Drug Retention Research Articles

The Optimal Head Position Following Intratympanic Injection: A Research Based on HRCT Reconstruction.

Objective: This study aimed to investigate the optimal head position (OHP) following intratympanic injection, a critical intervention in treating inner ear disorders. Identifying OHP is essential to maximize drug retention in the middle ear, thereby significantly enhancing the therapeutic efficacy by mitigating the significant issue of injectate leakage through the eustachian tube (ET). Exploratory various positions of ET orifice and round window (RW) were investigated and associated with head movements. Methods: Twenty-two (10 males and 12 females) anonymized high-resolution computed tomography (HRCT) datasets of patients without structural ear disease were selected from January 2022 to December 2022 in the study. The subjects were categorized into two groups: children (≤18 years) and adult group (>18 years). The reconstruction of the ET orifice and RW from HRCT were analyzed using Mimics software and the distances from the center point of ET orifice or the center point of RW to the reference plane were defined as distance of ET orifice (DET) and distance of RW (DRW). Results: In the supine position, the OHP for intratympanic injection was 23°of pronation and 24° of posterior extension, and the maximum distance between the ET orifice and RW (DET-RW) was 9.29 ± 2.13 mm. As the head position extended posteriorly beyond 43°, DET was relatively high compared with DRW, resulting in the OHP a fully posteriorly extended 90° of the head being the optimal position with DET-RW of 2.13 ± 1.60 mm in the supine position, however, it is not realized in human beings. Moreover, the OHP had no obvious relevance corresponding to age following intratympanic injections. Conclusion: Our study suggested that OHP after intratympanic injections treatment consists of supine position, along with a slight pronation and posterior extension.

Treatment of endophthalmitis using a novel methacrylic anhydride-modified hydroxypropyl methylcellulose hydrogels loaded with S-nitrosoglutathione: An ex-vivo keratitis model

Introductionpost-operative endophthalmitis (POE) following cataract surgery remains a significant concern due to its impact on vision and the associated socio-economic burden. S-Nitrosoglutathione (GSNO) shows promise due to its stability and antimicrobial properties. Hydroxypropyl methylcellulose (HPMC) is commonly used in eye drops for drug retention, while methacrylic anhydride (MA) modification enhances adhesion. In our study, we aimed to develop a novel GSNO-loaded HPMC-MA hydrogel, and used an ex-vivo corneal keratitis model to test the anti-inflammatory and anti-microbial effects of HPMC-MA hydrogels containing GSNO. Additionally, the study evaluated the irritative potential of the eye drop formulation containing GSNO-loaded HPMC-MA hydrogels on rabbit eyes. MethodWe prepared and tested the GSNO-loaded HPMC-MA hydrogels characters. Fourier Transform Infrared (FTIR) spectroscopy measurement to verify modification, cell viability assays, osmolality tests, in-vivo ocular irritation assessments, inflammatory cells genes expression using RT-PCR, bacterial concentration analysis with an ex-vivo S. aureus keratitis model were conducted. ResultsFTIR spectroscopy confirmed successful MA modification and GSNO incorporation. Cell viability experiments suggested optimal GSNO concentration at 80 μM. Osmolality tests indicated no significant changes in osmolality post-modification. Ocular irritation tests on rabbits showed no adverse reactions. In the ex-vivo keratitis model, GSNO-HPMC-MA reduced inflammation and inhibited bacterial growth, as reflected in gene expression and bacterial concentration analyses. ConclusionThe study demonstrates the successful development of GSNO-loaded HPMC-MA hydrogels with potential as a topical formulation for endophthalmitis treatment. This novel approach shows promise in addressing challenges related to drug delivery efficiency and antimicrobial efficacy in ocular infections.

