ABSTRACT
AIM: To evaluate the impact of the surface decoration of cannabidiol (CBD) loaded self-emulsifying drug delivery systems (SEDDS) on the efficacy of the formulations to cross the various barriers faced by orally administered drugs. METHODS: Polyethylene glycol (PEG)-free polyglycerol (PG)-based SEDDS, mixed zwitterionic phosphatidyl choline (PC)/PEG-containing SEDDS and PEG-based SEDDS were compared regarding stability against lipid degrading enzymes, surface properties, permeation across porcine mucus, cellular uptake and cytocompatibility. RESULTS: SEDDS with a size of about 200 nm with narrow size distributions were developed and loaded with 20-21 % of CBD. For PG containing PEG-free SEDDS increased degradation by lipid degrading enzymes was observed compared to PEG-containing formulations. The surface hydrophobicity of placebo SEDDS increased in the order of PG-based to mixed PC/PEG-based to PEG-based SEDDS. The influence of this surface hydrophobicity was also observed on the ability of the SEDDS to cross the mucus gel layer where highest mucus permeation was achieved for most hydrophobic PEG-based SEDDS. Highest cellular internalization was observed for PEG-based Lumogen Yellow (LY) loaded SEDDS with 92 % in Caco-2 cells compared to only 30 % for mixed PC/PEG-based SEDDS and 1 % for PG-based SEDDS, leading to a 100-fold improvement in cellular uptake for SEDDS having highest surface hydrophobicity. For cytocompatibility all developed placebo SEDDS showed similar results with a cell survival of above 75 % for concentrations below 0.05 % on Caco-2 cells. CONCLUSION: Higher surface hydrophobicity of SEDDS to orally deliver lipophilic drugs as CBD seems to be a promising approach to increase the intracellular drug concentration by an enhanced permeation through the mucus layer and cellular internalization.
ABSTRACT
Functional hydrogels are used for numerous biomedical applications such as tissue engineering, wound dressings, lubricants, contact lenses and advanced drug delivery systems. Most of them are based on synthetic or natural polymers forming a three-dimensional network that contains aqueous media. Among synthetic polymers, poly(meth)acrylates, polyethyleneglycols, poly(vinylalcohols), poly(vinylpyrrolidones), PLGA and poly(urethanes) are of high relevance, whereas natural polymers are mainly polysaccharides such as hyaluronic acid, alginate or chitosan and proteins such as albumin, collagen or elastin. In contrast to most synthetic polymers, natural polymers are biodegradable. Both synthetic and natural polymers are often chemically modified in order to improve or induce favorable properties and functions like high mechanical strength, stiffness, elasticity, high porosity, adhesive properties, in situ gelling properties, high water binding capacity or drug release controlling properties. Within this review we provide an overview about the broad spectrum of biomedical applications of functional hydrogels, summarize innovative approaches, discuss the concept of relevant functional hydrogels that are in clinical trials and highlight advanced products as examples for successful developments.
ABSTRACT
Nanofibers have been investigated in regenerative medicine. Dragon's blood (DB)- and poly helixan PF (PHPF) are natural materials used in cosmetics. Herein, we generated DB- and PHPF-loaded polyvinyl alcohol/chitosan (PVA/CS/DB and PVA/CS/PHPF, respectively) nanofibers. PVA/CS/DB and PVA/CS/PHPF nanofibers had an average diameter of 547.5 ± 17.13 and 521 ± 24.67 nm, respectively as assessed by SEM, and a degradation rate of 43.1 and 47.6 % after 14 days, respectively. PVA/CS/DB and PVA/CS/PHPF nanofibers had a hemolysis rate of 0.10 and 0.39 %, respectively, and a water vapor transmission rate of â¼2200 g.m-2.day-1. These nanofibers exhibited favorable antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Bacillus subtilis in vitro. PVA/CS/DB and PVA/CS/PHPF nanofibers demonstrated a sustained release of 77.91 and 76.55 % over 72 h. PVA/CS/DB and PVA/CS/PHPF nanofibers had a high rate of cytocompatibility and significantly improved the viability of NIH/3T3 cells as compared with free drugs or unloaded nanofibers. Histological inspection via H&E and Verhoeff's staining demonstrated PVA/CS/DB and PVA/CS/PHPF nanofibers enhanced the wound healing and damaged tissue recovery of unsplinted wound models by promoting epithelial layer formation, collagen deposition, and enhancing the presence of fibroblasts. Conclusively, PVA/CS/DB and PVA/CS/PHPF can be introduced as potential wound dressing candidates with favorable properties.
