Chitosan non-particulate vaccine delivery systems.

Chitosan is an extensively used polymer for drug delivery applications in particulate and non-particulate carriers. Chitosan-based particulate, nano-, and microparticle, carriers have been the most extensively studied for the delivery of therapeutics and vaccines. However, chitosan has also been used in vaccine applications for its adjuvant properties in various hydrogels or as a carrier coating material. The focus of this review will be on the usage of chitosan as a vaccine adjuvant based on its intrinsic immunogenicity; the various forms of chitosan-based non-particulate delivery systems such as thermosensitive hydrogels, microneedles, and conjugates; and the advantages of its role as a coating material for vaccine carriers.

Enzyme-Responsive DNA Origami-Antibody Conjugates for Targeted and Combined Therapy of Choroidal Neovascularization.

Monotherapy, especially the use of antibodies targeting vascular endothelial growth factor (VEGF), has shown limitations in treating choroidal neovascularization (CNV) since reactive oxygen species (ROS) also exacerbate CNV formation. Herein, we developed a combination therapy based on a DNA origami platform targeting multiple components of ocular neovascularization. Our study demonstrated that ocular neovascularization was markedly suppressed by intravitreal injection of a rectangular DNA origami sheet modified with VEGF aptamers (Ap) conjugated to an anti-VEGF antibody (aV) via matrix metalloproteinase (MMP)-cleavable peptide linkers in a mouse model of CNV. Typically, the DNA origami-based therapeutic platform selectively accumulates in neovascularization lesions owing to the dual-targeting ability of the aV and Ap, followed by the cleavage of the peptide linker by MMPs to release the antibody. Together, the released antibody and Ap inhibited VEGF activity. Moreover, the residual bare DNA origami could effectively scavenge ROS, reducing oxidative stress at CNV sites and thus maximizing the synergistic effects of inhibiting neovascularization.

Lung-specific supramolecular nanoparticles for efficient delivery of therapeutic proteins and genome editing nucleases.

Protein therapeutics play a critical role in treating a large variety of diseases, ranging from infections to genetic disorders. However, their delivery to target tissues beyond the liver, such as the lungs, remains a great challenge. Here, we report a universally applicable strategy for lung-targeted protein delivery by engineering Lung-Specific Supramolecular Nanoparticles (LSNPs). These nanoparticles are designed through the hierarchical self-assembly of metal-organic polyhedra (MOP), featuring a customized surface chemistry that enables protein encapsulation and specific lung affinity after intravenous administration. Our design of LSNPs not only addresses the hurdles of cell membrane impermeability of protein and nonspecific tissue distribution of protein delivery, but also shows exceptional versatility in delivering various proteins, including those vital for anti-inflammatory and CRISPR-based genome editing to the lung, and across multiple animal species, including mice, rabbits, and dogs. Notably, the delivery of antimicrobial proteins using LSNPs effectively alleviates acute bacterial pneumonia, demonstrating a significant therapeutic potential. Our strategy not only surmounts the obstacles of tissue-specific protein delivery but also paves the way for targeted treatments in genetic disorders and combating antibiotic resistance, offering a versatile solution for precision protein therapy.

Delivery platforms for reaching adolescents with nutrition interventions in low- and middle-income countries.

Adolescents in low- and middle-income countries (LMICs) are a vulnerable population given increased nutritional needs as puberty approaches. School-based nutrition programs exist in some settings, but the comprehensive provision of nutrition services requires knowledge of the mechanisms to reach out-of-school adolescents. A comprehensive scoping review was performed using formal and informal search strategies to landscape all potential delivery platforms with nutrition services to reach adolescents. Peer-reviewed studies, institutional strategies, program evaluations, and programmatic reports in LMICs were reviewed, including gray literature. A total of 87 out of 270 identified publications and reports describing nutrition programs for adolescents were identified. Although nutrition programs targeted at adolescents were sparse, various innovative and inclusive delivery platforms were included, such as school feeding programs, school-based anemia control, and nutrition-friendly school initiatives; health facility-based, youth-friendly health and nutrition services; social safety nets targeted at adolescents; community-based approaches targeting youth development and peer education within youth centers and faith-based settings; and technology-based platforms, including digital health services and mass media communication sensitization and mobilization efforts. Existing delivery mechanisms and platforms in health and other sectors that target adolescents offer great potential to extend nutrition interventions to this vulnerable yet hard-to-reach population.