Enhanced mucoadhesive properties of ionically cross-linked thiolated gellan gum films

Localized oral drug delivery offers several advantages for treating various disease conditions. However, drug retention at the disease site within the oral cavity is indeed a significant challenge due to the dynamic oral environment. The present study aimed to develop a mucoadhesive inner layer for a three-layer mucoadhesive bandage suitable for localized oral drug delivery. using gellan gum (GG) biopolymer. Gellan gum (GG) was modified using L-cysteine moieties via carbodiimide chemistry. Subsequently, gellan gum solution at different extents of thiolation was ionically cross-linked using aluminum ammonium sulfate. Thiolated gellan gum films of uniform thickness were prepared using a solvent casting method. The thickness of bare gellan gum film was 0.035 ± 0.0043 mm, whereas the thiolated gellan gum films, GG 1S and GG 2S showed a thickness of 0.0191 ± 0.0011 mm and 0.0188 ± 0.0004 mm respectively. A high work of adhesion was noted for thiolated gellan gum (GG 2S) with a value of 10 N.mm while using porcine buccal mucosa. An average tensile strength of 48.2 ± 2.46 MPa was measured for thiolated gellan gum films irrespective of the extent of thiolation. The high work of adhesion, favorable cytocompatibility, desirable mechanical properties, and free swell capacity in saline confirmed the suitability of ionically cross-linked thiolated gellan gum films as an inner mucoadhesive layer for the mucoadhesive bandage.

Development of an In-situ Nasal Gel Formulation of Bepotastine Besilate for the Treatment of Allergic Rhinitis

The objective of this research was to formulate and evaluate mucoadhesive in situ nasal gels as a novel delivery system for Bepotastine Besilate. Aiming to provide sustained drug release directly at the site of action, thereby reducing the need for frequent dosing due to the drug's rapid absorption and short half-life. A series of eight formulations were developed using varying ratios of Poloxamer 407 and Poloxamer 188. The formulations exhibited a visually clear sol phase, indicating uniform dispersion of ingredients, with gelling temperatures ranging from 33.3±0.41 to 36.7±0.73°C. The gelling time, an important parameter for user convenience and efficacy, ranged from 15.7±01.52 to 43.3±20.80 s, meeting practical application requirements. Furthermore, all formulations consistently achieved a drug content of over 95%, ensuring dosage uniformity and efficacy. The pH values of the formulations were within the acceptable range of 6.13±0.10 to 6.91±0.02, minimizing the risk of mucosal irritation upon application. Importantly, the mucoadhesive strength ranged from 1056±0.32 to 6456± 045 dyne/cm², indicating robust adhesion to nasal mucosa, which is critical for prolonged drug retention and sustained release. In vitro drug release studies demonstrated sustained release profiles exceeding 4 hours for all formulations, following Higuchi kinetics, suggesting controlled drug release from the gel matrix. Accelerated stability studies corroborated the formulations' stability over the test period, indicating their potential for long-term storage and commercial viability. Additionally, FTIR analysis revealed no evidence of drug-polymer interactions, confirming the compatibility of Bepotastine Besilate with the selected polymer matrix. These comprehensive findings support the potential of in situ nasal gels as an effective and promising strategy for enhancing the therapeutic efficacy of Bepotastine Besilate, thereby improving patient outcomes.

Formulation and Development of Nanofiber-Based Ophthalmic Insert for the Treatment of Bacterial Conjunctivitis.

A novel ophthalmic delivery system utilizing levofloxacin-loaded, preservative-free, nanofiber-based inserts was investigated. Polyvinyl alcohol (PVA) and Poloxamer 407 (Polox)were employed as matrix materials, while hydroxypropyl-beta-cyclodextrin (HP-β-CD) was a solubilizer. The formulations were prepared via electrospinning and characterized for fiber morphology, drug dissolution, cytotoxicity, and antimicrobial activity. Scanning electron microscopy confirmed uniform fibrous structures. Fourier Transform Infrared spectroscopy and X-ray diffraction analyses demonstrated the amorphous state of levofloxacin within the fibers. In vitro dissolution studies revealed a rapid (within 2 min) and complete drug release, with higher HP-β-CD levels slightly delaying the release. Cytotoxicity tests showed increased HP-β-CD concentrations induced irritation, that was mitigated by sodium hyaluronate. The antimicrobial efficacy of the nanofibers was comparable to conventional eye drops, with lower minimum inhibitory concentrations for most tested strains. The nanofibrous formulation prepared from a PVA-Polox-based viscous solution of the drug:CD 1:1 mol ratio, containing 0.4% (w/w) sodium hyaluronate) was identified as a particularly promising alternative formulation due to its rapid and complete dissolution, good biocompatibility, and effective antimicrobial properties. Its gelling properties indicate that the residence time on the eye surface can be increased, potentially reducing discomfort and enhancing therapeutic outcomes. The nanofibrous formulations enhanced antimicrobial efficacy, providing a preservative-free alternative that minimizes the potential eye irritation that might occur because of the preservative agent and reduces the administrated dose frequency by extending the drug's retention time on the eye's surface. Subsequently, it improves patients' adherence, which would reflect positively on the bioavailability. The levofloxacin-HP-β-CD nanofibers demonstrate promise as an alternative to traditional eye drops, offering advantages in solubility, stability, and patient compliance for ocular infection treatment.