Subject(s)
Bandages , Chitosan , Nanofibers , Polyvinyl Alcohol , Nanofibers/chemistry , Chitosan/chemistry , Polyvinyl Alcohol/chemistry , Animals , Mice , NIH 3T3 Cells , Wound Healing/drug effects , Hemolysis/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Cell Survival/drug effects , Plant ExtractsABSTRACT
Inspired by nature, tissue engineering aims to employ intricate mechanisms for advanced clinical interventions, unlocking inherent biological potential and propelling medical breakthroughs. Therefore, medical, and pharmaceutical fields are growing interest in tissue and organ replacement, repair, and regeneration by this technology. Three primary mechanisms are currently used in tissue engineering: transplantation of cells (I), injection of growth factors (II) and cellular seeding in scaffolds (III). However, to develop scaffolds presenting highest potential, reinforcement with polymeric materials is growing interest. For instance, natural and synthetic polymers can be used. Regardless, chitosan and keratin are two biopolymers presenting great biocompatibility, biodegradability and non-antigenic properties for tissue engineering purposes offering restoration and revitalization. Therefore, combination of chitosan and keratin has been studied and results exhibit highly porous scaffolds providing optimal environment for tissue cultivation. This review aims to give an historical as well as current overview of tissue engineering, presenting mechanisms used and polymers involved in the field.
ABSTRACT
AIM: This study aims to design chemically crosslinked thiolated cyclodextrin-based hydrogels and to evaluate their mucoadhesive properties via mucosal residence time studies on porcine small intestinal mucosa and on porcine buccal mucosa. METHODS: Free thiol groups of heptakis(6-deoxy-6-thio)-ß-cyclodextrin (ß-CD-SH) were S-protected with 2-mercaptoethanesulfonic acid (MESNA) followed by crosslinking with citric acid. Cytotoxicity was assessed by hemolysis as well as resazurin assay. Hydrogels were characterized by their rheological and mucoadhesive properties. Ritonavir was employed as model drug for in vitro release studies from these hydrogels. RESULTS: The structure of S-protected ß-CD-SH was confirmed by IR and 1H NMR spectroscopy. Degree of thiolation was 390 ± 7 µmol/g. Hydrogels based on native ß-CD showed hemolysis of 12.5 ± 2.5 % and 13.6 ± 2.7 % within 1 and 3 h, whereas hemolysis of just 3.5 ± 2.8 % and 3.9 ± 3.0 % was observed for the S-protected thiolated CD hydrogels, respectively. Both native and S-protected thiolated hydrogels showed minor cytotoxicity on Caco-2 cells. Rheological investigations of S-protected thiolated ß-CD-based hydrogel (16.2 % m/v) showed an up to 13-fold increase in viscosity in contrast to the corresponding native ß-CD-based hydrogel. Mucosal residence time studies showed that thiolated ß-CD-based hydrogel is removed to a 16.6- and 2.4-fold lower extent from porcine small intestinal mucosa and porcine buccal mucosa in comparision to the native ß-CD-based hydrogel, respectively. Furthermore, a sustained release of ritonavir from S-protected thiolated ß-CD-based hydrogels was observed. CONCLUSION: Because of their comparatively high mucoadhesive and release-controlling properties, S-protected thiolated ß-CD-based hydrogels might be promising systems for mucosal drug delivery.
