ABSTRACT
Antibiotics are essential for treating infections and reducing risks during medical interventions. However, many commonly used antibiotics lack the physiochemical properties for an efficient oral administration when treating systemic infection. Instead, we are reliant on intravenous delivery, which presents complications outside of clinical settings. Developing novel formulations for oral administration is a potential solution to this problem. We engineered hexosome and cubosome liquid crystal nanoparticles (LCNPs) characterized by small-angle X-ray scattering and cryogenic transmission electron microscopy, and could encapsulate the antibiotics vancomycin (VAN) and clarithromycin (CLA) with high loading efficiencies. By rationally choosing stable lipid building blocks, the loaded LCNPs demonstrated excellent resilience against enzymatic degradation in an in vitro gut model LCNP stability is crucial as premature antibiotic leakage can negatively impact the gut microbiota. In screens against the representative gut bacteria Enterococcus faecalis and Escherichia coli, our LCNPs provided a protective effect. Furthermore, we explored co-administration and dual loading strategies of VAN and CLA, and demonstrated effective loading, stability and protection for E. faecalis and E. coli. This work represents a proof of concept for the early-stage development of antibiotic-loaded LCNPs to treat systemic infection via oral administration, opening opportunities for combination antibiotic therapies.
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Background: Rani Therapeutics is developing a robotic pill (RP), an oral drug delivery platform called RaniPill™ that can deliver a number of biotherapeutics with high bioavailability; eliminating the need for injections. While patients in general prefer oral to injectable therapies, preference for a more frequent oral regimen compared to a less frequent injectable regimen is unknown. Two marketing surveys were conducted to gather data on preference for oral versus injectable therapies. A clinical study gathered data on participant preference for oral pills vs injections before and after swallowing a Mock-RP capsule. Methods: A total of 1689 adults taking injections (mean duration 3-7 years) to treat endocrine or inflammatory conditions were anonymously surveyed online for their preference to administer/prescribe medications orally via the RP. In the clinical study, 150 participants currently taking injections for chronic conditions evaluated the swallowability of a Mock-RP and completed a questionnaire regarding their preferences. Results: Majority of respondents surveyed stated they would be willing to convert to an oral alternative over their current parenteral therapy regardless of drug or disease. In the clinical study, all participants were able to swallow the Mock-RP and 91% indicated their preference for the oral route versus their current parenteral route of drug administration. Survey respondents and those in the clinical study using frequent injections were more willing to select a once-daily capsule compared to those injecting infrequently. Even study participants who inject infrequently (≥monthly: 80%) would prefer a once-daily pill over their injection regimen. Conclusion: Patients taking injections and prescribing physicians strongly prefer oral dosing to parenteral administration of biologics even if dosing frequency with the oral option, such as the RP, is increased.
ABSTRACT
BACKGROUND: Oral delivery of small interfering RNAs (siRNAs) draws significant attention, but the gastrointestinal tract (GIT) has many biological barriers that limit the drugs' bioavailability. The aim of this work was to investigate the potential of micro- and nano-sized CaCO3 and PLA carriers for oral delivery of siRNA and reveal a relationship between the physicochemical features of these carriers and their biodistribution. RESEARCH DESIGN AND METHODS: In vitro stability of carriers was investigated in simulated gastric and intestinal fluids. Toxicity and cellular uptake were investigated on Caco-2 cells. The biodistribution profiles of the developed CaCO3 and PLA carriers were examined using different visualization methods, including SPECT, fluorescence imaging, radiometry, and histological analysis. The delivery efficiency of siRNA loaded carriers was investigated both in vitro and in vivo. RESULTS: Micro-sized carriers were accumulated in the stomach and later localized in the colon tissues. The nanoscale particles (100-250 nm) were distributed in the colon tissues. nPLA was also detected in small intestine. The developed carriers can prevent siRNA from premature degradation in GIT media. CONCLUSION: Our results reveal how the physicochemical properties of the particles, including their size and material type can affect their biodistribution profile and oral delivery of siRNA.
