Delivery Of Bioactive Agents Research Articles

Hydroxyapatite Particles Induced Modulation of Collagen Expression and Secretion in Primary Human Dermal Fibroblasts.

BackgroundHydroxyapatite (HA) [Ca5(PO4)3(OH)] is a naturally occurring calcium phosphate which makes up 60–70% of the dry weight of human bones. Nano-scale HA particles are increasingly being used as carriers for controlled and targeted delivery of bioactive agents like drugs, proteins, and nucleic acids due to their high porosity, negative charge, and biodegradability.PurposeAlthough much effort has been devoted to understanding the delivery kinetics and effects of the payloads in such carriers, a thorough understanding of the influence of the carriers themselves is lacking.MethodsHA particles (300 µg/mL) were administered to primary human dermal fibroblasts (HDFs). The uptake and intracellular localization of the particles were determined by flow cytometry, confocal imaging, and transmission electron microscopy (TEM). Immunological assays and PCR were performed to determine the levels of pro-inflammatory cytokines and collagens in cell lysates and media supernatant.ResultsThe current study explores the effects of poly-dispersed HA particles on primary HDFs as a model system. The majority of the particles were determined to range between 150 and 200 nm in diameter. Upon exposure to HA suspensions, primary HDFs internalized the particles by endocytosis within 6 hours of exposure, showing maximum uptake at 72 hours following which the particles were exocytosed by 168 hours. This correlated to reduced secretion of various pro-inflammatory and pro-collagenic cytokines. Biochemical analysis further revealed a reduction in Type I collagen expression and secretion.ConclusionHA particles have an immune-modulatory effect on dermal fibroblasts and reduce collagen production, which may impact the integrity of the extracellular matrix (ECM). This study demonstrates the need to consider the secondary effects of particulate carriers like HA, beyond basic cytotoxicity, in the specific tissue environment where the intended function is to be realized.

Localization of Coated Iron Oxide (Fe3O4) Nanoparticles on Tomato Seeds and Their Effects on Growth.

Food demand due to the growing global population has been stretching the agriculture sector to the limit. This demands the cultivation of plants in shrinking land areas which makes the search for highly effective systems for plant nutrition and pest control important. In this context, the application of nanoparticles (NPs) in agriculture can have a transformative effect on food production techniques as it can enable the delivery of bioactive agents (including growth factors, pesticides, and fungicides) directly to plants. Herein, we report the application of unfunctionalized as well as amine-functionalized and polycaprolactone-coated Fe3O4 NPs to seed treatment in tomato (Solanum lycopersicum). The study reveals that the treatment has no side effects on plant germination and development. Furthermore, the translocation of NPs in seeds and seedlings posttreatment depends on the surface functionalization of the NPs. X-ray fluorescence spectroscopy analysis of seedlings suggested that around 66% of unfunctionalized Fe3O4 NPs were translocated in the cotyledons, while only 50% of functionalized NPs (both amine and polycaprolactone) were translocated. Our results demonstrate that all particles were taken up by the seeds, thus suggesting that the functionalized NPs can act as a versatile platform for delivering of active compounds, such as fungicides and growth factor agents.

Injectable in situ forming kartogenin-loaded chitosan hydrogel with tunable rheological properties for cartilage tissue engineering

Limited regeneration capacity of cartilage can be addressed by tissue engineering approaches including localized delivery of bioactive agents using biomaterials. Although chitosan hydrogels have been considered as appropriate candidates for these purposes, however, their poor mechanical properties limit their real applications. Here, we develop in situ forming chitosan hydrogels with enhanced shear modulus by chemical modification of chitosan using N-(β-maleimidopropyloxy) succinimide ester (BMPS). Moreover, we utilize β-Glycerophosphate (β-GP) in the hydrogels for achieving thermosensitivity. We investigate the effects of BMPS, β-GP and chitosan concentration on rheological and swelling properties of the hydrogels. Accordingly, we generate significant statistical models by response surface method to predict these properties. These models provide us beneficial tools to tune the hydrogel properties depending on the cartilage defect location and properties. Finally, we incorporate a recently discovered small biomolecule, kartogenin (KGN), for promoting chondrogenesis of stem cells into the optimized hydrogel. The hydrogel’s shear modulus is 78 ± 5 kPa which covers a wide range of human articular cartilage shear modulus (50–250 kPa). It can be injected to the defects non-invasively at room temperature which gels at 37 °C within minutes. Additionally, it provides a sustained KGN release for ∼40 days that may eliminate the need of multiple injections. In vitro chondrogenic results confirm enhanced chondrogenic differentiation of human adipose mesenchymal stem cells (hAMSCs) treated with KGN-loaded hydrogel, compared to pure KGN. Based on the enhanced hydrogel shear modulus, injectability, gelation behavior, long-term drug release and in vitro results, this thermosensitive hydrogel looks promising for cartilage tissue engineering.