Subject(s)
Hydrogels , Mouth Mucosa , Sulfhydryl Compounds , beta-Cyclodextrins , Hydrogels/chemistry , Animals , Humans , Caco-2 Cells , Swine , Sulfhydryl Compounds/chemistry , Mouth Mucosa/metabolism , beta-Cyclodextrins/chemistry , Intestinal Mucosa/metabolism , Rheology , Hemolysis/drug effects , Adhesiveness , Drug Liberation , Polymers/chemistry , Cell Survival/drug effects , Intestine, Small/metabolismABSTRACT
AIM: The study aimed to develop enzyme-degradable nanoparticles comprising polyphosphates and metal cations providing sustained release of the antibacterial drug ethacridine (ETH). METHODS: Calcium polyphosphate (Ca-PP), zinc polyphosphate (Zn-PP) and iron polyphosphate nanoparticles (Fe-PP NPs) were prepared by co-precipitation of sodium polyphosphate with cations and ETH. Developed nanocarriers were characterized regarding particle size, PDI, zeta potential, encapsulation efficiency and drug loading. Toxicological profile of nanocarriers was assessed via hemolysis assay and cell viability on human blood erythrocytes and HEK-293 cells, respectively. The enzymatic degradation of NPs was evaluated in presence of alkaline phosphatase (ALP) monitoring the release of monophosphate, shift in zeta potential and particle size as well as drug release. The antibacterial efficacy against Escherichia coli was determined via microdilution assay. RESULTS: NPs were obtained in a size range between 300 - 480 nm displaying negative zeta potential values. Encapsulation efficiency was in the range of 83.73 %- 95.99 %. Hemolysis assay underlined sufficient compatibility of NPs with blood cells, whereas drug and NPs showed a concentration dependent effect on HEK-293 cells viability. Ca- and Zn-PP NPs exhibited remarkable changes in zeta potential, particle size, monophosphate and drug release upon incubation with ALP, compared to Fe-PP NPs showing only minor differences. The released ETH from Ca- and Zn-PP nanocarriers retained the antibacterial activity against E. coli, whereas no antibacterial effect was observed with Fe-PP NPs. CONCLUSION: Polyphosphate nanoparticles cross-linked with divalent cations and ETH hold promise for sustained drug delivery triggered by ALP for parental administration.
Subject(s)
Nanoparticles , Phosphoric Monoester Hydrolases , Humans , Pharmaceutical Preparations , Phosphoric Monoester Hydrolases/pharmacology , Drug Liberation , Hemolysis , Escherichia coli , HEK293 Cells , Anti-Bacterial Agents/pharmacology , Cations , Polyphosphates , Particle Size , Drug Carriers/pharmacologyABSTRACT
Due to its versatility in formulation and manufacturing, self-emulsifying drug delivery systems (SEDDS) can be used to design parenteral formulations. Therefore, it is necessary to understand the effects of excipients on the behavior of SEDDS formulations upon parenteral administration, particularly their interactions with blood plasma and cell membranes. In this study, we prepared three neutrally charged SEDDS formulations composed of medium-chain triglycerides as the oil phase, polyoxyl-35 castor oil (EL35) and polyethylene glycol (15)-hydroxystearate (HS15) as the nonionic surfactants, medium-chain mono- and diglycerides as the co-surfactant, and propylene glycol as the co-solvent. The cationic surfactant, didodecyldimethylammonium bromide (DDA), and the anionic surfactant, sodium deoxycholate (DEO), were added to the neutral SEDDS preconcentrates to obtain cationic and anionic SEDDS, respectively. SEDDS were incubated with human blood plasma and recovered by size exclusion chromatography. Data showed that SEDDS emulsion droplets can bind plasma protein to different extents depending on their surface charge and surfactant used. At pH 7.4, the least protein binding was observed with anionic SEDDS. Positive charges increased protein binding. SEDDS stabilized by HS15 can adsorb more plasma protein and induce more plasma membrane disruption activity than SEDDS stabilized by EL35. These effects were more pronounced with the HS15 + DDA combination. The addition of DDA and DEO to SEDDS increased plasma membrane disruption (PMD) activities, and DDA (1% w/w) was more active than DEO (2% w/w). PMD activities of SEDDS were concentration-dependent and vanished at appropriate dilution ratios.