ABSTRACT
Colorectal cancer (CRC) is a major global health concern, and the development of effective treatment strategies is crucial. Enzyme prodrug therapy (EPT) shows promise in combating tumors but faces challenges in achieving sustained expression of therapeutic enzymes and optimal biological distribution. To address these issues, a fungi-triggered in situ chemotherapeutics generator (named as SC@CS@5-FC) was constructed via oral delivery of a prodrug (5-fluorocytosine, 5-FC) for the treatment of orthotopic colorectal tumor. When SC@CS@5-FC targets the tumor through tropism by Saccharomyces cerevisiae (SC), the chemotherapeutic generator could be degraded under abundant hyaluronidase (HAase) in the tumor microenvironment by an enzyme-responsive gate to release prodrug (5-FC). And nontoxic 5-FC was catalyzed to toxic chemotherapy drug 5-fluorouracil (5-FU) by cytosine deaminase (CD) of SC. Meanwhile, SC and zinc-coordinated chitosan nanoparticles could be used as immune adjuvants to activate antigen-presenting cells and further enhance the therapeutic effect. Our results demonstrated that SC@CS@5-FC could effectively inhibit tumor growth and prolong mouse survival in an orthotopic colorectal cancer model. This work utilizes living SC as a dynamotor and positioning system for the chemotherapeutic generator SC@CS@5-FC, providing a strategy for oral enzyme prodrug therapy for the treatment of orthotopic colorectal.
Subject(s)
Colorectal Neoplasms , Flucytosine , Fluorouracil , Immunotherapy , Prodrugs , Saccharomyces cerevisiae , Prodrugs/chemistry , Prodrugs/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Animals , Mice , Humans , Flucytosine/pharmacology , Flucytosine/chemistry , Administration, Oral , Fluorouracil/pharmacology , Fluorouracil/chemistry , Fluorouracil/administration & dosage , Cytosine Deaminase/metabolism , Chitosan/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Hyaluronoglucosaminidase/metabolism , Mice, Inbred BALB C , Nanoparticles/chemistry , Drug Screening Assays, AntitumorABSTRACT
The convergence of polymer and pharmaceutical sciences has advanced drug delivery systems significantly. Carbohydrate polymers, especially carboxymethylated ones, offer versatile benefits for pharmaceuticals. Interpenetrating polymer networks (IPNs) combine synthetic and natural polymers to enhance drug delivery. The study aims to develop IPN beads using sodium carboxymethyl cellulose (SCMC) and carboxymethyl konjac glucomannan (CMKGM) for controlled release of ibuprofen (IB) after oral administration. Objectives include formulation optimization, characterization of physicochemical properties, evaluation of pH-dependent swelling and drug release behaviors to advance biocompatible and efficient oral drug delivery systems. The beads were analyzed using SEM, FTIR, DSC, and XRD techniques. Different ratio of polymers (CMKGM:SCMS) and crosslinker concentrations (2&4 %w/v) were used, significantly impacting bead size, swelling, drug encapsulation, and release characteristics. DSC results indicated higher thermal stability in IPN beads compared to native polymers. XRD revealed IB dispersion within the polymer matrix. IPN beads size ranged from 580 ± 0.56 to 324 ± 0.27 µm, with a nearly spherical shape. IPN beads exhibited continuous release in alkaline conditions (pH 7.4) and minimal release in acidic media (pH 1.2). These findings suggest that the formulated IPN beads can modulate drug release in both acidic and alkaline environments, potentially mitigating the gastric adverse effects often associated with oral administration of IB.
