Drug Delivery最新文献

Anagrelide (ANA) is a phosphodiesterase 3A (PDE3A) inhibitor, commonly prescribed for essential thrombocythemia. It also functions as a molecular glue, inducing complex formation between PDE3A and Schlafen 12. This association either triggers apoptosis or inhibits proliferation in tumor cells, supporting its use in cancer therapy. Conventionally administered orally, ANA undergoes rapid metabolism and elimination, resulting in a short drug exposure time at the site of action. Here, we explored the pharmacokinetic profile of a subcutaneously (SC) injected ANA formulation in Sprague-Dawley rats by quantifying plasma ANA and metabolite concentrations using liquid-chromatography-tandem mass spectrometry. We further evaluated the in vivo tumor regression efficacy of orally and SC administered ANA in a patient-derived gastrointestinal stromal xenograft mouse model - UZLX-GIST2B - characterized by a KIT exon 9 driver mutation. The SC ANA exhibited extended-release plasma concentration-time profiles compared to intravenous and oral administrations. After a single administration in rats, plasma concentrations of ANA were detected up to 56 days later, and ANA metabolites up to 30 days later. The SC formulation also significantly reduced tumor volumes and demonstrated dose-dependent histological responses, nearly eradicating tumor tissue in 11 days with the highest dose. These findings suggest that the SC slow-release formulation maintains stable drug concentrations during treatment, potentially improving therapeutic efficacy at the target site.

Rheumatoid arthritis (RA) is an inflammatory immune-triggered disease that causes synovitis, cartilage degradation, and joint injury. In nanotechnology, conventional liposomes were extensively investigated for RA. However, they frequently undergo rapid clearance, reducing circulation time and therapeutic efficacy. Additionally, their stability in the bloodstream is often compromised, resulting in premature drug release. The current review explores the potential of targeted liposomal-based nanosystems in the treatment of RA. It highlights the pathophysiology of RA, explores selective targeting sites, and elucidates diverse mechanisms of novel liposomal types and their applications. Furthermore, the targeting strategies of pH-sensitive, flexible, surface-modified, PEGylated, acoustic, ROS-mediated, and biofunctionalized liposomes are addressed. Targeted nanoliposomes showed potential in precisely delivering drugs to CD44, SR-A, FR-β, FLS, and toll-like receptors through the high affinity of ligands. In vitro studies interpreted stable release profiles and improved stability. Ex vivo studies on skin demonstrated that ultradeformable and glycerol-conjugated liposomes enhanced drug penetrability. In vivo experiments for liposomal types in the arthritis rat model depicted remarkable efficacy in reducing joint swelling, pro-inflammatory cytokines, and synovial hyperplasia. In conclusion, these targeted liposomes represented a significant leap forward in drug delivery, offering effective therapeutic options for RA. In the future, integrating these advanced liposomes with artificial intelligence, immunotherapy, and precision medicine holds great promise.

The present study aimed to prepare and optimize lamotrigine-loaded bovine serum albumin nanoparticles (LAM-NP) using the Quality by Design (QbD) approach and to investigate both the in vitro and ex vivo effects of different cross-linking agents glutaraldehyde (GLUT), glucose (GLUC) and 1-(3-dimethylaminutesopropyl)-3-ethylcarbodiimide hydrochloride (EDC) on intranasal applicability. Cross-linked LAM-NP from EDC (NP-EDC-1) showed the lowest Z-average value (163.7 ± 1.9 nm) and drug encapsulation efficacy (EE%) of 97.31 ± 0.17%. The drug release of GLUC cross-linked LAM-NP (NP-GLUC-9), glutaraldehyde cross-linked LAM-NP (NP-GLUT-2), and NP-EDC-1 at blood circulation conditions was higher than the initial LAM. The results of the blood-brain barrier parallel artificial membrane permeability assay (BBB-PAMPA) showed an increase in the permeability of LAM through the BBB with NP-GLUC-9 and an increase in flux with all selected formulations. The ex vivo study showed that LAM diffusion from the selected formulations through the human nasal mucosa was higher than in case of initial LAM. The cytotoxicity study indicated that BSA-NP reduced LAM toxicity, and GLUC 9 mM and EDC 1 mg could be alternative cross-linking agents to avoid GLUT 2% v/v toxicity. Furthermore, permeability through Caco-2 cells showed that nasal epithelial transport/absorption of LAM was improved by using BSA-NPs. The use of BSA-NP may be a promising approach to enhance the solubility, permeability through BBB and decrease the frequency of dosing and adverse effects of LAM.