ABSTRACT
This study aimed at designing an S-protected thiolated ß-cyclodextrin (ß-CD) exhibiting enhanced mucoadhesive properties. The native ß-CD was thiolated with phosphorus pentasulfide resulting in a thiolated ß-CD (ß-CD-SH) and subsequently S-protected with 2-mercaptoethanesulfonate (MESNA) to form ß-CD-SS-MESNA. The structure of the novel excipient was confirmed by 1H NMR and Fourier-transform infrared spectroscopy. The sulfhydryl content of ß-CD-SH, determined by Ellman's test, was 2281.00 ± 147 µmol/g, and it was decreased to 45.93 ± 19.40 µmol/g by S-protection. Due to thiolation and S-protection, the viscosity of the mixture of mucus with ß-CD-SH and ß-CD-SS-MESNA increased 1.8 and 4.1-fold, compared to native ß-CD, respectively. The unprotected ß-CD-SH diffused to a lesser extent into the mucus than native ß-CD, while S-protected ß-CD-SS-MESNA showed the highest mucodiffusion among the applied CDs. A 1.5- and 3.0-fold higher cellular uptake of ß-CD-SH and ß-CD-SS-MESNA, compared to the native one, was established on Caco-2 cell line by flow cytometry, respectively, causing slightly decreased cell viability. On account of the enhanced mucoadhesion, this higher cellular uptake does not affect the application potential of ß-CD-SS-MESNA as an oral drug delivery system since the carrier remains in the mucus and does not reach the underlying epithelial layer. According to these results, the S-protection of ß-CD-SH with MESNA promotes improved mucodiffusion, strong mucoadhesion, and prolonged mucosal residence time.
ABSTRACT
It was the aim of this study to design charge converting lipid nanoparticles (LNP) via a microfluidic mixing technique used for the preparation and coating of LNP. LNP consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, N-(carbonyl-methoxypolyethyleneglycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (MPEG-2000-DSPE), and various cationic surfactants were prepared at diverging flow rate ratios (FRR) via microfluidic mixing. Utilizing a second chip in the microfluidic set-up, LNP were coated with polyoxyethylene (9) nonylphenol monophosphate ester (PNPP). LNP were examined for their stability in different physiologically relevant media as well as for hemolytic and cytotoxic effects. Finally, phosphate release and charge conversion of PNPP-coated LNP were evaluated after incubation with alkaline phosphatase and on Caco2-cells. LNP produced at an FRR of 5:1 exhibited a size between 80 and 150 nm and a positive zeta potential. Coating with PNPP within the second chip led to LNP exhibiting a negative zeta potential. After incubation with 1 U/ml alkaline phosphatase for 4 h, zeta potential of the LNP containing 1,2-dioleoyloxy-3-trimethylammonium-propane chloride (DOTAP) as cationic component shifted from - 35 mV to approximately + 5 mV. LNP prepared with other cationic surfactants remained slightly negative after enzymatic phosphate cleavage. Manufacturing of LNP containing PNPP and DOTAP via connection of two chips in a microfluidic instrument proves to show efficient change in zeta potential from negative to positive after incubation with alkaline phosphatase.
ABSTRACT
This study aims to compare the potential of Polyethylene glycol (PEG-free and PEG-based self-emulsifying drug delivery systems (SEDDS) for the oral administration of insulin glargine (IG). Hydrophobic ion pairs (HIPs) of IG are formed using various counterions. HIPs are assessed for log P octanol/water and dissociation behavior. They are incorporated into SEDDS based on polyglycerol (PG) and zwitterionic surfactant (ZW) using response surface methodology and compared to conventional PEG-SEDDS in size, stability, and log D SEDDS/release medium. Oral IG bioavailability in PG/ZW-SEDDS and PEG-SEDDS is evaluated in rats. Among the various counterions studied, IG-BIS (bis(isotridecyl)sulfosuccinate) HIPs demonstrated the highest log P and an improved dissociation profile. PG/ZW-SEDDS and PEG-SEDDS have similar ≈40 nm sizes and are stable over 24 h. Both formulations have log D > 4 in water and >2 in 50 mM phosphate buffer pH 6.8. PG/ZW-SEDDS yielded an oral bioavailability of 2.13 ± 0.66% for IG, while the employment of PEG-SEDDS resulted in an oral bioavailability of 1.15 ± 0.35%. This study highlights the prospective utilization of PEG-free SEDDS involving the concurrent application of PG and ZW surfactants, an alternative to conventional PEG surfactants, for improved oral therapeutic (poly) peptide delivery.