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In this study, a novel oral formulation of berberine hydrochloride (BBH) hydrogel was successfully synthesized through physical cross-linking using chitosan (CS) and carboxymethyl-ß-cyclodextrin (CMCD). The characterization results confirmed the successful synthesis of the CS/CMCD hydrogel and the subsequent loading of BBH into this composite (CS/CMCD/BBH) was effectively accomplished. The BBH was used as a model drug and the resulting hydrogel demonstrated a sustained drug release profile. In addition to its improved solubility and sustained release characteristics, the hydrogel exhibited excellent antibacterial activity against common pathogens such as Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Candida albicans (C. albicans). Additionally, in vitro studies indicated that the hydrogel was not cytotoxic to NIH3T3 and HaCaT cells, suggesting its safety for biomedical applications. This lack of cytotoxic effects, combined with the mechanical strength, solubility improvements, and antibacterial properties of the hydrogel, positions the CS/CMCD/BBH hydrogel as a promising candidate for the effective oral delivery of BBH. By addressing the solubility and delivery challenges of BBH, this hydrogel offers a viable solution for the oral administration of BBH, with potential applications in various biomedical fields.
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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.
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Medicines remain ineffective for over 50% of patients due to conventional mass production methods with fixed drug dosages. Three-dimensional (3D) printing, specifically selective laser sintering (SLS), offers a potential solution to this challenge, allowing the manufacturing of small, personalized batches of medication. Despite its simplicity and suitability for upscaling to large-scale production, SLS was not designed for pharmaceutical manufacturing and necessitates a time-consuming, trial-and-error adaptation process. In response, this study introduces a deep learning model trained on a variety of features to identify the best feature set to represent drugs and polymeric materials for the prediction of the printability of drug-loaded formulations using SLS. The proposed model demonstrates success by achieving 90% accuracy in predicting printability. Furthermore, explainability analysis unveils materials that facilitate SLS printability, offering invaluable insights for scientists to optimize SLS formulations, which can be expanded to other disciplines. This represents the first study in the field to develop an interpretable, uncertainty-optimized deep learning model for predicting the printability of drug-loaded formulations. This paves the way for accelerating formulation development, propelling us into a future of personalized medicine with unprecedented manufacturing precision.
Subject(s)
Deep Learning , Lasers , Powders , Precision Medicine , Printing, Three-Dimensional , Precision Medicine/methods , Drug Compounding/methods , Technology, Pharmaceutical/methods , Chemistry, Pharmaceutical/methodsABSTRACT
The therapeutic effects of orally administered nanocarriers depend on their ability to effectively permeate the intestinal mucosa, which is one of the major challenges in oral drug delivery. Microfold cells are specialized enterocytes in the intestinal epithelium known for their high transcytosis abilities. This study aimed to compare and evaluate two targeting approaches using surface modifications of polymer-based nanocarriers, whereas one generally addresses enterocytes, and one is directed explicitly to microfold cells via targeting the sialyl LewisA motif on their surface. We characterized the resulting carriers in terms of size and charge, supplemented by scanning electron microscopy to confirm their structural properties. For predictive biological testing and to assess the intended targeting effect, we implemented two human intestinal in vitro models containing microfold-like cells. Both models were thoroughly characterized prior to permeation studies with the different nanocarriers. Our results demonstrated improved transport for both targeted formulations compared to undecorated carriers in the in vitro models. Notably, there was an enhanced uptake in the presence of microfold-like cells, particularly for the nanocarriers directed by the anti-sialyl LewisA antibody. These findings highlight the potential of microfold cell targeting to improve oral administration of drugs and emphasize the importance of using suitable and well-characterized in vitro models for testing novel drug delivery strategies.