Resveratrol-loaded core-shell nanostructured delivery systems: Cyclodextrin-based metal-organic nanocapsules prepared by ionic gelation

In this study, cyclodextrin metal-organic framework/chitosan (CD-MOF/CS) nanocapsules, which have a hydrophobic core and a hydrophilic shell, were fabricated as delivery systems for bioactive agents. The nanocapsules were prepared by electrostatic deposition of cationic chitosan onto the anionic CD-MOF core. The presence of the CS coating reduced the mean diameter and polydispersity index of the nanocapsules, which was attributed to their ability to inhibit particle aggregation. Moreover, the encapsulation efficiency of resveratrol within the nanocapsules increased appreciably after coating them with chitosan (from 66.5 to 91.3%). The chitosan coating was also shown to increase the antioxidant activity and photostability of the encapsulated resveratrol. Information about the binding interactions of the resveratrol with the nanocapsules was obtained using fluorescence spectroscopy, infrared spectroscopy, and thermal analysis. The new nanocapsules created in this study may have applications for the encapsulation, protection, and delivery of bioactive agents in food, supplement, and pharmaceutical applications.

Natural deep eutectic solvent supported targeted solid-liquid polymer carrier for breast cancer therapy.

Solid–liquid nanocarriers (SLNs) are at the front of the rapidly emerging field of medicinal applications with a potential role in the delivery of bioactive agents. Here, we report a new SLN of natural deep eutectic solvent (NADES) and biotin-conjugated lysine–polyethylene glycol copolymer. The SLN system was analyzed for its functional groups, thermal stability, crystalline nature, particle size, and surface morphology through the instrumental analysis of FT-IR, TGA, XRD, DLS, SEM, and TEM. Encapsulation of PTX (paclitaxel) and 7-HC (7-hydroxycoumarin) with the SLN was carried out by dialysis, and UV-visible spectra evidenced the drug loading capacity and higher encapsulation efficiency obtained. The enhanced anticancer potential of PTX- and 7-HC-loaded SLN was assessed in vitro, and the system reduces the cell viability of MDA-MB-231 cells. The PTX- and 7-HC-loaded SLN system was investigated in a breast cancer-induced rat model via in vivo studies. It shows decreased lysosomal enzymes and increased levels of caspase to cure breast tumors. It very well may be reasoned that the designed PTX- and 7-HC-loaded SLN system has strong anticancer properties and exhibits potential for delivery of drug molecules in cancer treatment.

Ethosomes: A Novel Drug Delivery System And Their Therapeutic Applications -A Review

“Ethosomes” are soft vesicles made up of Phospholipids, Ethanol and water. They are “novel carrier system” used for delivery of drugs having low penetration through biological membrane i.e., Skin “Transdermal delivery of drugs” plays a major role in the Ethosomes. In this review we are going to discuss about various applications of ethosomes i.e. Delivery of antibiotic, Delivery of NSAIDS, Anti-cancer, Anti-fungal, Skin cancer, Anti-Acne etc. Ethosomes are loaded with drugs like Indomethacin (NSAIDS), Clotrimazole (Anti-fungal), Raloxifene HCl (Anti-cancer), Fluconazole (Antibiotic) etc. This review explains about the preparation methods used in the preparation of ethosomes such as cold method, Hot method, Injection method, Mechanical dispersion method and Classic methods. Evaluation tests performed in the ethosomes are Drug entrapment efficiency, permeation characteristics, Assay of HPLC, FT-IR studies, stability studies, size analysis, zeta potential etc. Various Penetrtion enhancers like Labrasol, Transcutol, and Terpenes were used in the formulation of ethososmes. Improve the penetration of both lipophilic and hydrophilic drugs through stratum corneum [SC] into deeper layers of the skin very effectively when compared with liposomes. Ethosomes can act as a carrier for large and diverse group of drugs with different physicochemical properties and found a number of applications in pharmaceutical, biotechnological and cosmetic fields. Enhanced delivery of bioactive molecules through the skin and cellular membranes by means of an ethosomal transporter opens numerous confronts and prospects for the research and future development of novel improved therapies. The formulation of ethosomes possesses promising future in effective dermal or transdermal delivery of bioactive agents.

