Drug Delivery and Translational Research最新文献

Baricitinib, an inhibitor of Janus kinase 1/2 receptors majorly involved in the dysregulation of immune responses in atopic dermatitis, is currently approved for managing atopic dermatitis in Europe. The delivery of baricitinib through oral route is associated to several adverse effects due to off-target effects. Therefore, the current study is aimed at formulation of baricitinib loaded nanoemulgel for evaluation of topical delivery potential in the treatment of atopic dermatitis. The baricitinib-loaded nanoemulsions (0.05 and 0.1% w/w) revealed an average globule size of 162.86 ± 0.37 and 173.66 ± 4.88 nm respectively with narrow PDI. The optimized batch of baricitinib nanoemulsion was converted to nanoemulgel by the addition of the mixture of gel bases SEPINEO™ DERM and SEPINEO™ P 600 along with propylene glycol, resulting in pseudoplastic shear thinning behaviour. The optimized nanoemulgels have shown prominent retention of baricitinib in the skin along with permeation. The skin distribution study of coumarin-6 loaded nanoemulgel demonstrated high fluorescence in the epidermal layer. The western blot analysis revealed significant inhibition of phosphorylated signal transducers and activators of transcriptions 1 (##p < 0.01) and 3 (#p < 0.05) by application of 0.05 and 0.1% baricitinib nanoemulgel. The baricitinib nanoemulgels have shown anti-inflammatory activity by significantly reducing expressions of various inflammatory markers. Histopathological analysis of skin tissues treated with baricitinib nanoemulgel has demonstrated a marked reduction in acanthosis, hyperkeratosis, and intact outer epidermis. These results supported the potential role of baricitinib-loaded nanoemulgel in reducing the inflammation and disease severity associated with atopic dermatitis.

Bevacizumab is a monoclonal antibody (mAb) that prevents the growth of new blood vessels and is currently employed in the treatment of colorectal cancer (CRC). However, like other mAb, bevacizumab shows a limited penetration in the tumors, hampering their effectiveness and inducing adverse reactions. The aim of this work was to design and evaluate albumin-based nanoparticles, coated with dextran, as carriers for bevacizumab in order to promote its accumulation in the tumor and, thus, improve its antiangiogenic activity. These nanoparticles (B-NP-DEX50) displayed a mean size of about 250 nm and a payload of about 110 µg/mg. In a CRC mice model, these nanoparticles significantly reduced tumor growth and increased tumor doubling time, tumor necrosis and apoptosis more effectively than free bevacizumab. At the end of study, bevacizumab plasma levels were higher in the free drug group, while tumor levels were higher in the B-NP-DEX50 group (2.5-time higher). In line with this, the biodistribution study revealed that nanoparticles accumulated in the tumor core, potentially improving therapeutic efficacy while reducing systemic exposure. In summary, B-NP-DEX can be an adequate alternative to improve the therapeutic efficiency of biologically active molecules, offering a more specific biodistribution to the site of action.

With the developing manufacturing technologies, the use of 3D printers in microneedle production is becoming widespread. Hydrogel-forming microneedles (HFMs), a variant of microneedles, demonstrate distinctive features such as a high loading capacity and controlled drug release. In this study, the conical microneedle master molds with approximately 500 μm needle height and 250 μm base diameter were created using a Stereolithography (SLA) 3D printer and were utilized to fabricate composite HFMs containing diclofenac sodium. Using Box-Behnken Design, the effects of different polymers on swelling index and mechanical strength of the developed HFMs were evaluated. The optimum HFMs were selected according to experimental design results with the aim of the highest mechanical strength with varying swelling indexes, which was needed to use 20% Gantrez S97 and 0.1% (F22), 0.42% (F23), and 1% (F24) hyaluronic acid. The skin penetration and drug release properties of the optimum formulations were assessed. Ex vivo studies were conducted on formulations to determine drug penetration and accumulation. F24, which has the highest mechanical strength and optimized swelling index, achieved the highest drug accumulation in the skin tissue (17.70 ± 3.66%). All optimum HFMs were found to be non-cytotoxic by the MTT cell viability test (> 70% cell viability). In in vivo studies, the efficacy of the F24 was assessed for the treatment of xylene-induced ear edema by contrasting it to the conventional dosage form. It was revealed that HFMs might be an improved replacement for conventional dosage forms in terms of dermal diseases such as actinic keratosis.