Subject(s)
Drug Carriers , Drug Delivery Systems , Intestinal Mucosa , M Cells , Nanoparticles , Humans , Administration, Oral , Caco-2 Cells , Drug Carriers/chemistry , Drug Delivery Systems/methods , Enterocytes/metabolism , Enterocytes/drug effects , Intestinal Absorption/drug effects , Intestinal Mucosa/metabolism , M Cells/metabolism , Nanoparticles/chemistry , Permeability , Polymers/chemistryABSTRACT
The aim of this study was to assess the effectiveness of neroli-flavored chewing gum in reducing anxiety. A single-blind, two-group study was conducted on 72 university students. Participants were randomly assigned to either the commercial neroli-flavored chewing gum (CNC) group or the natural hydro-distilled neroli-flavored chewing gum (NNC) group. The research instrument used was Spielberger's State-Anxiety questionnaire. While there was no significant difference in anxiety scores between the CNC and NNC groups before the intervention, a significant difference was observed in anxiety scores 20 min after the intervention. Within-group comparisons indicated statistically significant differences between pre-test and post-test values of anxiety in the NNC group. The results of this study suggest that natural hydro-distilled neroli-flavored chewing gum can reduce anxiety in university students.
ABSTRACT
Food-derived extracellular vesicles (FEVs) are nanoscale membrane vesicles obtained from dietary materials such as breast milk, plants and probiotics. Distinct from other EVs, FEVs can survive the harsh degrading conditions in the gastrointestinal tract and reach the intestines. This unique feature allows FEVs to be promising prebiotics in health and oral nanomedicine for gut disorders, such as inflammatory bowel disease. Interestingly, therapeutic effects of FEVs have recently also been observed in non-gastrointestinal diseases. However, the mechanisms remain unclear or even mysterious. It is speculated that orally administered FEVs could enter the bloodstream, reach remote organs, and thus exert therapeutic effects therein. However, emerging evidence suggests that the amount of FEVs reaching organs beyond the gastrointestinal tract is marginal and may be insufficient to account for the significant therapeutic effects achieved regarding diseases involving remote organs such as the liver. Thus, we herein propose that FEVs primarily act locally in the intestine by modulating intestinal microenvironments such as barrier integrity and microbiota, thereby eliciting therapeutic impact remotely on the liver in non-gastrointestinal diseases via the gut-liver axis. Likewise, drugs delivered to the gastrointestinal system through FEVs may act via the gut-liver axis. As the liver is the main metabolic hub, the intestinal microenvironment may be implicated in other metabolic diseases. In fact, many patients with non-alcoholic fatty liver disease, obesity, diabetes and cardiovascular disease suffer from a leaky gut and dysbiosis. In this review, we provide an overview of the recent progress in FEVs and discuss their biomedical applications as therapeutic agents and drug delivery systems, highlighting the pivotal role of the gut-liver axis in the mechanisms of action of FEVs for the treatment of gut disorders and metabolic diseases.
Subject(s)
Extracellular Vesicles , Liver , Humans , Extracellular Vesicles/metabolism , Liver/metabolism , Gastrointestinal Microbiome , Animals , Gastrointestinal Tract/metabolism , FoodABSTRACT
The self-assembling aggregated structures of natural products have gained significant interest due to their simple synthesis, lack of carrier-related toxicity, and excellent biological efficacy. However, the mechanisms of their assembly and their ability to traverse the gastrointestinal (GI) barrier remain unclear. This review summarizes various intermolecular non-covalent interactions and aggregated structures, drawing on research indexed in Web of Science from 2010 to 2024. Cheminformatics analysis of the self-assembly behaviors of natural small molecules and their supramolecular aggregates reveals assembly-favorable conditions, aiding drug formulation. Additionally, the review explores the self-assembly properties of macromolecules like polysaccharides, proteins, and exosomes, highlighting their role in drug delivery. Strategies to overcome gastrointestinal barriers and enhance drug bioavailability are also discussed. This work underscores the potential of natural products in oral drug delivery and offers insights for designing more effective drug delivery systems.