Emergency department utilization among adults with epilepsy: A multi-state cross-sectional analysis, 2010-2019.

OBJECTIVE: We described patterns and trends in ED use among adults with epilepsy in the United States. METHODS: Utilizing inpatient and ED discharge data from seven states, we conducted a cross-sectional analysis to identify adult ED visits diagnosed with epilepsy or seizures from 2010 to 2019. Using ED visit counts and estimates of state-level epilepsy prevalence, we calculated ED visit rates overall and by payer, condition, and year. RESULTS: Our data captured 304,935 ED visits with epilepsy as a primary or secondary diagnosis in 2019. Across the seven states, visit rates ranged between 366 and 726 per 1000 and were higher than rates for adults without epilepsy in all states but one. ED visit rates were highest among Medicare and Medicaid beneficiaries (vs commercial or self-pay). Adults with epilepsy were more likely to be admitted as inpatients. Visits for nervous system disorders were 6.3-8.2 times higher among people with epilepsy, and visits for mental health conditions were 1.2-2.6 times higher. Increases in ED visit rates from 2010 to 2019 among people with epilepsy exceeded increases among adults without by 6.0-27.3 percentage points. CONCLUSION: Adults with epilepsy visit the ED frequently and visit rates have been increasing over time. These results underscore the importance of identifying factors contributing to ED use and designing tailored interventions to improve ambulatory care quality.

A series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structure for drugs delivery systems of paclitaxel: Synthesis, structure-activity relationship and anti-tumors effect.

Aggregation-induced emission (AIE) materials are attracting great attention in biomedical fields such as sensors, bioimaging, and cancer treatment, et al. due to their strong fluorescence emission in the aggregated state. In this contribution, a series of tetraphenylene-acetonitrile AIE compounds with D-A-D' structures were synthesized by Suzuki coupling reaction and Knoevenagel condensation, and their relationship of chemical structure and fluorescence properties was investigated in detail, among which TPPA compound was selected as the monomer owing to the longest emission wavelength at about 530 nm with low energy band gap ΔE 3.09 eV of neutral TPPA and 1.43 eV of protonated TPPA. Novel amphiphilic AIE PEG-TA copolymers were prepared by RAFT polymerization of TPPA and PEGMA with about 1.44×104 Mw and narrow PDI, and the molar ratio of TPPA in the PEG-TA1 and PEG-TA2 copolymers was about 23.4 % and 29.6 %. The as-prepared PEG-TA copolymers would self-assembled in aqueous solution to form core-shell structures with a diameter of 150-200 nm, and their emission wavelength could reversibly convert from 545 nm to 650 nm with excellent pH sensitivity. The CLSM images showed that the PEG-TA FONs and PTX drugs-loaded PTX-TA FONs could be endocytosed by cells and mainly enriched in the cytoplasm, and CCK-8 results showed that the PEG-TA FONs had excellent biocompatibility but PTX-TA FONs had high inhibition ratio for A549 cells, moreover, the flow cytometry also showed that PTX-TA FONs could result in the apoptosis of A549 cells with some extent anti-tumor effect.

"Necessity is the mother of invention": Experiences of accessing and delivering dementia-related support services by information communication technology during the pandemic in the UK.