Development and evaluation of methotrexate-loaded nanoemulsion formulation for topical treatment of psoriasis.

Psoriasis is a chronic inflammatory disease that is becoming widespread and is associated with many kinds of additional severe diseases. The present study aimed to develop a methotrexate-loaded almond oil-based nanoemulsion formulation (MTX NE) for topical administration. The drug-loaded nanoemulsion formulation was prepared by high shear homogenization technique. The formulation's stability, as well as other physical and chemical characteristics, including entrapment effectiveness, drug release kinetics, skin permeability, skin irritation, and in vivo evaluation of the optimized formulation, was assessed. Additionally, imiquimod-induced psoriasis in rats was employed to investigate the efficacy of MTX NE against skin disorders. The MTX NE formulation was developed with a particle size of 18.74 ± 9.748nm, a polydispersity index (PDI) of 0.198 ± 0.01, and an average entrapment efficiency of 79.65 ± 3.84%. The release kinetics model estimates 81.08% drug release at pH 5.5 after 24h. The major layers of the skin, the epidermis, and dermis were successfully fluidized by the optimized MTX NE formulation, as shown by FTIR results, most likely enhancing drug retention and permeability. However, since Tween 80 and PEG 400 are well-known penetration enhancers, their application greatly accelerates these effects. Permeation data indicate that after 24h, methotrexate was released from the nano-emulsion at 76.83 ± 4.98g/cm2 with a flux rate of 2.385 ± 0.61µg/cm2/h. The in vivo study conducted on rabbit skin showed that the enhanced skin penetration of the prepared MTX-loaded nanoemulsion formulation does not cause any structural modifications in the inter-cellular lipid layers of the stratum corneum. Rabbits used in the in vivo anti-psoriatic investigation demonstrated that MTX NE produced a 95% reduction in PASI. The pharmacokinetic profile revealed that the Cmax, Tmax, and t1/2 values were 8.63µg/mL, 12.5h, and 17.77 ± 2.21h, respectively. These findings suggest that the formulation MTX NE is effective in treating psoriasis and may reduce psoriasis symptoms.

Beneficial effects of the Achillea millefolium green-formulated zinc nanoparticles in mice with heart failure following myocardial infarction

Myocardial infarction is a significant contributor to illness and death on a global scale. Limited advancements have been made in regenerative therapies due to the inadequate natural regeneration of the adult mammalian myocardium and difficulties in drug delivery. Nanocarriers such as exosomes, nanoparticles, and liposomes present numerous potential benefits for treating myocardial infarction, such as enhanced drug delivery, extended, and retention therapeutic effects. Nevertheless, numerous obstacles have hindered the extensive clinical application of these technologies. Zinc nanoparticles (Zn NPs) are frequently used in the healthcare industry, specifically in cardiovascular treatments. The research documented a sustainable method for synthesizing Zn NPs by Achillea millefolium extract, utilizing eco-friendly practices. Ultraviolet–visible (UV–VIS) spectrophotometry, field emission scanning electron microscope (FE-SEM), energy dispersive X-ray (EDX), transmission electron microscopy (TEM) and Fourier-transform infrared spectroscopy (FTIR) were utilized to examine the Zn NPs, while also exploring their potential in treating myocardial infarction. The Achillea millefolium extract contains tannin at 16.49 %, phenols at 39.19 %, saponin at 14.21 %, steroids at 22.84 %, flavonoids at 7.11 %, and alkaloids at 0.16 %. The animals were classified into three separate groups: (1) isoproterenol; (2) control; (3) Zn NPs + isoproterenol (100 μg/ml). Mice were given isoproterenol to induce myocardial infarction. Real-time PCR and western blot techniques were employed to quantify the activation of PPAR-Υ/NF-κB and the subsequent release of cytokines induced by lipopolysaccharide. Following the administration of varying doses of Zn NPs, the assessment of cardiac function was carried out through biochemical, histochemical, and electrocardiogram (ECG) analysis. The nanoparticles displayed a round shape when they were created. Recent research indicates that Zn NPs exhibit cardioprotective characteristics against myocardial infarction, potentially by suppressing NF-κB signaling and stimulating PPAR-γ. Zn NPs administration led to a reduction in interleukin 6 (IL-6), IL-1β, and TNF-α in the mice hearts. The use of Zn NPs notably decreased cell death and inflammatory cytokines expression. The beneficial impacts of Zn NPs may potentially stem from the gene expression normalization in PPAR-Υ/NF-κB/ΙκB-α/ΙΚΚα/β and PPAR-Υ phosphorylation pathways. The levels of myocardial injury markers are significantly inhibited by Zn NPs, leading to a reduction in mortality rates and an amelioration in the ventricular wall infarction condition. Furthermore, the administration of Zn NPs effectively prevents the characteristic ST segment depression observed in animals with myocardial infarction.