Pancreatic cancer (PC) is currently a leading cause of death worldwide and its incidence is expected to increase in the following years. Chemotherapy with gemcitabine (GEM) is precluded by extensive enzymatic inactivation and clearance, and the nonspecific tissue distribution contributes to unwanted systemic toxicity and tumor resistance. In this work, GEM was encapsulated in d-ɑ-tocopheryl polyethylene glycol succinate (TPGS) micelles by 'stapling' GEM at 4-NH₂ position with vitamin E succinate (VES) through a highly stable amide bond, achieving successful GEM hydrophobization by means of a prodrug system (VES-GEM). Recurring to solvent evaporation methodology, TPGS/VES-GEM (6/1 molar ratio) micelles were prepared, optimized regarding TPGS-to-VES-GEM ratio, and characterized regarding size, surface charge, polydispersity index, morphology, drug loading, and encapsulation efficiency (EE). Furthermore, purification methods were explored together with VES-GEM release profile and stability. Lastly, cell viability and cellular uptake of the formulation were analyzed in 2D and 3D BxPC3 cell line models. TPGS/VES-GEM micelles (6/1) showed ultra-small size (∼30 nm), and remarkable EE (>95%) together with ability to retain VES-GEM for long period of time (>7 days) with high stability. The micelles demonstrated exceptional cell cytotoxic activity for concentrations of 10 and 100 µM VES-GEM (∼0% cell viability) which may be explained by concerted action of GEM, VES, and TPGS. The nanocarrier was further enriched with PC cell membrane nanovesicles, displaying size ∼150 nm, ZP ∼ -30 mV and PDI ∼0.2 to improve biointerfacing properties and targeting properties. BxPC3 cell membrane-modified TPGS/VES-GEM micelles may be attractive biomimetic nanosystem for next-generation PC therapeutics.

Primary bronchus cancer is one kind of lung cancer with a very high mortality rate. Magnetic drug targeting (MDT) technology could concentrate drugs in a specific area, which could have useful application in lung cancer therapy. Due to a bulk superconducting magnet's ability to generate a superior magnetic field strength and gradient in comparison to conventional permanent magnets, there is great potential for achieving MDT external to the body. However, current research in this area is still in its infancy, and numerical simulations exploring the guidance ability of this technology have been limited to only two-dimensional geometries, which limits further exploration toward clinical transformation. In this work, a three-dimensional lung and bulk superconducting magnet model have been built in the finite-element software package COMSOL Multiphysics. The model is used to simulate the drug delivery process in the lung via the superconducting magnet. The influence of various parameters on the capture efficiency is investigated, including lung-magnet distance, bulk superconductor properties, particle properties, and physiological or tumor structural parameters. The results demonstrate that the bulk superconducting magnet can effectively improve the capture efficiency of magnetic drugs or drug carriers within a suitable distance outside of the body, which could potentially guide the design of a practical, external superconducting MDT system in the near future.

Vesicular systems have demonstrated efficacy in the management of Rheumatoid Arthritis (RA). This study explores the synergistic effect of edge-activated ethosomal gel to enhance the transdermal delivery of Curcumin (CUR) and Cyclosporine (CYC). Ethosomal vesicles prepared via the ethanol injection method were incorporated into a gel, with the optimized formulation exhibiting an average particle size of 93.3 ± 1.17 nm and a zeta potential of -29.2 ± 0.17 mV. Ex vivo diffusion studies on porcine ear skin demonstrated 97.115 ± 0.40% CUR and 98.331 ± 1.08% CYC release over 18 hours, exhibiting Hixson-Crowell diffusion mechanisms. The steady-state flux and permeability coefficients were 0.095 µg/cm²/hr and 0.0095 cm/hr for CUR, and 0.0804 µg/cm²/hr and 0.01608 cm/hr for CYC respectively. In anti-inflammatory tests on lipopolysaccharide (LPS)-induced RAW 264.7 cells, the gel significantly increased IL-10 levels (p < 0.001), inhibited prostaglandin-E2, and reduced IL-6 and TNF-α levels (p < 0.001). Moreover, the ethosomal gel demonstrated nonirritating properties and exhibited significant reduction in arthritic symptoms in the Complete Freund's Adjuvant induced 28-day rat model, surpassing the effects of marketed and conventional gel. These findings highlight the synergistic benefits of combining CUR and CYC in an ethosomal gel, offering a promising alternative for RA management. Future clinical investigations are warranted to validate its safety and efficacy in humans and facilitate potential therapeutic integration.

Age-related macular degeneration is a degenerative eye condition that affects the macula and results in central vision loss. Phytoconstituents show great promise in the treatment of AMD. AMD therapy can benefit from the advantages of phytoconstituents loaded nanofibers. There are opportunities to improve the effectiveness of phytoconstituents in the treatment of age-related macular degeneration (AMD) through the use of nanofiber-based delivery methods. These novel platforms encapsulate and distribute plant-derived bioactives by making use of the special qualities of nanofibers. These qualities include their high surface area-to-volume ratio, variable porosity, and biocompatibility. Exploring the use of nanofiber-based delivery methods to provide phytoconstituents in AMD treatment is a great choice for enhancing patient adherence, safety, and efficacy in managing this condition. This article explores the potential of nanofiber-based delivery methods to revolutionize AMD treatment, providing an innovative and effective approach to treat this condition.

