Poly (L-lactic acid) (PLLA) and the diblock copolymer, methoxypolyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used to fabricate microspheres, which were then characterized in terms of size, drug encapsulation efficiency, and in vitro release profiles. The optimized formulation (PLGA with diblock copolymer) showed high drug encapsulation efficiency (>80%), low burst release (~10%) and a gradual release of MTX. The amphipathic diblock copolymer is known to render the microsphere surface more biocompatible. In vivo, these microspheres were effective in reducing fibrotic tissue which was confirmed by quantitative measurement of type I collagen and α-smooth muscle actin expression, demonstrating that MTX can be efficiently encapsulated in PLGA microspheres to provide a delayed, gradual release in wound beds to reduce fibrosis in vivo. Full article

Protein therapeutics have the potential to treat a wide range of ailments due to the high specificity in their function and their ability to replace missing or mutated genes that encode for key cellular processes. Despite these advantages, protein drugs alone can cause adverse effects, such as the development of cross-reactive neutralizing antibodies. Through the encapsulation of proteins into nanoparticles, adverse effects and protein degradation can be minimized, thus improving protein delivery to sites of interest in the body. Nanoparticles comprised of poly(lactic acid-co-glycolic acid)-polyethylene glycol (PLGA-PEG) diblock copolymer are promising protein delivery systems as they are well characterized, non-toxic, and biocompatible. Desirable nanoparticle characteristics, such as neutral surface charge and uniformity in size and dispersity, can be achieved but often require the iterative manipulation of formulation parameters. Chain conformations in the formulation process are very important, and determining whether or not an extended or semi-collapsed polymer chain in the presence of a protein results in more favorable binding has yet to be investigated experimentally. Therefore, this work used atomistic molecular dynamics to examine the role of polymer extension on protein binding and its impact on the encapsulation process within PLGA-PEG nanoparticles. Three polymers (PLGA-PEG, PLGA, and PEG) were evaluated and iduronate-2-sulphatase (ID2S) was used as a model protein. We found highly expanded PLGA-PEG conformations led to more favorable binding with ID2S. Furthermore, PEG oligomers were observed to undergo transient binding with ID2S that was generally less favorable when compared to the other polymer types. The results also suggest that the relaxation times of the PLGA homopolymer and the PLGA-PEG copolymer at different molecular weights in relevant solvent mediums should be considered. Full article

Excessive fibrosis following surgical procedures is a challenging condition with serious consequences and no effective preventive or therapeutic option. Our group has previously shown the anti-fibrotic effect of kynurenic acid (KynA) in vitro and as topical cream formulations or nanofiber dressings in open wounds. Here, we hypothesized that the implantation of a controlled release drug delivery system loaded with KynA in a wound bed can prevent fibrosis in a closed wound. Poly (lactic-co-glycolic acid) (PLGA), and a diblock copolymer, methoxy polyethylene glycol-block-poly (D, L-lactide) (MePEG-b-PDLLA), were used for the fabrication of microspheres which were evaluated for their characteristics, encapsulation efficiency, in vitro release profile, and in vivo efficacy for reduction of fibrosis. The optimized formulation exhibited high encapsulation efficiency (>80%), low initial burst release (~10%), and a delayed, gradual release of KynA. In vivo evaluation of the fabricated microspheres in the PVA model of wound healing revealed that KynA microspheres effectively reduced collagen deposition inside and around PVA sponges and α-smooth muscle actin expression after 66 days. Our results showed that KynA can be efficiently encapsulated in PLGA microspheres and its controlled release in vivo reduces fibrotic tissue formation, suggesting a novel therapeutic option for the prevention or treatment of post-surgical fibrosis. Full article

Polymeric nanoparticles’ drug delivery systems represent a promising platform for targeted controlled release since they are capable of improving the bioavailability and tissue localization of drugs compared to traditional means of administration. Investigation of key parameters of nanoparticle preparation and their impact on performance, such as size, drug loading, and sustained release, is critical to understanding the synthesis parameters surrounding a given nanoparticle formulation. This comprehensive and systematic study reports for the first time and focuses on the development and characterization of formoterol polymeric nanoparticles that have potential application in a variety of acute and chronic diseases. Nanoparticles were prepared by a variety of solvent emulsion methods with varying modifications to the polymer and emulsion system with the aim of increasing drug loading and tuning particle size for renal localization and drug delivery. Maximal drug loading was achieved by amine modification of polyethylene glycol (PEG) conjugated to the poly(lactic-co-glycolic acid) (PLGA) backbone. The resulting formoterol PEGylated PLGA polymeric nanoparticles were successfully lyophilized without compromising size distribution by using either sucrose or trehalose as cryoprotectants. The physicochemical characteristics of the nanoparticles were examined comprehensively, including surface morphology, solid-state transitions, crystallinity, and residual water content. In vitro formoterol drug release characteristics from the PEGylated PLGA polymeric nanoparticles were also investigated as a function of both polymer and emulsion parameter selection, and release kinetics modeling was successfully applied. Full article

Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer’s disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native peptide. Despite promising results and numerous potential applications, clinical applications of PNA5 glycopeptide are limited by its short half-life, and frequent injections are required to ensure adequate treatment for cognitive impairment. Therefore, sustained-release injectable formulations of PNA5 glycopeptide are needed to improve its bioavailability, protect the peptide from degradation, and provide sustained drug release over a prolonged time to reduce injection administration frequency. Two types of poly(D,L-lactic-co-glycolic acid) (PLGA) were used in the synthesis to produce nanoparticles (≈0.769–0.35 µm) and microparticles (≈3.7–2.4 µm) loaded with PNA5 (ester and acid-end capped). Comprehensive physicochemical characterization including scanning electron microscopy, thermal analysis, molecular fingerprinting spectroscopy, particle sizing, drug loading, encapsulation efficiency, and in vitro drug release were conducted. The data shows that despite the differences in the size of the particles, sustained release of PNA5 was successfully achieved using PLGA R503H polymer with high drug loading (% DL) and high encapsulation efficiency (% EE) of >8% and >40%, respectively. While using the ester-end PLGA, NPs showed poor sustained release as after 72 h, nearly 100% of the peptide was released. Also, lower % EE and % DL values were observed (10.8 and 3.4, respectively). This is the first systematic and comprehensive study to report on the successful design, particle synthesis, physicochemical characterization, and in vitro glycopeptide drug release of PNA5 in PLGA nanoparticles and microparticles. Full article

Poly(ethylene glycol)-b-poly(d,l-lactide-co-glycolide) (PEG-b-PLGA) diblock copolymers are widely known as polymeric surfactants for biomedical applications, and exhibit high solubility in water compared to PLGA-b-PEG-b-PLGA triblock copolymers known as gelation agents. In order to overcome the difficulties in the preparation of thermo-responsive hydrogels based on PLGA-b-PEG-b-PLGA due to the low solubility in water, the fabrication of thermo-responsive hydrogels based on PEG-b-PLGA with high solubility in water was attempted by adding laponite to the PEG-b-PLGA solution. In detail, PEG-b-PLGA with high solubility in water (i.e., high PEG/PLGA ratio) were synthesized. Then, the nanocomposite solution based on PEG-b-PLGA and laponite (laponite/PEG-b-PLGA nanocomposite) was fabricated by mixing the PEG-b-PLGA solutions and the laponite suspensions. By using the test tube inversion method and dynamic mechanical analysis (DMA), it was found that thermo-responsive hydrogels could be obtained by using PEG-b-PLGA, generally known as polymeric surfactants, and that the gelation temperature was around the physiological temperature and could be regulated by changing the solution composition. Furthermore, from the structural analysis by small angle neutron scattering (SANS), PEG-b-PLGA was confirmed to be on the surface of the laponite platelets, and the thermosensitive PEG-b-PLGA on the laponite surface could trigger the thermo-responsive connection of the preformed laponite network. Full article

Self-assembling block copolymers (poloxamers, PEG/PLA and PEG/PLGA diblock and triblock copolymers, PEG/polycaprolactone, polyether modified poly(Acrylic Acid)) with large solubility difference between hydrophilic and hydrophobic moieties have the property of forming temperature dependent micellar aggregates and, after a further temperature increase, of gellifying due to micelle aggregation or packing. This property enables drugs to be mixed in the sol state at room temperature then the solution can be injected into a target tissue, forming a gel depot in-situ at body temperature with the goal of providing drug release control. The presence of micellar structures that give rise to thermoreversible gels, characterized by low toxicity and mucomimetic properties, makes this delivery system capable of solubilizing water-insoluble or poorly soluble drugs and of protecting labile molecules such as proteins and peptide drugs. Full article