Subject(s)
Biological Products , Drug Delivery Systems , Biological Products/chemistry , Biological Products/pharmacokinetics , Biological Products/administration & dosage , Humans , Administration, Oral , Drug Delivery Systems/methods , Biological Availability , Polysaccharides/chemistry , Polysaccharides/pharmacokinetics , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Animals , Gastrointestinal Tract/metabolism , Exosomes/chemistryABSTRACT
Archaeosomes were manufactured from natural archaeal lipids by a microfluidics-assisted single-step production method utilizing a mixture of di- and tetraether lipids extracted from Sulfolobus acidocaldarius. The primary aim of this study was to investigate the exceptional stability of archaeosomes as potential carriers for oral drug delivery, with a focus on powdered formulations. The archaeosomes were negatively charged with a size of approximately 100 nm and a low polydispersity index. To assess their suitability for oral delivery, the archaeosomes were loaded with two model drugs: calcein, a fluorescent compound, and insulin, a peptide hormone. The archaeosomes demonstrated high stability in simulated intestinal fluids, with only 5% of the encapsulated compounds being released after 24 h, regardless of the presence of degrading enzymes or extremely acidic pH values such as those found in the stomach. In a co-culture cell model system mimicking the intestinal barrier, the archaeosomes showed strong adhesion to the cell membranes, facilitating a slow release of contents. The archaeosomes were loaded with insulin in a single-step procedure achieving an encapsulation efficiency of approximately 35%. These particles have been exposed to extreme manufacturing temperatures during freeze-drying and spray-drying processes, demonstrating remarkable resilience under these harsh conditions. The fabrication of stable dry powder formulations of archaeosomes represents a promising advancement toward the development of solid dosage forms for oral delivery of biological drugs.
ABSTRACT
Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they are regularly accompanied with long-standing disadvantages that negatively impact efficacy, thus necessitating the need for effective and child-friendly pharmacotherapeutic interventions. Recent advancements in drug delivery technologies, particularly oral formulations, have shown tremendous progress in enhancing the effectiveness of paediatric medicines. Generally, these delivery methods target, and address challenges associated with palatability, dosing accuracy, stability, bioavailability, patient compliance, and caregiver convenience, which are important factors that can influence successful treatment outcomes in children. Some of the emerging trends include moving away from creating liquid delivery systems to developing oral solid formulations, with the most explored being orodispersible tablets, multiparticulate dosage forms using film-coating technologies, and chewable drug products. Other ongoing innovations include gastro-retentive, 3D-printed, nipple-shield, milk-based, and nanoparticulate (e.g., lipid-, polymeric-based templates) drug delivery systems, possessing the potential to improve therapeutic effectiveness, age appropriateness, pharmacokinetics, and safety profiles as they relate to the paediatric population. This manuscript therefore highlights the evolving landscape of oral pharmacotherapeutic interventions for leading paediatric infectious diseases, crediting the role of innovative drug delivery technologies. By focusing on the current trends, pointing out gaps, and identifying future possibilities, this review aims to contribute towards ongoing efforts directed at improving paediatric health outcomes associated with the management of these infectious ailments through accessible and efficacious drug treatments.
ABSTRACT
To treat colonic diseases more effectively, improved therapies are urgently needed. In this respect, delivering drugs locally to the colon is a key strategy to achieve higher local drug concentrations while minimizing systemic side effects. Understanding the luminal environment is crucial to efficiently develop such targeted therapies and to predict drug disposition in the colon. In this clinical study, we collected colonic contents from an undisturbed fasted proximal colon via colonoscopy and characterized their composition with regard to drug disposition. Colonic pH, osmolality, protein content, bile salts, lipids, phospholipids and short-chain fatty acids were investigated in 10 healthy volunteers (8 male and 2 female, age 19-25). The unique environment of the proximal colon was reflected in the composition of the sampled luminal fluids and the effect of the microbiota could be observed on the pH (median 6.55), the composition of bile salts (majority deconjugated and secondary), and the abundance of short-chain fatty acids. At the same time, an increase in phospholipid concentration, osmolality and total protein content compared to reported ileal values was seen, likely resulting from desiccation. Lipids could only be found in low quantities and mainly in the form of cholesterol and free fatty acids, showing almost complete digestion and absorption by the time luminal contents reach the colon. All characteristics also displayed the considerable intersubject variability found in different regions of the gastrointestinal tract. This study contributes to an improved understanding of the luminal conditions in the proximal colon and facilitates the development of new predictive tools to study colonic drug absorption.