Synthesis and application of magnetic nanoparticles (MNPs) in drug delivery to the retina

AbstractIntroductionThe development of an innovative drug delivery system to target, after topical administration, the retina with bioactive agents against retinal pathologies is a major challenge. Currently, the sole approach to target these tissues is through intravitreous injection, but this is not free from problematics such as severe side effects and rapid clearance of small molecules from the vitreous.PurposeWe aim to synthesize, develop and formulate a new magnetic nanoparticle‐mediated delivery technology that shall allow achieving needle‐free, anesthesia‐free delivery of active drugs to the retina after topical administration assisted by magnetic targeting.Methods MNPs have been synthesized, physico‐chemically characterized and loaded with small organic drugs (valproic acid/Guanabenz). The MNPs biocompatibility have been studied in vitro on retinal pigmented epithelium and photoreceptor cell lines and in vivo after topical administration. The MNPs have been applied on mice under the influence of an external magnetic field to guide them towards the retina. The in vivo histological and functional assays have been monitored to determine the biological effect of the treatment. ResultsThe iron oxide‐based MNPs have spherical shape, a hydrodynamic size less than 150nm and they were not affected by the drug‐loading process. HPLC measurements demonstrate the high loading capacity of the MNPs and reproducibility of the method. Cell proliferation assays showed that MNPs are fully biocompatible.ConclusionsMNPs combined with magnetic targeting is a promising technology for the delivery of bioactive agents to the retina after topical, needle‐free administration.

Traumatic Brain Injuries: Pathophysiology and Potential Therapeutic Targets.

Traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality amongst civilians and military personnel globally. Despite advances in our knowledge of the complex pathophysiology of TBI, the underlying mechanisms are yet to be fully elucidated. While initial brain insult involves acute and irreversible primary damage to the parenchyma, the ensuing secondary brain injuries often progress slowly over months to years, hence providing a window for therapeutic interventions. To date, hallmark events during delayed secondary CNS damage include Wallerian degeneration of axons, mitochondrial dysfunction, excitotoxicity, oxidative stress and apoptotic cell death of neurons and glia. Extensive research has been directed to the identification of druggable targets associated with these processes. Furthermore, tremendous effort has been put forth to improve the bioavailability of therapeutics to CNS by devising strategies for efficient, specific and controlled delivery of bioactive agents to cellular targets. Here, we give an overview of the pathophysiology of TBI and the underlying molecular mechanisms, followed by an update on novel therapeutic targets and agents. Recent development of various approaches of drug delivery to the CNS is also discussed.

Mitochondrial peptides-appropriate options for therapeutic exploitation.

Besides their well-known function in cellular bioenergetics, the role of mitochondria in signaling regulation of cells homeostasis and survival has been uncovered during the past few decades. Possessing an independent genome and a unique genetic code, mitochondria biosynthesize protective stress response factors, the "mitochondrial-derived peptides," import and deposit peptides within their matrix and are the target of peptides bound to bioactive agents, aiming at alleviation of pathology-related malfunction of the electron transport chain. As the rapidly evolving field of mitochondrial peptides is appropriate for therapeutic exploitation, a brief overview of the major recent findings is timely needed. Here, the focus is on the following issues: (i) the biological effects of mitochondrial-derived peptides (humanin, humanin-like peptides and MOTS-c) and their use in therapy, (ii) the abnormal accumulation of β-amyloid peptide within the mitochondrial matrix and (iii) the effectiveness of "mitochondrial cell-penetrating/targeting peptides" as vehicles for delivery of bioactive agents into dysfunctional mitochondria.