INTRODUCTION: The remote delivery of dementia-related support services by information communication technology, defined as any hardware or software, including the telephone and videoconferencing software, increased during the coronavirus pandemic. To guide the future use of information communication technology, this study explored the experiences of delivering and accessing social care and support services during the pandemic in the UK. METHOD: Remote semi-structured interviews with social care and support providers, people with dementia and family carers were conducted between May-December 2022. Topic guides were co-developed with two public advisors (one former family carer, one person with dementia) and garnered information on delivering and accessing services during the pandemic. Audio recordings were transcribed verbatim. Employing a mixture of inductive and deductive analytic approaches, a thematic analysis was conducted. RESULTS: Twenty-one interviews (n = 14 social care and support providers; n = 6 family carers; n = 2 people with dementia) were conducted. Three themes were generated: adapting to changing circumstances; responding to unmet needs by information communication technology and information communication technology should be a tool, not the default. Social care and support providers' creativity and motivation facilitated the adoption of information communication technology, however, available resources and guidance varied. While some people with dementia and family carers benefitted from accessing services by information communication technology to address some needs, the format was not suitable for everyone. CONCLUSIONS: Beyond the coronavirus pandemic, the use of information communication technology within service delivery needs to be carefully considered, to avoid disenfranchising some people with dementia and family carers, while empowering people with the option of how to access services. Digital training and guidelines advising the use of information communication technology within service delivery may facilitate its improved use during the current landscape, and amidst future pandemics.

Microbial messengers: nucleic acid delivery by bacteria.

The demand for diverse nucleic acid delivery vectors, driven by recent biotechnological breakthroughs, offers opportunities for continuous improvements in efficiency, safety, and delivery capacity. With their enhanced safety and substantial cargo capacity, bacterial vectors offer significant potential across a variety of applications. In this review, we explore methods to engineer bacteria for nucleic acid delivery, including strategies such as engineering attenuated strains, lysis circuits, and conjugation machinery. Moreover, we explore pioneering techniques, such as manipulating nanoparticle (NP) coatings and outer membrane vesicles (OMVs), representing the next frontier in bacterial vector engineering. We foresee these advancements in bacteria-mediated nucleic acid delivery, through combining bacterial pathogenesis with engineering biology techniques, as a pivotal step forward in the evolution of nucleic acid delivery technologies.

Physicochemical and biological properties of dental materials and formulations with silica nanoparticles: A narrative review.

OBJECTIVE: Silica nanoparticles (SNPs) have been extensively studied and used in different dental applications to promote improved physicochemical properties, high substance loading efficiency, in addition to sustained delivery of substances for therapeutic or preventive purposes. Therefore, this study aimed to review the SNPs applications in nanomaterials and nanoformulations in dentistry, discussing their effect on physicochemical properties, biocompatibility and ability to nanocarry bioactive substances. DATA RESOURCES: Literature searches were conducted on PubMed, Web of Science, and Scopus databases to identify studies examining the physicochemical and biological properties of dental materials and formulations containing SNPs. Data extraction was performed by one reviewer and verified by another STUDY SELECTION: A total of 50 were reviewed. In vitro studies reveal that SNPs improved the general properties of dental materials and formulations, such as microhardness, fracture toughness, flexural strength, elastic modulus and surface roughness, in addition to acting as efficient nanocarriers of substances, such as antimicrobial, osteogenic and remineralizing substances, and showed biocompatibility CONCLUSIONS: SNPs are biocompatible, improve properties of dental materials and serve as effective carriers for bioactive substances CLINICAL SIGNIFICANCE: Overall, SNPs are a promising drug delivery system that can improve dental materials biological and physicochemical and aesthetic properties, increasing their longevity and clinical performance. However, more studies are needed to elucidate SNPs short- and long-term effects in the oral cavity, mainly on in vivo and clinical studies, to prove their effectiveness and safety.

Examining dental providers counseling on human papillomavirus vaccine: Insights from parents and dental professionals.