Subject(s)
Bile Acids and Salts , Colon , Fasting , Humans , Female , Male , Adult , Colon/metabolism , Fasting/metabolism , Bile Acids and Salts/metabolism , Young Adult , Hydrogen-Ion Concentration , Phospholipids/metabolism , Osmolar Concentration , Lipids , Fatty Acids, Volatile/metabolismABSTRACT
Amorphous solid dispersion (ASD) has been widely used to enhance the oral bioavailability of water-insoluble drugs for oral delivery because of its advantages of enhancing solubility and dissolution rate. However, the problems related to drug recrystallization after drug dissolution in media or body fluid have constrained its application. Recently, a self-nanomicellizing solid dispersion (SNMSD) has been developed by incorporating self-micellizing polymers as carriers to settle the problems, markedly improving the ability of supersaturation maintenance and enhancing the oral bioavailability of drug. Spontaneous formation and stability of the self-nanomicelle (SNM) have been proved to be the key to supersaturation maintenance of SNMSD system. This offers a novel research direction for maintaining supersaturation and enhancing the bioavailability of ASDs. To delve into the advantages of SNMSDs, we provide a concise review introducing the formation mechanism, characterization methods and stability of SNMs, emphasizing the advantages of SNMSDs for oral drug delivery facilitated by SNM formation, and discussing relevant research prospects.
Subject(s)
Drug Delivery Systems , Micelles , Administration, Oral , Humans , Nanoparticles/chemistry , Solubility , Biological Availability , Drug Carriers/chemistryABSTRACT
The success of colon-targeted oral hybrid systems relies in the proper control over the release of the entrapped nanostructures at the colon. This work describes the design of hybrid systems for their colonic enzyme-triggered release. The hybrid systems were constituted by nanoemulsions, with adequate characteristics for the treatment of ulcerative colitis, included in a pectin hydrogel-like matrix. For that purpose, pectins with similar degrees of methylation (< 50%) and increasing degree of amidation, i.e. 0, 13 and 20%, were selected. Hybrid systems were formulated by a novel aggregation induced gelation method, using Ca2+, Ba2+ or Zn2+ as aggregating agents, as well as by a polyelectrolyte condensation approach, obtaining structures in the micrometric range (< 10 µm). Despite the resistance of pectins to the upper gastrointestinal tract stimuli, the analysis of the behaviour of the different prototypes showed that the non-covalent crosslinks that allow the formation of the hybrid structure may play a relevant role on the performance of the formulation.Our results indicated that the partial disassembling of the hybrid system's microstructure due to the intestinal conditions may facilitate the stimuli-triggered release of the nanoemulsions at the colon. More interestingly, the particle tracking experiments showed that the condensation process that occurs during the formation of the system may affect to the enzymatic degradation of pectin. In this sense, the effect of the high degree of amidation of pectin may be more prevalent as structural feature rather than as a promoter of the enzyme-triggered release.
Subject(s)
Colon , Pectins , Pectins/chemistry , Colon/metabolism , Hydrogels/chemistry , Hydrogels/administration & dosage , Drug Delivery Systems , Emulsions , HumansABSTRACT
BACKGROUND: Type I interferons (IFN-I)-a group of cytokines with immunomodulatory, antiproliferative, and antiviral properties-are widely used as therapeutics for various cancers and viral diseases. Since IFNs are proteins, they are highly susceptible to degradation by proteases and by hydrolysis in the strong acid environment of the stomach, and they are therefore administered parenterally. In this study, we examined whether the intestinal bacterium, enteropathogenic Escherichia coli (EPEC), can be exploited for oral delivery of IFN-Is. EPEC survives the harsh conditions of the stomach and, upon reaching the small intestine, expresses a type III secretion system (T3SS) that is used to translocate effector proteins across the bacterial envelope into the eukaryotic host cells. RESULTS: In this study, we developed an attenuated EPEC strain that cannot colonize the host but can secrete functional human IFNα2 variant through the T3SS. We found that this bacteria-secreted IFN exhibited antiproliferative and antiviral activities similar to commercially available IFN. CONCLUSION: These findings present a potential novel approach for the oral delivery of IFN via secreting bacteria.