Subject(s)
Biological Availability , Drug Delivery Systems , Peptides , Polyethylene Glycols , Polyethylene Glycols/chemistry , Drug Delivery Systems/methods , Administration, Oral , Animals , Peptides/chemistry , Peptides/pharmacokinetics , Emulsions/chemistry , Rats , Male , Rats, Sprague-Dawley , Surface-Active Agents/chemistry , Glycerol/chemistry , Glycerol/analogs & derivativesABSTRACT
Ulcerative colitis (UC) is an idiopathic disease characterized by colonic mucosal tissue destruction secondary to an excessive immune response. We synthesized pH-sensitive cross-linked chitosan/Eudragit® S100 nanoparticles (EU S100/CS NPs) as carriers for 5-aminosalicylic acid (5-ASA) and hesperidin (HSP), then conducted in-vitro and in-vivo studies and evaluated the therapeutic effects. In-vitro analysis revealed that the 5-ASA-loaded EU S100/CS NPs and the HSP-loaded EU S100/CS NPs had smooth and curved surfaces and ranged in size between 250 and 300 nm, with a zeta potential of 32 to 34 mV. FTIR analysis demonstrated that the drugs were loaded on the nanoparticles without significant alterations. The loading capacity and encapsulation efficiency of loading 5-ASA onto EU S100/CS NPs were 25.13 % and 60.81 %, respectively. Regarding HSP, these values were 38.34 % and 77.84 %, respectively. Drug release did not occur in simulated gastric fluid (SGF), while a slow-release pattern was recorded for both drugs in simulated intestinal fluid (SIF). In-vivo macroscopic and histopathological examinations revealed that both NPs containing drugs significantly relieved the symptoms of acetic acid (AA)-induced UC in Wistar rats. We conclude that the synthesized pH-sensitive 5-ASA/EU S100/CS NPs and HSP/EU S100/CS NPs offer promise in treating UC.
Subject(s)
Chitosan , Colitis, Ulcerative , Hesperidin , Nanoparticles , Polymethacrylic Acids , Rats , Animals , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/chemically induced , Drug Carriers/therapeutic use , Chitosan/therapeutic use , Mesalamine , Rats, Wistar , Drug Delivery Systems , Hydrogen-Ion ConcentrationABSTRACT
In this study, we present a novel approach for overcoming intestinal barriers by utilizing heparanase-responsive charge-converting nanocarriers (NCs). These NCs are designed to undergo charge conversion in response to the activity of heparanase (HPSE), an enzyme commonly overexpressed in cancer cells. Nanostructured lipid carriers (NLCs) and solid lipid nanocarriers (SLNs) with a positively charged core were coated with heparin (Hep), resulting in a negative surface charge and a size between 195 and 220 nm. However, upon encountering heparanase, heparin undergoes enzymatic cleavage, resulting in zeta potential shift from -22.1 to +8.3 mV for NLC-Hep and from -19.8 to +5.1 mV for SLN-Hep. Heparin-coated NCs showed more than 6-fold higher mucus permeating properties compared to the uncoated NCs. In vitro experiments using the heparanase-expressing cancer cell line HT29 demonstrated an up to 4-fold improved cellular uptake of the heparin coated NCs compared to co-incubation with the HPSE inhibitor suramin. Furthermore, cellular uptake was investigated on Caco-2 cells and on a Caco-2/HT29-MTX co-culture. Overall, this study highlights the potential of heparanase-responsive charge-converting NCs as a promising strategy for overcoming intestinal barriers and enhancing cellular uptake.