OBJECTIVES: To (1) assess perceptions of parents of patients ages 9-17 years regarding human papillomavirus (HPV) vaccine counseling and a same-day HPV vaccine program, and (2) assess perceptions among dental staff who actively participated in the same administration program. METHODS: We conducted a post-evaluation, convenience survey of parents of patients aged 9-17 and dental staff at a large-urban federally qualified healthcare center (FQHC) from July 25, 2022, to August 26, 2022. Parent and staff perceptions were assessed using validated instruments whenever possible. Data were analyzed descriptively. RESULTS: Overall, 101 parents participated (response rate: 89%). Overall, 80 parents (74.3%) reported wanting to discuss diseases prevented by the HPV vaccine with their dental provider. Twenty parents (20%) reported receiving counseling on the HPV vaccine by their dentist; 95% (n = 19) of those parents reported it did not change their comfort with their provider and 60% (n = 12) reported their child received the vaccine that day. Overall, 44 dental staff members (32% DDS/DMD, 14% RDH-BS-Dental Hygiene, 55% Other) completed surveys (response rate: 100%). Of these, 39 (88.6%) were willing to recommend the HPV vaccine and participate in a referral program. Nearly all dentists and hygienists (95%) reported discussing the vaccine was within their scope of practice, and most (65%) agreed vaccine administration should be within their scope. CONCLUSION: In a single site convenience survey within an urban, federally qualified health care system, most parents, and dental staff perceived HPV vaccine counseling and administration favorably and clinically appropriate during routine dental visits.

Dual-Action Protein-siRNA Conjugates for Targeted Disruption of CD47-Signal Regulatory Protein α Axis in Cancer Therapy.

A series of successes in RNA interference (RNAi) therapies for liver diseases using lipid nanoparticles and N-acetylgalactosamine have heralded a current era of RNA therapeutics. However, alternative delivery strategies are required to take RNAi out of the comfort zone of hepatocytes. Here we report SIRPα IgV/anti-CD47 siRNA (vS-siCD47) conjugates that selectively and persistently disrupt the antiphagocytic CD47/SIRPα axis in solid tumors. Conjugation of the SIRPα IgV domain protein to siRNAs enables tumor dash through CD47-mediated erythrocyte piggyback, primarily blocking the physical interaction between CD47 on cancer cells and SIRPα on phagocytes. After internalization of the vS-siCD47 conjugates within cancer cells, the detached free-standing anti-CD47 siRNAs subsequently attack CD47 through the RNAi mechanism. The dual-action approach of the vS-siCD47 conjugate effectively overcomes the "don't eat me" barrier and stimulates phagocyte-mediated tumor destruction, demonstrating a highly selective and potent CD47-blocking immunotherapy. This delivery strategy, employing IgV domain protein-siRNA conjugates with a dual mode of target suppression, holds promise for expanding RNAi applications beyond hepatocytes and advancing RNAi-based cancer immunotherapies for solid tumors.

Structural regression modelling of peptide based drug delivery vectors for targeted anti-cancer therapy.

Drug resistance in cancer poses a serious challenge in finding an effective remedy for cancer patients, because of the multitude of contributing factors influencing this complex phenomenon. One way to counter this problem is using a more targeted and dose-limiting approach for drug delivery, rather than relying on conventional therapies that exhibit multiple pernicious side-effects. Stability and specificity have traditionally been the core issues of peptide-based delivery vectors. In this study, we employed a structural regression modelling approach in the design, synthesis and characterization of a series of peptides that belong to approximately same topological cluster, yet with different electrostatic signatures encoded as a result of their differential positioning of amino acids in a given sequence. The peptides tagged with the fluorophore 5(6)-carboxyfluorescein, showed higher uptake in cancer cells with some of them colocalizing in the lysosomes. The peptides tagged with the anti-cancer drug methotrexate have displayed enhanced cytotoxicity and inducing apoptosis in triple-negative breast cancer cells. They also showed comparable uptake in side-population cells of lung cancer with stem-cell like properties. The most-optimized peptide showed accumulation in the tumor resulting in significant reduction of tumor size, compared to the untreated mice in in-vivo studies. Our results point to the following directives; (i) peptides can be design engineered for targeted delivery (ii) stereochemical engineering of peptide main chain can resist proteolytic enzymes and (iii) cellular penetration of peptides into cancer cells can be modulated by varying their electrostatic signatures.

Magnetically Guided Microcatheter for Targeted Injection of Magnetic Particle Swarms.

