Drug Delivery最新文献

Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.

Purpose: Targeted drug delivery to the optic nerve head may be useful in the preclinical study and later clinical management of optic neuropathies, however, there are no FDA-approved drug delivery systems to achieve this. The purpose of this work was to develop an optic nerve head drug delivery technique.

Methods: Different strategies to approach the optic nerve head were investigated, including standard intravitreal and retroorbital injections. A novel SupraChoroidal-to-Optic-NervE (SCONE) delivery was optimized by creating a sclerotomy and introducing a catheter into the suprachoroidal space. Under direct visualization, the catheter was guided to the optic nerve head. India ink was injected. The suprachoroidal approach was performed in New Zealand White rabbit eyes in vivo (25 animals total). Parameters, including microneedle size and design, catheter design, and catheter tip angle, were optimized ex vivo and in vivo.

Results: Out of the candidate optic nerve head approaches, intravitreal, retroorbital, and suprachoroidal approaches were able to localize India ink to within 2 mm of the optic nerve. The suprachoroidal approach was further investigated, and after optimization, was able to deposit India ink directly within the optic nerve head in up to 80% of attempts. In eyes with successful SCONE delivery, latency and amplitude of visual evoked potentials was not different than the naïve untreated eye.

Conclusions: SCONE delivery can be used for targeted drug delivery to the optic nerve head of rabbits without measurable toxicity measured anatomically or functionally. Successful development of this system may yield novel opportunities to study optic nerve head-specific drug delivery in animal models, and paradigm-shifting management strategies for treating optic neuropathies.

Translational relevance: Here we demonstrate data on a new method for targeted delivery to the optic nerve head, addressing a significant unmet need in therapeutics for optic neuropathies.

Methotrexate (MTX) is a folic acid antagonist routinely used in cancer treatment, characterized by poor water solubility and low skin permeability. These issues could be mitigated by using drug delivery systems, such as functionalized gold nanoparticles (AuNPs), known for their versatility and unique properties. This study aimed to develop multi-shell AuNPs functionalized with MTX for the improvement of MTX antitumoral, antioxidant, and biocompatibility features. Stable phosphine-coated AuNPs were synthesized and functionalized with tailored polyethylene glycol (PEG) and short-branched polyethyleneimine (PEI) moieties, followed by MTX covalent binding. Physicochemical characterization by UV-vis and Fourier-transform infrared spectroscopy (FTIR) spectroscopy, dynamic light scattering (DLS), scanning transmission electron microscopy (STEM), and X-ray photoelectron spectroscopy (XPS) confirmed the synthesis at each step. The antioxidant activity of functionalized AuNPs was determined using DPPH radical scavenging assay, ferric ions' reducing antioxidant power (FRAP), and cupric reducing antioxidant capacity (CUPRAC) assays. Biocompatibility and cytotoxicity were assessed using MTT and LDH assays on HaCaT human keratinocytes and CAL27 squamous cell carcinoma. MTX functionalized AuNPs demonstrated enhanced antioxidant activity and a pronounced cytotoxic effect on the tumoral cells compared to their individual components, highlighting their potential for improving cancer therapy.

Subarachnoid hemorrhage (SAH) is a life-threatening acute hemorrhagic cerebrovascular disease, with early brain injury (EBI) being the main cause of high mortality and severe neurological dysfunction. Oxidative stress plays a crucial role in the pathogenesis of EBI. In this study, we synthesized antioxidant stress nanoparticles based on self-assembled oleanolic acid (OA) using the solvent volatilization method. X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and transmission electron microscopy (TEM) techniques were employed to analyze and understand the self-assembly mechanism of oleic acid nanoparticles (OA NPs). The TUNEL assay, Nissl staining, and brain water content measurements were conducted to investigate the impact of OA NPs on cortical neuronal injury. Additionally, Western blot analysis was performed to investigate the antioxidant stress mechanism of OA NPs. The result showed that OA NPs exhibited a spherical structure with an average diameter of 168 nm. The application of OA NPs in SAH has been found to contribute to the reduction of keap1 protein levels and an increase in the nuclear level of Nrf2. As a result, the transcription of antioxidant stress proteins, including HO1 and NQO1, is triggered. The activation of the antioxidant stress pathway by OA NPs ultimately leads to a decrease in neuron damage and an improvement in neurological dysfunction. In conclusion, we successfully designed and synthesized OA NPs that can efficiently target the site of SAH. These nanoparticles have demonstrated their potential as antioxidants for the treatment of SAH, offering significant clinical applications.

Microneedle (MN) delivery devices are more accepted by people than regular traditional needle injections (e.g. vaccination) due to their simplicity and adaptability. Thus, patients of chronic diseases like diabetes look for alternative pain-free treatment regimens circumventing regular subcutaneous injections. Insulin microneedles (INS-MNs) are a thoughtfully researched topic (1) to overcome needle phobia in patients, (2) for controlled delivery of the peptide, (3) decreasing the frequency of drug administration, (4) to ease the drug administration procedure, and (5) thus increasing patient adherence to the treatment dosage regimes. MNs physically disrupt the hard outer skin layer to create minuscule pores for insulin (INS) to pass through the dermal capillaries into the systemic circulation. Biodegradable polymeric MNs are of greater significance for INS and vaccine delivery than silicon, metal, glass, or non-biodegradable polymeric MNs due to their ease of fabrication, mass production, cost-effectiveness, and bioerodability. In recent years, INS-MNs have been researched to deliver INS through the transdermal implants, buccal mucosa, stomach wall, intestinal mucosal layers, and colonic mucosa apart from the usual transdermal delivery. This review focuses on the design characteristics and the applications of biodegradable/dissolvable polymeric INS-MNs in transdermal, intra-oral, gastrointestinal (GI), and implantable delivery. The prospective approaches to formulate safe, controlled-release INS-MNs were highlighted. Biodegradable/dissolvable polymers, their significance, their impact on MN morphology, and INS release characteristics were outlined. The developments in biodegradable polymeric INS-MN technology were briefly discussed. Bio-erodible polymer selection, MN fabrication and evaluation factors, and other design aspects were elaborated.