Main features and applications of organogels in cosmetics.

Cosmetic treatments aim at improving skin appearance through vehicles of good sensory properties. Those vehicles are mainly emulsions and gels designed to deliver safe and effective compounds to skin. Creams and serums are widely used to achieve these goals, but recently a new type of formulation known as organogels triggered scientific attention, particularly in the design of both topical and cosmetic formulations. It has been established that the lipophilic nature of organogels makes it an excellent candidate for the delivery of cosmetic molecules through skin. In this review, we discuss the properties and characteristics of organogels and present the advantages of the application of these systems in cosmetics.

Hydrogel-Based Strategies to Advance Therapies for Chronic Skin Wounds.

Chronic skin wounds are the leading cause of nontraumatic foot amputations worldwide and present a significant risk of morbidity and mortality due to the lack of efficient therapies. The intrinsic characteristics of hydrogels allow them to benefit cutaneous healing essentially by supporting a moist environment. This property has long been explored in wound management to aid in autolytic debridement. However, chronic wounds require additional therapeutic features that can be provided by a combination of hydrogels with biochemical mediators or cells, promoting faster and better healing. We survey hydrogel-based approaches with potential to improve the healing of chronic wounds by reviewing their effects as observed in preclinical models. Topics covered include strategies to ablate infection and resolve inflammation, the delivery of bioactive agents to accelerate healing, and tissue engineering approaches for skin regeneration. The article concludes by considering the relevance of treating chronic skin wounds using hydrogel-based strategies.

Liposomes as a Novel Drug Delivery System: Fundamental and Pharmaceutical Application

Liposomes are spherical vesicles consisting of one or more phospholipid bilayers, which are under extensive investigation as drug carriers for improving the delivery of bioactive agents and many different compounds in biological, pharmaceutical, and medical and nutritional research. The majority of those clinically approved have diameters of 50–300 nm. Among several talented new drug delivery systems, liposomes characterize an advanced technology to deliver active molecules to the site of action and reduce undesirable side effects improving its in vitro and in vivo activity, as well as reducing the toxicity of the drug and enhancing the efficacy of the encapsulated drug. The present review will briefly explain the characteristics, advantages, scalable techniques based on the type of produced liposomes and potential applications of liposomes in food, cosmetics, gen genetic engineering, immunology, cancer therapy, infection, and also the diagnosis.

Sequentially Moldable and Bondable Four-Dimensional Hydrogels Compatible with Cell Encapsulation.

Hydrogels have captivated the attention of several research and industry segments, including bioengineering, tissue engineering, implantable/wearable sensors and actuators, bioactive agent delivery, food processing, and industrial processes optimization. A common limitation of these systems is their fixed shape. The concept of hydrogel moldability is often assigned to the injectability potential of liquid precursors, and this feature is often lost right after hydrogel formation. Hydrogel modulation is a recent trend that advocates the importance of designing materials with shape fitting ability targeting on-demand responses or defect filling purposes. Here, we present a compliant and cell encapsulation-compatible hydrogel prepared from unmodified natural origin polymers with the ability to undergo extreme sequential shape alterations with high recovery of its mechanical properties. Different fragments of these hydrogels could be bonded together in spatiotemporally controlled shape- and formulation-morphing structures. This material is prepared with affordable off-the-shelf polysaccharides of natural origin using a mild and safe processing strategy based solely on polyelectrolyte complexation followed by an innovative partial coacervate compaction and dehydration step. These unique hydrogels hold potential for multifield industrial and healthcare applications. In particular, they may find application as defect filling agents or highly compliant wound healing patches for cargo release and/or cell delivery for tissue regeneration and cell-based therapies.