Formulation of Polymeric Nanoparticles Loading Baricitinib as a Topical Approach in Ocular Application.

Topical ocular drug delivery faces several challenges due to the eye's unique anatomy and physiology. Physiological barriers, tear turnover, and blinking hinder the penetration of drugs through the ocular mucosa. In this context, nanoparticles offer several advantages over traditional eye drops. Notably, they can improve drug solubility and bioavailability, allow for controlled and sustained drug release, and can be designed to specifically target ocular tissues, thus minimizing systemic exposure. This study successfully designed and optimized PLGA and PCL nanoparticles for delivering baricitinib (BTB) to the eye using a factorial design, specifically a three-factor at five-levels central rotatable composite 23+ star design. The nanoparticles were small in size so that they would not cause discomfort when applied to the eye. They exhibited low polydispersity, had a negative surface charge, and showed high entrapment efficiency in most of the optimized formulations. The Challenge Test assessed the microbiological safety of the nanoparticle formulations. An ex vivo permeation study through porcine cornea demonstrated that the nanoparticles enhanced the permeability coefficient of the drug more than 15-fold compared to a plain solution, resulting in drug retention in the tissue and providing a depot effect. Finally, the in vitro ocular tolerance studies showed no signs of irritancy, which was further confirmed by HET-CAM testing.

Quality by design driven development of lipid nanoparticles for cutaneous targeting: a preliminary approach.

Fungal infections are the fourth common cause of infection affecting around 50 million populations across the globe. Dermatophytes contribute to the majority of superficial fungal infections. Clotrimazole (CTZ), an imidazole derivative is widely preferred for the treatment of topical fungal infections. Conventional topical formulations enable effective penetration of CTZ into the stratum corneum, however, its low solubility results in poor dermal bioavailability, and variable drug levels limit the efficacy. The aim was to increase dermal bioavailability and sustain drug release, thereby potentially enhancing drug retention and reducing its side effects. This work evaluated the CTZ loaded solid lipid nanoparticles (SLN) consisting of precirol and polysorbate-80 developed using high pressure homogenization and optimized with QbD approach. Prior to release studies, CTZ-SLNs were characterized by different analytical techniques. The laser diffractometry and field emission scanning electron microscopy indicated that SLNs were spherical in shape with mean diameter of 450 ± 3.45nm. DSC and XRD results revealed that the drug remained molecularly dispersed in the lipid matrix. The CTZ-SLNs showed no physicochemical instability during 6months of storage at different temperatures. Further, the Carbopol with its pseudoplastic behavior showed a crucial role in forming homogenous and stable network for imbibing the CTZ-SLN dispersion for effective retention in skin. As examined, in-vitro drug release was sustained up to 24h while ex-vivo skin retention and drug permeation studies showed the highest accumulation and lowest permeation with nanogel in comparison to pure drug and Candid® cream. Further, the in-vivo antifungal efficacy of nanogel suggested once-a-day application for 10days, supported by histopathological analysis for complete eradication infection. In summary, the findings suggest, that nanogel-loaded with CTZ-SLNs has great potential for the management of fungal infections caused by Candida albicans.