Tacrolimus (FK506) is widely used in ocular diseases such as corneal transplantation-host disease, uveitis, conjunctivitis, and dry eye disease (DED). However, its low aqueous solubility and poor ocular retention pose challenges for its application in the eye diseases. This study developed a novel FK506-loaded maleimide-functionalized cationic niosomes (FK506 M-CNS), aiming to prolong the retention time of FK506 in the eye and enhance its therapeutic efficacy. FK506 M-CNS had a particle size of 87.69 ± 1.05 nm and zeta potential of 22.06 ± 1.01 mV. Results of histological evaluation through H&E staining and in vitro cytotoxicity of human corneal epithelial cells consistently revealed the excellent biocompatibility of FK506 M-CNS. FK506 M-CNS exhibited superior ocular retention compared to the market product Talymus^®. FK506 M-CNS significantly alleviated the symptoms of DED and promoted the recovery of corneal epithelia. FK506 M-CNS group had the lowest expression levels of inflammatory factors associated with DED. These superiorities might be due to the electrostatic interaction between cationic niosomes and negatively charged mucin in the eye, and the covalent binding of maleimide with the thiol group in the mucin. The maleimide group improved the ocular retention and efficacy of FK506, but did not increase the toxicity. Results indicated that FK506 M-CNS had great potential as a nanopharmaceutical in the treatment of ocular diseases, and M-CNS could be a promising drug carrier for ophthalmic drug delivery systems.

Undifferentiated thyroid cancer (ATC) is highly malignant and does not respond well to sorafenib (SRF) treatment owing to the lack of specificity of SRF targeting. Drug delivery nanosystems can improve the efficiencies of drug in treating various cancer types. However, many conventional drug delivery nanosystems lack targeting and exhibit unresponsive drug release. Therefore, we developed a pH-responsive nano-targeted drug delivery systems using human serum albumin (HSA) as a carrier to generate manganese dioxide (MnO₂)@HSA nanoparticles (NPs), then encapsulated SRF and the fluorescent dye indocyanine green (ICG) and finally modifyed the targeting antibody pertuzumab in the outer layer of the nano complexes, resulting in SRF/ICG/MnO₂@HSA-pertuzumab (HISMP) NPs. This system targets human epidermal growth factor receptor 2 on the cell membrane surface of thyroid cancer cells and is designed to accumulate at tumor sites. Then, pH-responsive release of divalent manganese ions, ICG, and SRF enables magnetic resonance/fluorescence (MR/NIRF) dual-modality imaging and precise drug delivery for diagnostic and therapeutic integration. Various characterization analyses including transmission electron microscopy, Fourier infrared spectroscopy, and particle size analysis confirm that we successfully synthesized HISMP NPs with a diameter of 150.709 nm. The results of CCK8 cytotoxicity and apoptosis assays show that HISMP NPs exhibited high cytotoxicity and induce apoptosis in thyroid cancer cells. In vivo MR/NIRF imaging experiments confirmed that the HISMP NPs specifically aggregated at tumor sites and have good in vivo MR/NIRF imaging ability and effective anti-tumor activity. The nano-delivery system is expected to provide a theoretical foundation for the efficient ATC diagnosis and therapy.

Transdermal drug delivery (TDD) using electrically assisted microneedle (MN) systems has emerged as a promising alternative to traditional drug administration routes. This review explores recent advancements in this technology across various therapeutic applications. Integrating iontophoresis (IP) and electroporation (EP) with MN technology has shown significant potential in improving treatment outcomes for various conditions. Studies demonstrate their effectiveness in enhancing vaccine and DNA delivery, improving diabetes management, and increasing efficacy in dermatological applications. The technology has also exhibited promise in delivering nonsteroidal anti-inflammatory drugs (NSAIDs), treating multiple sclerosis, and advancing obesity and cancer therapy. These systems offer improved drug permeation, targeted delivery, and enhanced therapeutic effects. While challenges remain, including safety concerns and technological limitations, ongoing research focuses on optimizing these systems for broader clinical applications. The future of electrically assisted MN technologies in TDD appears promising, with potential advancements in personalized medicine, smart monitoring systems, and expanded therapeutic applications.