Encapsulation for delivering bioactives in aquaculture

AbstractThe exploitation of wild fisheries has driven the seafood industry to develop more sustainable resources and high‐intensity aquaculture. However, high‐density aquaculture is prone to outbreaks of diseases. The use of chemicals and antimicrobial drugs in aquaculture is common practice, but such chemicals can have serious detrimental environmental impacts and antibiotics may result in bacterial resistance in many species. The development of non‐antibiotic and green strategies, such as using probiotics and immunostimulants, aims for a more sustainable practice for health maintenance in aquaculture. Although the efficacy of such strategies has been demonstrated in cultivations settings, the effective delivery of bioactives remains a challenge. Conventional delivery methods are often ineffective in terms of dosage, stability and species specificity, and can possibly cause widespread environmental contamination. However, recently developed drug delivery systems may provide innovative ways to improve delivery with minimal waste and improved environmental protection. Indeed, such cutting‐edge drug delivery systems have already provided measurable benefits in human medicine over the past two decades. New technologies, such as encapsulation and controlled release systems, can be used readily in scaled‐up operations to improve the delivery of bioactives and ultimately increase production and profitability in aquaculture. This review critically analyses the use of encapsulation technology with a focus on microparticles for delivery of bioactive agents to farmed aquatic animals. This review discusses various potential encapsulation materials, their properties and a range of methods that can be applied and scaled‐up for aquaculture. Finally, practical considerations for designing an efficient delivery system for aquaculture are discussed.

Characterization and in vitro release kinetics of antimalarials from whey protein-based hydrogel biocomposites

In this research, hydrogel biocomposites were prepared from whey protein isolate (WPI), reduced graphene oxide (rGO), and synthetic polymers in varied ratios. Their physicochemical properties were evaluated by FTIR, SEM, TGA, AFM, and TEM. FTIR spectra revealed significant peaks at 1167 cm−1 for C–O–C peak and at 1449 cm−1 for O–H bending for WPI and rGO, respectively. The hydrogels were loaded with proguanil hydrochloride and chloroquine diphosphate and in vitro release kinetics of individual drugs from the biocomposites were studied. The SEM images of the biocomposites after drug release confirmed that they are biodegradable. The drug release was controlled, pH-dependent which further confirmed that the hydrogels are pH-sensitive. The release of proguanil from the hydrogels was slow when compared to chloroquine, suggesting that the solubility of the drug influenced their rate of release. The drug release from the biocomposites fitted the Korsmeyer–Peppas model with n values for chloroquine between 0.46 and 0.49 at pH of 1.2 and between 0.72 and 1.41 at pH of 7.4. The n values for proguanil were between 0.66 and 0.83 at pH 1.2 and 0.85–0.92 at pH 7.4. The results obtained suggested that the biocomposites are potential systems that can be tailored for controlled delivery of bioactive agents.

ORGANOGELS AS A POTENTIAL TOPICAL DRUG DELIVERY SYSTEM

Semisolid preparations for external application to skin have gained much demand, since it is easily absorbed through the skin layers. Many novel topical dosage forms have been discovered, among which organogels appears to play an important role. Interest in organogels has increased in a wide variety of fields including chemistry, biotechnology and pharmaceutics. Organogels are thermodynamically stable, biocompatible, isotropic gel, which not only give localized effect, but also systemic effect through percutaneous absorption. Organogels are semi-solid systems, in which an organic liquid phase is immobilized by a three-dimensional network composed of self assembled, intertwined gelator fibers. The apolar phase gets immobilized within spaces of the three-dimensional networked structure formed due to the physical interactions amongst the self assembled structures of compounds regarded as gelators. Organogels have been explored as matrices for the delivery of bioactive agents. Compared to conventional topical dosage forms, these novel formulations are found to be more advantageous and efficient. In future, organogels can give way to many promising discoveries in the field of topical dosage forms. The current review aims at giving an idea about organogels, its applications and importance in topical delivery.

Mannosylated Constructs as a Platform for Cell-Specific Delivery of Bioactive Agents.

Dictating the transport of drug carriers and augmenting the drug concentration at the desired anatomical site with high selectivity are worthwhile pursuits of current pharmaceutical research. Such approaches to drug targeting have been classified into passive and active strategies. As discussed in this article, active targeting promises greater selectivity because it exploits the incorporation of appropriate ligands, which are recognized by the target cells. Ligands, such as folate, peptides, transferrin, antibodies and their fragments, sugar, and sugar-mimetics, etc., with affinity to the molecules typical to or enriched in target tissues, have been investigated in this context. Mannose receptors (MRs) are abundantly expressed on a variety of cells, such as antigen-presenting cells, dendritic cells, and macrophages. Mannose receptors have lectin recognition domains that exhibit a high binding affinity for mannose. As a result, specific recognition of mannose-functionalized constructs has extensively been explored in the cell-specific targeting of drugs, vaccines, and other bioactive agents. This review outlines and discusses the key aspects of synthesis of mannosylated constructs, their mode of cellular uptake and application to targeted delivery of bioactive agents.