The initial delivery of small-scale magnetic devices such as microrobots is a key, but often overlooked, aspect for their use in clinical applications. The deployment of these devices within the dynamic environment of the human body presents significant challenges due to their dispersion caused by circulatory flows. Here, a method is introduced to effectively deliver a swarm of magnetic nanoparticles in fluidic flows. This approach integrates a magnetically navigated robotic microcatheter equipped with a reservoir for storing the magnetic nanoparticles. The microfluidic flow within the reservoir facilitates the injection of magnetic nanoparticles into the fluid stream, and a magnetic field gradient guides the swarm through the oscillatory flow to a target site. The microcatheter and reservoir are engineered to enable magnetic steering and injection of the magnetic nanoparticles. To demonstrate this approach, experiments are conducted utilizing a spinal cord phantom simulating intrathecal catheter delivery for applications in the central nervous system. These results demonstrate that the proposed microcatheter successfully concentrates nanoparticles near the desired location through the precise manipulation of magnetic field gradients, offering a promising solution for the controlled deployment of untethered magnetic micro-/nanodevices within the complex physiological circulatory systems of the human body.

Engineered nanoparticles potentials in male reproduction.

BACKGROUND: The escalating prevalence of fertility problems in the aging population necessitates a comprehensive exploration of contributing factors, extending beyond environmental concerns, work-related stress, and unhealthy lifestyles. Among these, the rising incidence of testicular disorders emerges as a pivotal determinant of fertility issues. Current treatment challenges are underscored by the limitations of high-dose and frequent drug administration, coupled with substantial side effects and irreversible trauma inflicted by surgical interventions on testicular tissue. MATERIAL AND METHODS: The formidable barrier posed by the blood-testis barrier compounds the complexities of treating testicular diseases, presenting a significant therapeutic obstacle. The advent of nanocarriers, with their distinctive attributes, holds promise in overcoming this impediment. These nanocarriers exhibit exceptional biocompatibility, and membrane penetration capabilities, and can strategically target the blood-testis barrier through surface ligand modification, thereby augmenting drug bioavailability and enhancing therapeutic efficacy. RESULTS AND DISCUSSION: This review concentrates on the transformative potential of nanocarriers in the delivery of therapeutic agents to testicular tissue. By summarizing key applications, we illuminate the strides made in utilizing nanocarriers as a novel avenue to effectively treat testicular diseases. CONCLUSIONS: Nanocarriers are critical in delivering therapeutic agents to testicular tissue.

Anti-inflammatory potential of casein enzymatic hydrolysate/gelatin methacryloyl scaffolds for vital pulp therapy.

OBJECTIVES: To synthesize casein enzymatic hydrolysate (CEH)-laden gelatin methacryloyl (GelMA) fibrous scaffolds and evaluate the cytocompatibility and anti-inflammatory effects on dental pulp stem cells (DPSCs). MATERIALS AND METHODS: GelMA fibrous scaffolds with 10%, 20%, and 30% CEH (w/w) and without CEH (control) were obtained via electrospinning. Chemo-morphological, degradation, and mechanical analyses were conducted to evaluate the morphology and composition of the fibers, mass loss, and mechanical properties, respectively. Adhesion/spreading and viability of DPSCs seeded on the scaffolds were also assessed. The anti-inflammatory potential on DPSCs was tested after the chronic challenge of cells with lipopolysaccharides (LPS), followed by treatment with extracts obtained after immersing the scaffolds in α-MEM. The synthesis of the pro-inflammatory cytokines IL-6, IL-1α, and TNF-α was measured by ELISA. Data were analyzed by ANOVA/post-hoc tests (α = 5%). RESULTS: CEH-laden electrospun fibers had a larger diameter than pure GelMA (p ≤ 0.036). GelMA scaffolds laden with 20% and 30% CEH had a greater mass loss. Tensile strength was reduced for the 10% CEH fibers (p = 0.0052), whereas no difference was observed for the 20% and 30% fibers (p ≥ 0.6736) compared to the control. Young's modulus decreased with CEH (p < 0.0001). Elongation at break increased for the 20% and 30% CEH scaffolds (p ≤ 0.0038). Over time, DPSCs viability increased across all groups, indicating cytocompatibility, with CEH-laden scaffolds exhibiting greater cell viability after seven days (p ≤ 0.0166). Also, 10% CEH-GelMA scaffolds decreased the IL-6, IL-1α, and TNF-α synthesis (p ≤ 0.035). CONCLUSION: CEH-laden GelMA scaffolds facilitated both adhesion and proliferation of DPSCs, and 10% CEH provided anti-inflammatory potential after chronic LPS challenge. CLINICAL RELEVANCE: CEH incorporated in GelMA fibrous scaffolds demonstrated the potential to be used as a cytocompatible and anti-inflammatory biomaterial for vital pulp therapy.