It was the aim of this study to evaluate the potential of reverse micelles (RM) and hydrophobic ion pairs (HIP) for incorporation of semaglutide into self-emulsifying oral drug delivery systems. Reverse micelles loaded with semaglutide were formed with a cationic (ethyl lauroyl arginate, ELA) and an anionic surfactant (docusate, DOC), whereas HIP were formed between semaglutide and ELA. Maximum solubility of the peptide and the rate of dissolution was evaluated in various lipophilic phases (glycerol monocaprylocaprate:caprylic acid 1:4 (m/m), glycerol monolinoleate:caprylic acid 1:4 (m/m) and glycerol monocaprylocaprate:glycerol monolinoleate 1:4 (m/m)). Self-emulsifying drug delivery systems (SEDDS) loaded with RM and HIP were characterized regarding size distribution, zeta potential, cytocompatibility and Caco-2 permeability. Droplet sizes between 50 and 300 nm with polydispersity index (PDI) around 0.3 and zeta potentials between - 45 mV (RM_DOC) and 36 mV (RM_ELA) were obtained. RM provided an almost 2-fold higher lipophilicity of semaglutide than HIP resulting in a 4.2-fold higher payload of SEDDS compared to HIP. SEDDS containing RM or HIP showed high cytocompatibilities with a cell survival above 75% for concentrations up to 0.1% on Caco-2 cells and acceptable hemolytic activity. Permeation studies across Caco-2 monolayer revealed an at least 2-fold increase in permeability of semaglutide for the developed formulations.

Vat photopolymerisation 3D printing is being actively explored for manufacturing personalised medicines due to its high dimensional accuracy and lack of heat application. However, several challenges have hindered its clinical translation, including the inadequate printing speeds, the lack of resins that give soluble matrices, and the need for non-destructive quality control measures. In this study, for the first time, a rapid approach to producing water-soluble vat photopolymerised matrices and a means of non-destructively verifying their drug content were investigated. Volumetric printing, a novel form of vat photopolymerisation, was used to fabricate personalised warfarin-loaded 3D-printed tablets (printlets). Eight different formulations containing varying amounts of warfarin (0.5-6.0% w/w) were used to print two different sized torus-shaped printlets within 6.5 to 11.1 s. Nuclear magnetic resonance (NMR) spectroscopy revealed the presence of only trace amounts of unreacted acrylate monomers, suggesting that the photopolymerisation reaction had occurred to near completion. All printlets completely solubilised and released their entire drug load within 2.5 to 7 h. NIR spectroscopy (NIRS) was used to non-destructively verify the dose of warfarin loaded into the vat photopolymerised printlets. The partial least square regression model built showed strong linearity (R² = 0.980), and high accuracy in predicting the drug loading of the test sample (RMSEP = 0.205%). Therefore, this study advances pharmaceutical vat photopolymerisation by demonstrating the feasibility of producing water-soluble printlets via volumetric printing and quantifying the drug load of vat photopolymerised printlets with NIRS.

Medication use during pregnancy poses risks to both the mother and the fetus. These risks include an elevated potential for fetotoxicity due to placental drug transport. Nanomedicines offer a promising solution by potentially preventing trans-placental passage. Targeted nanomedicines could enhance safety and efficacy in treating maternal or placental pathophysiology. Our study investigates placental transfer kinetics of targeted lipid nanoparticles (LNPs) in an ex vivo human placenta cotyledon perfusion model. We collected human placentas for dual-side ex vivo placental perfusions. Targeted LNPs with a fluorescence tag were introduced into the maternal circuit of each placenta. To establish if there was trans-placental passage of LNPs to the fetal circuit, we collected samples from maternal and fetal circuits throughout the six hours of the perfusion. We determined the fluorescence signal using a multi-mode microplate reader and Multiphoton microscopy to localize the LNPs in the placenta tissue. Data from perfused placenta tissue showed no significant transfer of the fluorescently labeled LNPs across the placental barrier to the fetal circuit. Localization of targeted LNPs in tissue samples is mainly observed in the maternal blood space of the placenta. Our results suggest that targeted LNPs present a promising strategic approach to prevent trans-placental passage to the fetus. Our future perspectives involve investigating the efficacy of targeted LNPs as well as loading targeted LNPs with nucleic acid-based therapeutics to investigate their therapeutic potential.