Degree of Unsaturation and Backbone Orientation of Amphiphilic Macromolecules Influence Local Lipid Properties in Large Unilamellar Vesicles.

Liposomes have become increasingly common in the delivery of bioactive agents due to their ability to encapsulate hydrophobic and hydrophilic drugs with excellent biocompatibility. While commercial liposome formulations improve bioavailability of otherwise quickly eliminated or insoluble drugs, tailoring formulation properties for specific uses has become a focus of liposome research. Here, we report the design, synthesis, and characterization of two series of amphiphilic macromolecules (AMs), consisting of acylated polyol backbones conjugated to poly(ethylene glycol) (PEG) that can serve as the sole additives to stabilize and control hydrophilic molecule release rates from distearoylphosphatidylcholine (DSPC)-based liposomes. As compared to DSPC alone, all AMs enable liposome formation and stabilize their colloidal properties at low incorporation ratios, and the AM's degree of unsaturation and hydrophobe conformation have profound impacts on stability duration. The AM's chemical structures, particularly hydrophobe unsaturation, also impact the rate of hydrophilic drug release. Course-grained molecular dynamics simulations were utilized to better understand the influence of AM structure on lipid properties and potential liposomal stabilization. Results indicate that both hydrophobic domain structure and PEG density can be utilized to fine-tune liposome properties for the desired application. Collectively, AMs demonstrate the potential to simultaneously stabilize and control the release profile of hydrophilic cargo.

Self-Assembly of Thermoresponsive Recombinant Silk-Elastinlike Nanogels.

Recombinant silk-elastinlike protein polymers (SELPs) combine the biocompatibility and thermoresponsiveness of human tropoelastin with the strength of silk. Direct control over structure of these monodisperse polymers allows for precise correlation of structure with function. This work describes the fabrication of the first SELP nanogels and evaluation of their physicochemical properties and thermoresponsiveness. Self-assembly of dilute concentrations of SELPs results in nanogels with enhanced stability over micelles due to physically crosslinked beta-sheet silk segments. The nanogels respond to thermal stimuli via size changes and aggregation. Modifying the ratio and sequence of silk to elastin in the polymer backbone results in alterations in critical gel formation concentration, stability, aggregation, size contraction temperature, and thermal reversibility. The nanogels sequester hydrophobic compounds and show promise in delivery of bioactive agents.

Skin Tissue Engineering: Biological Performance of Electrospun Polymer Scaffolds and Translational Challenges

Skin tissue engineering for wound healing requires a biomimetic scaffold that provides a physical, chemical, and biological environment to guide cells toward regeneration. The nanofibrous architecture provided by electrospun scaffolds, as well as the ability to tailor their surface chemistry and offer controlled delivery of bioactive agents, makes them a promising candidate for skin replacements. In this mini-review, we describe the wound healing process and the currently available engineered skin substitutes, motivating the need for a next generation of engineered skin scaffolds. We analyze how the polymeric constituents, microstructure, and biological milieu work together in electrospun scaffolds to promote a favorable behavior of skin cells. We provide a critical analysis of the optimization of physicochemical-structural properties of scaffolds and their in vivo biological performance in animal models, considering how the scaffolds perform on both a structural and biochemical level. Finally, we consider new perspectives and technological advances toward clinical implementation of electrospun scaffolds for wound healing. Wound healing especially in diabetic patients is problematic, and currently available treatment such as dermal substitutes present various limitations. To improve upon the currently available products, the development of polymeric nanoscaffolds on which dermal cells have been seeded proves to be more effective to regenerate and remodel tissue. This review discusses the choice of the polymers, the fabrication of mats at the nanoscale, the type of biological agents required to guide healing, and the results of in vitro and in vivo studies and how they may be further improved and scaled up toward clinical implementation.