The therapeutic efficacy of nanoparticle (NP)-encapsulated cytotoxic drugs has remained limited by poor penetration into solid tumors. To address this challenge, we developed a novel strategy using minoxidil-loaded nanoliposomes (Lip-MXD) to induce tumor vasodilation and enhance the delivery of PEGylated liposomal doxorubicin (PLD). We developed a remote loading method utilizing a calcium acetate gradient to encapsulate MXD into liposomes, achieving a high MXD encapsulation efficiency (87%). The resulting Lip-MXD formulation displayed an average particle size of 111 nm, a polydispersity index of 0.05, and a zeta potential of -15.7 mV. Pretreatment with Lip-MXD demonstrated multifunctional effects. It significantly downregulated CLDN-1 expression, improving NP penetration into advanced, fibrotic tumors. The stability of interaction between CLDN-1 and MXD was confirmed by molecular dynamics (MD) simulation. Immunohistochemistry and gene expression analyses in mouse models of colorectal (CRC) and pancreatic (PCa) cancers revealed that Lip-MXD administration significantly reduced the number of tumor-associated stromal cells. Furthermore, Lip-MXD mitigated tumor hypoxia and substantially enhanced PLD permeability within the dense microenvironment of desmoplastic tumors through its vasodilatory effects. A single dose of PLD following Lip-MXD pretreatment exhibited significant antitumor activity, resulting in a prolonged survival rate of 60% in the Lip-MXD+PLD-treated group in CRC models. In nude mice bearing PCa, the Lip-MXD+PLD-treated group achieved a significant reduction in tumor volume compared to the PLD group over a 14-day evaluation period. This MXD liposomal formulation offers a promising method to overcome tumor penetration, enhance NP delivery and improve therapeutic outcomes in CRC and PCa cancers, meriting further investigation.

Efficient formulation of SN-38 for broad-spectrum chemotherapy remains an unmet medical need. The limited solubility of SN-38 in both aqueous and organic solvents poses a major challenge for formulation development. As a result, the predominant strategy, polymer-SN-38 drug conjugates, often involves complex synthetic procedures and low drug loading (1-5% w/w). Such limitations hinder their large-scale production and clinical translation. In this study, we developed an encapsulation strategy that utilizes the reversible lactone-carboxylate equilibrium of SN-38 to simplify the formulation process and achieve enhanced drug loading. The major issue of SN-38 solubility in organic solvents was effectively addressed by sodium hydroxide (NaOH)-induced conversion of the lactone to the carboxylate form. We have demonstrated that SN-38 carboxylate, once encapsulated within human serum albumin-polylactic acid (HSA-PLA) nanoparticles, retains its reversibility and can be converted back to the active lactone form simply by the addition of hydrochloric acid (HCl). The drug loading capacity of SN-38 in the HSA-PLA nanoparticles was increased to 19% w/w. In vitro cytotoxicity assays confirmed that HSA-PLA (SN-38) nanoparticles exhibited significantly lower IC₅₀ values (0.5-194 nM) across multiple cancer cell lines compared to the clinical standard, irinotecan (CPT-11), indicating superior potency under physiological conditions. In vivo studies in 4T1 and MDA-MB-231 tumor-bearing mice further validated the enhanced therapeutic efficacy of this formulation. Overall, this study presents a promising alternative strategy for SN-38 delivery via encapsulation rather than polymer-drug conjugation, significantly simplifying the formulation process and enhancing the translational potential of SN-38 for broad chemotherapeutic applications.

Acute lung injury (ALI) is a lung disease characterized by pulmonary edema caused by an excessive inflammatory response within the lungs and disruption of the alveolar capillary barrier, with a high morbidity and mortality rate in critically ill patients. Dry powder inhalers (DPI) are an effective way of administering medication to improve efficacy, and inhalation administration not only improves efficacy but also increases the bioavailability of the drug. Synephrine, a natural ingredient derived from the fruit of the citrus plant in the Brassicaceae family, has anti-inflammatory and antioxidant properties. In the present study, we prepared a synephrine dry powder inhaler (SYN-DPI) by anti-solvent precipitation method and evaluated it in vivo and in vitro. The in vitro results show that SYN-DPI has low hygroscopicity and good aerodynamic properties. The in vitro and in vivo efficacy results showed that SYN-DPI not only had low toxicity but also possessed good anti-inflammatory and antioxidant capacity, which could significantly reduce inflammation, oxidative stress, and lung injury. Pharmacokinetic results showed that inhalation administration significantly increased SYN bioavailability. In conclusion, this study provides inhalation administration of synephrine as an inhalable formulation that can be used to improve ALI.