Unlocking the potential of beta-glucans: a comprehensive review from synthesis to drug delivery carrier potency.

Modernization and lifestyle changes have resulted in a number of diseases, including cancer, that require complicated and thorough treatments. One of the most important therapies is the administration of antibiotics and medicines. This is known as chemotherapy for cancer, and it is a regularly utilised treatment plan in which the medications used have negative side effects. This has resulted in extensive research on materials capable of delivering pharmaceuticals to particular targets over an extended period of time. Biopolymers have often been preferred as effective drug delivery carriers. Of these, ß-glucan, a natural polysaccharide, has not been extensively studied as a drug delivery carrier, despite its unique properties. This review discusses the sources, extraction techniques, structures, and characteristics of ß-glucan to provide an overview. Furthermore, the different methods employed to encapsulate drugs into ß-glucan and its role as an efficient drug, SiRNA and Plasmid DNA carrier have been elaborated in this article. The capacity of ß-glucan-based to specifically target and alter tumour-associated macrophages, inducing an immune response ultimately resulting in tumour suppression has been elaborated. Finally, this study aims to stimulate further research on ß-glucan by thoroughly describing its many characteristics and demonstrating its effectiveness as a drug delivery vehicle.

Biodegradable silica nanoparticles for efficient linear DNA gene delivery.

Targeting, safety, scalability, and storage stability of vectors are still challenges in the field of nucleic acid delivery for gene therapy. Silica-based nanoparticles have been widely studied as gene carriers, exhibiting key features such as biocompatibility, simplistic synthesis, and enabling easy surface modifications for targeting. However, the ability of the formulation to incorporate DNA is limited, which restricts the number of DNA molecules that can be incorporated into the particle, thereby reducing gene expression. Here we use polymerase chain reaction (PCR)-generated linear DNA molecules to augment the coding sequences of gene-carrying nanoparticles, thereby maximizing nucleic acid loading and minimizing the size of these nanocarriers. This approach results in a remarkable 16-fold increase in protein expression six days post-transfection in cells transfected with particles carrying the linear DNA compared with particles bearing circular plasmid DNA. The study also showed that the use of linear DNA entrapped in DNA@SiO2 resulted in a much more efficient level of gene expression compared to standard transfection reagents. The system developed in this study features simplicity, scalability, and increased transfection efficiency and gene expression over existing approaches, enabled by improved embedment capabilities for linear DNA, compared to conventional methods such as lipids or polymers, which generally show greater transfection efficiency with plasmid DNA. Therefore, this novel methodology can find applications not only in gene therapy but also in research settings for high-throughput gene expression screenings.

Environment-responsive dopamine nanoplatform for tumor synergistic therapy.