Subject(s)
Drug Carriers , Glucuronidase , Nanoparticles , Humans , Caco-2 Cells , Lipids , Heparin , Particle SizeABSTRACT
Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated ß-cyclodextrins (ß-CD-SHs) as inhibitors of P-gp-mediated efflux in Caco-2 cells. Through a series of transport assays, intracellular accumulation, and efflux of the P-gp substrates Rhodamine 123 (Rh123) and Calcein-AM with and without co-administration of ß-CD-SHs were assessed. The results revealed that the cellular uptake of Rh123 and Calcein-AM were enhanced up to 7- and 3-fold, compared to the control, respectively. In efflux studies an up to 2.5-fold reduction of the Rh123 efflux was reached compared the control, indicating a substantial decrease of Rh123 efflux by ß-CD-SHs. Furthermore, it was observed that ß-CD-SHs led to a decrease in the reactivity of fluorescence-labeled anti-P-gp, suggesting additional effects on the conformation of P-gp. Overall, this study demonstrates the potential of ß-CD-SHs as effective modulator of P-gp-mediated drug efflux in Caco-2 cells.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1 , Cyclodextrins , Humans , Caco-2 Cells , Cyclodextrins/pharmacology , Rhodamine 123ABSTRACT
The aim of this study was to design surfactants based on histidine (His) for hydrophobic ion-pairing and evaluate their safety and efficacy. Lauryl, palmitoyl and oleyl alcohol, as well as 2-hexyl-1-decanol were converted into surfactants with histidine as head-group via esterification. The synthesized His-surfactants were characterized regarding pKa, critical micellar concentration (CMC), biodegradability, toxicity on Caco-2 cells, and ability to provide endosomal escape. Furthermore, the suitability of these agents to be employed as counterions in hydrophobic ion pairing was evaluated. Chemical structures were confirmed by 1H-NMR, FT-IR, and MS. The synthesized surfactants showed pKa values ranging from 4.9 to 6.0 and CMC values in the range of 0.3 to 7.0 mM. Their biodegradability was proven by enzymatic cleavage within 24 h. Below the CMC, His-surfactants did not show cytotoxic effects on Caco-2 cells (cell viability > 80%). All His-surfactants showed the ability to provide endosomal escape in a pH-dependent manner in the range of 5.2 to 6.8. Complexes formed between His-surfactants and heparin or plasmid DNA (pDNA) via hydrophobic ion pairing showed at least 100-fold higher lipophilicity than the correspondent model drugs. According to these results, His-surfactants might be a promising safe tool for delivering hydrophilic macromolecular drugs and nucleic acids.
Subject(s)
Cell Survival , Histidine , Hydrophobic and Hydrophilic Interactions , Surface-Active Agents , Humans , Surface-Active Agents/chemistry , Caco-2 Cells , Histidine/chemistry , Cell Survival/drug effects , Heparin/chemistry , Plasmids , Drug Delivery Systems , DNA/administration & dosage , DNA/chemistry , Cations/chemistry , MicellesABSTRACT
AIMS AND BACKGROUND: Echis carinatus venom is a toxic substance naturally produced by special glands in this snake species. Alongside various toxic properties, this venom has been used for its therapeutic effects, which are applicable in treating various cancers (liver, breast, etc.). OBJECTIVE: Nanotechnology-based drug delivery systems are suitable for protecting Echis carinatus venom against destruction and unwanted absorption. They can manage its controlled transfer and absorption, significantly reducing side effects. METHODS: In the present study, chitosan nanoparticles were prepared using the ionotropic gelation method with emulsion cross-linking. The venom's encapsulation efficiency, loading capacity, and release rate were calculated at certain time points. Moreover, the nanoparticles' optimal formulation and cytotoxic effects were determined using the MTT assay. RESULTS: The optimized nanoparticle formulation increases cell death induction in various cancerous cell lines. Moreover, chitosan nanoparticles loaded with Echis carinatus venom had a significant rate of cytotoxicity against cancer cells. CONCLUSION: It is proposed that this formulation may act as a suitable candidate for more extensive assessments of cancer treatment using nanotechnology-based drug delivery systems.