Niosome preparation of atorvastatin drug with green preparation approach for in-vitro study of transdermal absorption with lavender essential oil

Introduction: Studies have pointef to anti-inflammatory properties of atorvastatin. In this research, noisome nanoparticles have been used to increase skin penetration and drug retention. Method: Atorvastatin niosomes were prepared using the sonication method. The effect of cholesterol: surfactant mixture ratio was investigated on physicochemical properties of nanoparticles. Studies have been performed on the morphological features, and characterization of nanoparticles. The toxicity of optimal formulation was investigated on a normal human fibroblast cell line. Different percentages of lavender essential oil were added to the optimal formulation gel, and skin drug delivery studies were performed. Results: The optimal formulation had the optimum particle size, PDI, zeta potential, and EE%, which leads to higher stability and dissolution of atorvastatin in the body. Morphological studies conducted on properties of nanoparticles illustrated a spherical shape and no interference with other formulation components. No cytotoxicity was detected for improved formulation of nanoparticles, including atorvastatin. In-vitro skin permeation results indicated that gel containing 0.5% lavender essential oil atorvastatin noisome (Atrosome) could enhance the dermal delivery of atorvastatin where a higher concentration of atorvastatin can be detected in skin layers. Conclusion: As evidenced by the results of this study, preparing nanoparticles from atorvastatin and adding essential oil to the final formulation exerts a positive effect on local drug delivery. Moreover, drug delivery with nanocarriers significantly increased the percentage of drug retention in the target site.

M1 macrophage-membrane-cloaked paclitaxel/β-elemene nanoparticles targeting cervical cancer for enhanced therapy

Cervical cancer is a leading cause of cancer-related mortality in females worldwide, necessitating urgent solutions for effective treatment. Paclitaxel (PTX), a natural diterpene alkaloid compound, has the ability to inhibit mitosis and induce programmed apoptosis in tumor cells. However, its toxicity and drug resistance limit its efficacy in certain cervical cancer patients. β-elemene (β-ELE) can reverse multidrug resistance by inhibiting ATP-binding cassette transporters, thereby enhancing chemotherapy drug retention. Therefore, we propose a combination therapy using PTX/β-ELE to improve chemotherapy sensitivity. To enhance targeted drug delivery, we developed M1-macrophage-membrane-coated nanoparticles (M1@PLGA/PTX/β-ELE) for co-delivery of PTX&β-ELE. Through both in vitro and in vivo cervical cancer models, we demonstrated that M1@PLGA/PTX/β-ELE effectively suppressed tumor progression and polarization of tumor-associated macrophages. Furthermore, H&E staining confirmed the high therapeutic biosafety of M1@PLGA/PTX/β-ELE as there was no significant damage observed in major organs throughout the entire therapeutic process. Overall, this study presents a targeted biomimetic nanoplatform and combinatorial strategy that synergistically enhances chemosensitivity in malignant tumors.

Metabolic reprogramming of poly(morpho)nuclear giant cells determines glioblastoma recovery from doxorubicin-induced stress

BackgroundMulti-drug resistance of poly(morpho)nuclear giant cells (PGCs) determines their cytoprotective and generative potential in cancer ecosystems. However, mechanisms underlying the involvement of PGCs in glioblastoma multiforme (GBM) adaptation to chemotherapeutic regimes remain largely obscure. In particular, metabolic reprogramming of PGCs has not yet been considered in terms of GBM recovery from doxorubicin (DOX)-induced stress.MethodsLong-term proteomic and metabolic cell profiling was applied to trace the phenotypic dynamics of GBM populations subjected to pulse DOX treatment in vitro, with a particular focus on PGC formation and its metabolic background. The links between metabolic reprogramming, drug resistance and drug retention capacity of PGCs were assessed, along with their significance for GBM recovery from DOX-induced stress.ResultsPulse DOX treatment triggered the transient formation of PGCs, followed by the appearance of small expanding cell (SEC) clusters. Development of PGCs was accompanied by the mobilization of their metabolic proteome, transient induction of oxidative phosphorylation (OXPHOS), and differential intracellular accumulation of NADH, NADPH, and ATP. The metabolic background of PGC formation was confirmed by the attenuation of GBM recovery from DOX-induced stress following the chemical inhibition of GSK-3β, OXPHOS, and the pentose phosphate pathway. Concurrently, the mobilization of reactive oxygen species (ROS) scavenging systems and fine-tuning of NADPH-dependent ROS production systems in PGCs was observed. These processes were accompanied by perinuclear mobilization of ABCB1 and ABCG2 transporters and DOX retention in the perinuclear PGC compartments.ConclusionsThese data demonstrate the cooperative pattern of GBM recovery from DOX-induced stress and the crucial role of metabolic reprogramming of PGCs in this process. Metabolic reprogramming enhances the efficiency of self-defense systems and increases the DOX retention capacity of PGCs, potentially reducing DOX bioavailability in the proximity of SECs. Consequently, the modulation of PGC metabolism is highlighted as a potential target for intervention in glioblastoma treatment.