Subject(s)
Enteropathogenic Escherichia coli , Type III Secretion Systems , Enteropathogenic Escherichia coli/metabolism , Humans , Type III Secretion Systems/metabolism , Interferon-alpha/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/metabolism , Interferon alpha-2/metabolism , Cell Proliferation/drug effectsABSTRACT
Oral devices, such as foil-type devices, show great potential for the delivery of poorly permeable macromolecules by enabling unidirectional release of the loaded pharmaceutical composition in close proximity to the epithelium in the small intestine or colon. However, one of the primary concerns associated with the use of foil-type devices so far has been the utilization of nonbiodegradable elastomers in the fabrication of the devices. Therefore, research into biodegradable substitute materials with similar characteristics enables drug delivery in a sustainable and environmentally friendly manner. In this study, a biodegradable elastomer, polyoctanediol citrate (POC), was synthesized via a one-pot reaction, with subsequent purification and microscale pattern replication via casting. The microstructure geometry was designed to enable fabrication of foil-type devices with the selected elastomer, which has a high intrinsic surface free energy. The final elastomer was demonstrated to have an elastic modulus ranging up to 2.2 ± 0.1 MPa, with strain at failure up to 110.1 ± 1.5%. Devices were loaded with acetaminophen and enterically coated, demonstrating 100% release at 2.5 h, following dissolution for 1 h in 0.1 M hydrochloric acid and 1.5 h in pH 6.8 phosphate-buffered saline. The elastomer demonstrated promising properties based on mechanical testing, surface free energy evaluation, and degradation studies.
Subject(s)
Biocompatible Materials , Elastomers , Materials Testing , Particle Size , Elastomers/chemistry , Biocompatible Materials/chemistry , Biocompatible Materials/chemical synthesis , Drug Delivery Systems , Humans , Acetaminophen/chemistry , Acetaminophen/administration & dosage , Administration, Oral , Citrates/chemistry , Macromolecular Substances/chemistry , Macromolecular Substances/chemical synthesis , Polymers/chemistryABSTRACT
The oral route of administration is considered the optimal choice for treating chronic diseases due to its convenience and non-invasiveness, which can help prevent physical and mental harm to patients undergoing long-term treatment. However, challenges such as safety, gastrointestinal stability, and bioavailability of oral drugs often limit their effectiveness. Natural biomacromolecule micelles, known for their safety, stability, biocompatibility, and diverse functions, have emerged as promising carriers for oral treatment of chronic diseases like systemic lupus erythematosus (SLE) with fat-soluble drugs. This study introduces an innovative approach by developing an oral delivery system using chemically synthesized natural biomacromolecules to load artesunate for treating SLE. By synthesizing amphiphilic polymer micelles from pectin and casein through a carbodiimide reaction, a more stable structure is achieved. The hydrophobic core of these micelles encapsulates artesunate, resulting in the formation of an oral delivery system (PC-AS) with several advantages, including high drug loading and encapsulation efficiency, small particle size, negative potential, strong stability in the gastrointestinal tract, low toxicity and side effects, strong adhesion in the small intestine, and high bioavailability. These advantages facilitate efficient absorption of artesunate in the gastrointestinal tract, leading to improved bioavailability and effective alleviation of SLE-like symptoms in MRL/lpr mice. By utilizing chemically synthesized natural macromolecular micelles for delivering artesunate in the treatment of SLE, this study overcomes the oral barriers associated with the original drug and presents a novel solution for the long-term oral treatment of chronic diseases.