Subject(s)
Antineoplastic Agents , Cell Survival , Chitosan , Drug Screening Assays, Antitumor , Nanoparticles , Chitosan/chemistry , Chitosan/pharmacology , Humans , Nanoparticles/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Survival/drug effects , Viper Venoms/chemistry , Viper Venoms/pharmacology , Cell Proliferation/drug effects , Animals , Dose-Response Relationship, Drug , Structure-Activity Relationship , Particle Size , Molecular Structure , Viperidae , Cell Line, Tumor , Echis , Venomous Snakes , PolyphosphatesABSTRACT
The past two decades have witnessed a rapid progress in the development of surface charge-reversible nanoparticles (NPs) for drug delivery and diagnosis. These NPs are able to elegantly address the polycation dilemma. Converting their surface charge from negative/neutral to positive at the target site, they can substantially improve delivery of drugs and diagnostic agents. By specific stimuli like a shift in pH and redox potential, enzymes, or exogenous stimuli such as light or heat, charge reversal of NP surface can be achieved at the target site. The activated positive surface charge enhances the adhesion of NPs to target cells and facilitates cellular uptake, endosomal escape, and mitochondrial targeting. Because of these properties, the efficacy of incorporated drugs as well as the sensitivity of diagnostic agents can be essentially enhanced. Furthermore, charge-reversible NPs are shown to overcome the biofilm formed by pathogenic bacteria and to shuttle antibiotics directly to the cell membrane of these microorganisms. In this review, the up-to-date design of charge-reversible NPs and their emerging applications in drug delivery and diagnosis are highlighted.
Subject(s)
Drug Carriers , Nanoparticles , Drug Carriers/chemistry , Drug Delivery Systems , Nanoparticles/chemistry , Anti-Bacterial AgentsABSTRACT
Quercetin (Q) has many potential health benefits, but its low stability limits its use in functional foods and pharmaceuticals. The low stability of quercetin is a challenge that needs to be addressed to fully realize its therapeutic potential. The purpose of this study was therefore to design a proper carrier based on porous starch (PS) and inulin (IN) in order to improve the stability of Q. The scanning electron microscopy (SEM) images denoted that the Q molecules were adsorbed in the PS pores and partially adhered to the surface of the granules. Both types of the wall material could remarkably enhance the protection of Q against thermal and light degradation. The retention index of Q under different environmental conditions was higher for the PS:IN-Q than PS-Q. The results of Fourier transform infrared spectroscopy (FT-IR) revealed that Q interacted with the wall materials through non-covalent bonds. X-ray diffraction (XRD) also confirmed the encapsulation of Q in the wall materials. The bonding between Q and the hydrogen groups of starch compacted the crystalline regions and increased the relative crystallinity in PS-Q and PS:IN-Q. The DPPH and ABTS scavenging activities of the microcapsules containing the PS and IN were higher than those of free Q. Examination of the in-vitro release profile indicated that the Q release rate was lower from the PS:IN-Q microcapsules (21.6%) than from the PS-Q ones (33.7%). Our findings highlight the significant potential of this novel biopolymer mixture (PS/IN) as a promising wall material for the protection and delivery of bioactive compounds.
Subject(s)
Antioxidants , Quercetin , Quercetin/chemistry , Antioxidants/chemistry , Inulin , Starch/chemistry , Porosity , Spectroscopy, Fourier Transform Infrared , CapsulesABSTRACT
Nanoemulsions can be tuned toward enhanced gastro-intestinal retention time by incorporating thiolated surfactants into their surface. Tailoring the chemical reactivity of the thiol headgroup has major influence on mucoadhesive features of the nanoemulsion. Two generations of thiolated surfactants were synthetically derived from PEG-40-stearate featuring either a free thiol group or an S-protected thiol group. The surfactants were characterized regarding critical micelle concentration (CMC), hemolytic activity, and cytotoxicity. Subsequently, they were incorporated into nanoemulsions and the resulting nanoemulsions were characterized regarding particle size, polydispersity index (PDI), zeta potential, and time-dependent stability. Afterward, mucosal interactions as well as mucoadhesion on porcine intestinal mucosa were investigated. Successful synthesis of Cysteine-PEG-40-stearate (CYS-PEG-40-stearate) and MNA-Cysteine-PEG-40-stearate (MNA-CYS-PEG-40-stearate) was confirmed by 1H NMR spectroscopy. Both chemical modifications led to slightly elevated CMC values while preserving low cytotoxicity and hemotoxicity. Incorporation into nanoemulsions had minor influence on overall physical particle characteristics, while interactions with mucus and mucoadhesiveness of the nanoemulsions were drastically improved resulting in the rank order PEG-40-stearate < CYS-PEG-40-stearate < MNA-CYS-PEG-40-stearate. Accordingly, thiolated surfactants, especially S-protected derivatives, are versatile tools to generate highly mucoadhesive nanoemulsions.