Nanoparticle-based photothermal therapy (PTT) has emerged as a promising approach in tumor treatment due to its high selectivity and low invasiveness. However, the penetration of near-infrared light (NIR) is limited, leading it fails to induce damage to the deep-seated tumor cells within the tumor tissue. Additionally, inefficient uptake of photothermal nanoparticles by tumor cells results in suboptimal outcomes for PTT. In this study, we utilized the adhesive properties of photothermal material, polydopamine (PDA), which can successfully load the photosensitizer indocyanine green (ICG) and chemotherapeutic drug doxorubicin (DOX) to achieve photothermal and chemotherapy synergy treatment (PDA/DOX&ICG), aiming to compensate the defects of single tumor treatment. To extending the blood circulation time of PDA/DOX&ICG nanoparticles, evading clearance by the body immune system and achieving targeted delivery to tumor tissues, a protective envelopment was created using erythrocyte membranes modified with folate acid (FA-EM). After reaching the tumor tissue, the obtained FA-EM@PDA/DOX&ICG nanoparticles can specific bind with folate acid receptors on the surface of tumor cells, which can improve the uptake behavior of FA-EM@PDA/DOX&ICG nanoparticles by tumor cells, and leading to the release of loaded DOX and ICG in response to the unique tumor microenvironment. ICG, as a typical photosensitizer, significantly enhances the photothermal conversion performance of FA-EM@PDA/DOX&ICG nanoparticles, thus inducing tumor cells damage. In vitro and in vivo experimental results demonstrated that the coordinated NIR treatment with FA-EM@PDA/DOX&ICG not only effectively inhibits tumor growth, but also exhibits superior biocompatibility, effectively mitigating DOX-induced tissue damage.

Sustained release of 5-aminosalicylic acid from azoreductase-responsive polymeric prodrugs for prolonged colon-targeted colitis therapy.

Ulcerative colitis (UC) is a challenging inflammatory gastrointestinal disorder, whose therapies encounter limitations in overcoming insufficient colonic retention and rapid systemic clearance. In this study, we report an innovative polymeric prodrug nanoformulation for targeted UC treatment through sustained 5-aminosalicylic acid (5-ASA) delivery. Amphiphilic polymer-based 13.5 nm micelles were engineered to incorporate azo-linked 5-ASA prodrug motifs, enabling cleavage via colonic azoreductases. In vitro, micelles exhibited excellent stability under gastric/intestinal conditions while demonstrating controlled 5-ASA release over 24 h in colonic fluids. Orally administered micelles revealed prolonged 24-h retention and a high accumulation within inflamed murine colonic tissue. At an approximately 60% dose reduction from those most advanced recent studies, the platform halted DSS colitis progression and outperformed standard 5-ASA therapy through a 77-97% suppression of inflammatory markers. Histological analysis confirmed intact colon morphology and restored barrier protein expression. This integrated prodrug nanoformulation addresses limitations in colon-targeted UC therapy through localized bioactivation and tailored pharmacokinetics, suggesting the potential of nanotechnology-guided precision delivery to transform disease management.

ATP-binding cassette transporter inhibitor potency and substrate drug affinity are critical determinants of successful drug delivery enhancement to the brain.

BACKGROUND: Pharmacotherapy for brain diseases is severely compromised by the blood-brain barrier (BBB). ABCB1 and ABCG2 are drug transporters that restrict drug entry into the brain and their inhibition can be used as a strategy to boost drug delivery and pharmacotherapy for brain diseases. METHODS: We employed elacridar and tariquidar in mice to explore the conditions for effective inhibition at the BBB. Abcg2;Abcb1a/b knockout (KO), Abcb1a/b KO, Abcg2 KO and wild-type (WT) mice received a 3 h i.p. infusion of a cocktail of 8 typical substrate drugs in combination with elacridar or tariquidar at a range of doses. Abcg2;Abcb1a/b KO mice were used as the reference for complete inhibition, while single KO mice were used to assess the potency to inhibit the remaining transporter. Brain and plasma drug levels were measured by LC-MS/MS. RESULTS: Complete inhibition of ABCB1 at the BBB is achieved when the elacridar plasma level reaches 1200 nM, whereas tariquidar requires at least 4000 nM. Inhibition of ABCG2 is more difficult. Elacridar inhibits ABCG2-mediated efflux of weak but not strong ABCG2 substrates. Strikingly, tariquidar does not enhance the brain uptake of any ABCG2-subtrate drug. Similarly, elacridar, but not tariquidar, was able to inhibit its own brain efflux in ABCG2-proficient mice. The plasma protein binding of elacridar and tariquidar was very high but similar in mouse and human plasma, facilitating the translation of mouse data to humans. CONCLUSIONS: This work shows that elacridar is an effective pharmacokinetic-enhancer for the brain delivery of ABCB1 and weaker ABCG2 substrate drugs when a plasma concentration of 1200 nM is exceeded.