Green Solid Lipid Nanoparticles by Fatty Acid Coacervation: An Innovative Nasal Delivery Tool for Drugs Targeting Cerebrovascular and Neurological Diseases.

Cerebrovascular and neurological diseases are characterized by neuroinflammation, which alters the neurovascular unit, whose interaction with the choroid plexus is critical for maintaining brain homeostasis and producing cerebrospinal fluid. Dysfunctions in such process can lead to conditions such as idiopathic normal pressure hydrocephalus, a common disease in older adults. Potential pharmacological treatments, based upon intranasal administration, are worthy of investigation because they might improve symptoms and avoid surgery by overcoming the blood-brain barrier and avoiding hepatic metabolism. Nasal lipid nanocarriers, such as solid lipid nanoparticles, may increase the nasal retention and permeation of drugs. To this aim, green solid lipid nanoparticles, obtained by coacervation from natural soaps, are promising vehicles due to their specific lipid matrix composition and the unsaponifiable fraction, endowed with antioxidant and anti-inflammatory properties, and thus suitable for restoring the neurovascular unit function. In this experimental work, such green solid lipid nanoparticles, fully characterized from a physico-chemical standpoint, were loaded with a drug combination suitable for reverting hydrocephalus symptoms, allowing us to obtain a non-toxic formulation, a reduction in the production of the cerebrospinal fluid in vitro, and a vasoprotective effect on an isolated vessel model. The pharmacokinetics and biodistribution of fluorescently labelled nanoparticles were also tested in animal models.

A Novel PAMAM G3 Dendrimer-Based Foam with Polyether Polyol and Castor Oil Components as Drug Delivery System into Cancer and Normal Cells.

One of the intensively developed tools for cancer therapy is drug-releasing matrices. Polyamidoamine dendrimers (PAMAM) are commonly used as nanoparticles to increase the solubility, stability and retention of drugs in the human body. Most often, drugs are encapsulated in PAMAM cavities or covalently attached to their surface. However, there are no data on the use of PAMAM dendrimers as a component of porous matrices based on polyurethane foams for the controlled release of drugs and biologically active substances. Therefore, in this work, porous materials based on polyurethane foam with incorporated third-generation poly(amidoamine) dendrimers (PAMAM G3) were synthesized and characterized. Density, water uptake and morphology of foams were examined with SEM and XPS. The PAMAM was liquefied with polyether polyol (G441) and reacted with polymeric 4,4'-diphenylmethane diisocyanate (pMDI) in the presence of silicone, water and a catalyst to obtain foam (PF1). In selected compositions, the castor oil was added (PF2). Analogs without PAMAM G3 were also synthesized (F1 and F2, respectively). An SEM analysis of foams showed that they are composed of thin ribs/walls forming an interconnected network containing hollow bubbles/pores and showing some irregularities in the structure. Foam from a G3:G441:CO (PF2) composition is characterized by a more regular structure than the foam from the composition without castor oil. The encapsulation efficiency of drugs determined by the XPS method shows that it varies depending on the matrix and the drug and ranges from several to a dozen mass percent. In vitro biological studies with direct contact and extract assays indicated that the F2 matrix was highly biocompatible. Significant toxicity of dendrimeric matrices PF1 and PF2 containing 50% of PAMAM G3 was higher against human squamous carcinoma cells than human immortalized keratinocytes. The ability of the matrices to immobilize drugs was demonstrated in the example of perspective (Nimesulide, 8-Methoxypsolarene) or approved anticancer drugs (Doxorubicin-DOX, 5-Aminolevulinic acid). Release into the culture medium and penetration of DOX into the tested SCC-15 and HaCaT cells were also proved. The results show that further modification of the obtained matrices may lead to their use as drug delivery systems, e.g., for anticancer therapy.