Subject(s)
Cysteine , Drug Delivery Systems , Animals , Swine , Cysteine/chemistry , Drug Delivery Systems/methods , Surface-Active Agents/pharmacology , Stearates , Sulfhydryl Compounds/chemistryABSTRACT
This study aims to design an anionic, thiolated cellulose derivative and to evaluate its mucoadhesive and permeation-enhancing properties utilizing enoxaparin as a model drug. 2-Mercaptosuccinic acid-modified cellulose (cellulose-mercaptosuccinate) was synthesized by the reaction of cellulose with S-acetylmercaptosuccinic anhydride. The chemical structure of the target compound was confirmed by FTIR and 1H NMR spectroscopy. The thiol content was determined by Ellman's test. The conjugate exhibited 215.5 ± 25 µmol/g of thiol groups and 84 ± 16 µmol/g of disulfide bonds. Because of thiolation, mucoadhesion on porcine intestinal mucosa was 9.6-fold enhanced. The apparent permeability (Papp) of the model dye Lucifer yellow was up to 2.2-fold improved by 0.5% cellulose-mercaptosuccinate on a Caco-2 cell monolayer. Enoxaparin permeation through rat intestinal mucosa increased 2.4-fold in the presence of 0.5% cellulose-mercaptosuccinate compared with the drug in buffer only. In vivo studies in rats showed an oral bioavailability of 8.98% using cellulose-mercaptosuccinate, which was 12.5-fold higher than that of the aqueous solution of the drug. Results of this study show that the modification of cellulose with 2-mercaptosuccinic acid provides mucoadhesive and permeation-enhancing properties, making this thiolated polymer an attractive excipient for oral drug delivery.
Subject(s)
Enoxaparin , Polymers , Humans , Rats , Animals , Swine , Polymers/pharmacology , Polymers/chemistry , Caco-2 Cells , Cellulose/chemistry , Drug Delivery Systems/methods , Sulfhydryl Compounds/chemistry , Pharmaceutical Preparations , Intestinal MucosaABSTRACT
AIM: The current study aimed to develop enzyme-activated charge-reversal lipid nanoparticles (LNPs) as novel gene delivery systems. METHODS: Palmitic acid was covalently bound to protamine being utilised as transfection promoter to anchor it on the surfaces of LNPs. Green fluorescent protein (GFP) encoding plasmid DNA (pDNA) was ion paired with various cationic counter ions to achieve high encapsulation in LNPs. Protamine-decorated LNPs were prepared by solvent injection method followed by coating with sodium tripolyphosphate (TPP) to generate a bio-inert anionic outer surface. Resulting LNPs were characterised regarding size, polydispersity, zeta potential and encapsulation efficiency. Enzyme-triggered charge-reversal of LNPs was investigated using isolated alkaline phosphatase (ALP) monitoring changes in zeta potential as well as monophosphate release. Furthermore, monophosphate release, cell viability and transfection efficiency were evaluated on a human alveolar epithelial (A549) cell line. RESULTS: Protamine-decorated and TPP-coated (Prot-pDNA/DcChol-TPP) LNPs displayed a mean size of 298.8 ± 17.4 nm and a zeta potential of -13.70 ± 0.61 mV. High pDNA encapsulation was achieved with hydrophobic ion pairs of pDNA with 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol hydrochloride (DcChol). Zeta potential of Prot-pDNA/DcChol-TPP LNPs reversed to positive values with a total Δ26.8 mV shift upon incubation with ALP. Conformably, a notable amount of monophosphate was released upon incubation of Prot-pDNA/DcChol-TPP LNPs with isolated as well as cell-associated ALP. A549 cells well tolerated LNPs displaying more than 95 % viability. Compared with naked pDNA, unmodified LNPs and control LNPs, Prot-pDNA/DcChol-TPP LNPs showed a significantly increased transfection efficiency. CONCLUSION: Prot-pDNA/DcChol-TPP LNPs can be regarded as promising gene delivery systems.