A supramolecular hydrogel eye-drop alleviates inflammation via clathrin-mediated endocytosis

The modulation of inflammation is effective to treat many ocular surface diseases. Thus the low bioavailability of common anti-inflammatory eye-drops urges the development of ocular drug delivery systems to extend the ocular retention and enhance the cellular uptake for improving anti-inflammatory effect of eye-drops. Here we covalently conjugate two molecules of clinically anti-inflammatory drug (i.e., dexamethasone) with a small peptide (i.e., Tyr–Glu–Asn–Pro–Thr–Tyr) to generate an anti-inflammatory hydrogel eye-drop. With a self-assembled ability, the designed supramolecular hydrogel achieves gel–sol–gel transition by varying shearing forces which increases the pre-corneal retention of drug. The fluorescent imaging reveals the efficient cellular uptake of designed conjugate via clathrin-mediated endocytosis. A rodent model of endotoxin-induced uveitis verifies that the supramolecular hydrogel eye-drop suppresses inflammation responses without ocular irritation. As a rational approach to design anti-inflammatory drugs as eye-drops, this work overcomes the frequent instillation of clinical eye-drops and further improves the bioavailability of anti-inflammatory drugs, which may provide an effective and household way to fight ocular surface inflammation.

Advancing Ocular Medication Delivery with Nano-Engineered Solutions: A Comprehensive Review of Innovations, Obstacles, and Clinical Impact.

Recent advancements in ocular drug delivery have led to the introduction of a range of nanotechnology-based systems, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, inorganic nanoparticles, niosomes, liposomes, nanosuspensions, dendrimers, nanoemulsions, and microemulsions. These systems enhance drug retention, penetration, bioavailability, and targeted delivery, promising prolonged drug release, and improved patient compliance. However, their interactions with biological systems pose potential toxicity risks, necessitating a careful evaluation of nanoparticle size, shape, surface charge, and coating. Traditional ocular drug delivery methods, like topical applications and injections, face challenges due to anatomical and physiological barriers, leading to frequent dosing and systemic toxicity risks. Nanocarriers offer solutions by improving drug permeation and targeted delivery, yet translating these innovations from research to clinical practice involves overcoming hurdles related to manufacturing scale-up, quality control, regulatory approval, and cost-effectiveness. The quality by design (QbD) framework provides a systematic approach to optimize nanocarrier formulation and process design, ensuring safety and efficacy. Assessing the safety of nanocarriers through in vivo and in vitro studies is crucial for their clinical application. This review explores the use of various nanomedicines in ocular drug delivery, highlighting the current state of ocular medication delivery and considering critical aspects such as scaling up and clinical applications.

Letter to the Editor, “Drug Retention Time of Immunosuppressive Therapy in Behcet’s Uveitis.”

Letter to the Editor, “Drug Retention Time of Immunosuppressive Therapy in Behcet’s Uveitis.”

A Coupling-Induced Assembly Strategy for Constructing Artificial Shell on Mitochondria in Living Cells.

The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.

A Coupling‐Induced Assembly Strategy for Constructing Artificial Shell on Mitochondria in Living Cells

The strategy of in vivo self‐assembly has been developed for improved enrichment and long‐term retention of anticancer drug in tumor tissues. However, most self‐assemblies with non‐covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling‐induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation‐responsive peptide‐porphyrin conjugate P1 is synthesized, which self‐assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2‐fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria‐targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.

In Situ Gelation Strategy for Efficient Drug Delivery in a Gastrointestinal System.

Developing a microenvironment-responsive drug delivery system (DDS) for the gastrointestinal system is of great interest to enhance drug efficiency and minimize side effects. Unfortunately, the rapid-flowing digestive juice in the gastrointestinal tract and the continuous contraction and peristalsis of the gastrointestinal tract muscle accelerate the elimination of drug carriers. In this study, a boric hydroxyl-modified mesoporous Mg(OH)2 drug carrier is prepared to prolong the drug retention time. Results show that the newly designed DDS presents high biocompatibility and can immediately turn the free polyhydric alcohol molecules into a gelation form. The in situ-formed gelation network presents high viscosity and can prevent the drug carriers from being washed away by the digestive juice in the gastrointestinal tract.