The local injection of therapeutic drugs, including cells, oncolytic viruses and nucleic acids, into different organs is an administrative route used to achieve high drug exposure at the site of action. However, after local injection, material backflow and side effect reactions can occur. Hence, this study was carried out to investigate the effect of gelatin on backflow reduction in local injection. Gelatin particles (GPs) and hydrolyzed gelatin (HG) were injected into tissue models, including versatile training tissue (VTT), versatile training tissue tumor-in type (VTT-T), and broiler chicken muscles (BCM), using needle gauges between 23 G and 33 G. The backflow material fluid was collected with filter paper, and the backflow fluid rate was determined. The backflow rate was significantly reduced with 35 μm GPs (p value < .0001) at different concentrations up to 5% and with 75 μm GPs (p value < .01) up to 2% in the tissue models. The reduction in backflow with HG of different molecular weights showed that lower-molecular-weight HG required a higher-concentration dose (5% to 30%) and that higher-molecular-weight HG required a lower-concentration dose (7% to 8%). The backflow rate was significantly reduced with the gelatin-based formulation, in regard to the injection volumes, which varied from 10 μL to 100 μL with VTT or VTT-T and from 10 μL to 200 μL with BCM. The 35 μm GPs were injectable with needles of small gauges, which included 33 G, and the 75 μm GPs and HG were injectable with 27 G needles. The backflow rate was dependent on an optimal viscosity of the gelatin solutions. An optimal concentration of GPs or HG can prevent material backflow in local injection, and further studies with active drugs are necessary to investigate the applicability in tumor and organ injections.

The application of multidisciplinary techniques in the management of endocrine-related cancers is crucial for harnessing the advantages of multiple disciplines and their coordinated efforts in eliminating tumors. Due to the malignant characteristics of cancer cells, they possess the capacity to develop resistance to traditional treatments such as chemotherapy and radiotherapy. Nevertheless, despite diligent endeavors to enhance the prediction of outcomes, the overall survival rate for individuals afflicted with endocrine-related malignancy remains quite miserable. Hence, it is imperative to investigate innovative therapy strategies. The latest advancements in therapeutic tactics have offered novel approaches for the therapy of various endocrine tumors. This paper examines the advancements in nano-drug delivery techniques and the utilization of nanomaterials for precise cancer cures through targeted therapy. This review provides a thorough analysis of the potential of combined drug delivery strategies in the treatment of thyroid cancer, adrenal gland tumors, and pancreatic cancer. The objective of this study is to gain a deeper understanding of current therapeutic approaches, stimulate the development of new drug DDS, and improve the effectiveness of treatment for patients with these diseases. The intracellular uptake of pharmaceuticals into cancer cells can be significantly improved through the implantation of synthetic or natural substances into nanoparticles, resulting in a substantial reduction in the development of endocrine malignancies.

Co-delivery strategies have become an integral active delivery approach, although understanding of how the microstructural characteristics could be deployed to achieve independently regulated active co-delivery profiles, is still an area at its infancy. Herein, the capacity to provide such control was explored by utilizing Pickering emulsions stabilized by lipid particles, namely solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These dual functional species, regarding their concurrent Pickering stabilization and active carrying/delivery capabilities, were formulated with different solid lipid and surfactant types, and the effect on the release and co-release modulation of two hydrophobic actives separately encapsulated within the lipid particles themselves and within the emulsion droplets was investigated. Disparities between the release profiles from the particles in aqueous dispersions or at an emulsion interface, were related to the specific lipid matrix composition. Particles composed of lipids with higher oil phase compatibility of the emulsion droplets were shown to exert less control over their release regulation ability, as were particles in the presence of surfactant micelles in the continuous phase. Irrespective of their formulation characteristics, all particles provided a level of active release control from within the emulsion droplets, which was dependant on the permeability of the formed interfacial layer. Specifically, use of a bulkier particle surfactant or particle sintering at the droplet interface resulted in more sustained droplet release rates. Compared to sole release, the co-release performance remained unaffected by the co-existence of the two hydrophobic actives with the co-release behavior persisting over a storage period of 1 month.

Burn injuries can result in a significant inflammatory response, often leading to hypertrophic scarring (HTS). Local drug therapies e.g. corticoid injections are advised to treat HTS, although they are invasive, operator-dependent, extremely painful and do not permit extended drug release. Polymer-based microneedle (MN) arrays can offer a viable alternative to standard care, while allowing for direct, painless dermal drug delivery with tailorable drug release profile. In the current study, we synthesized photo-crosslinkable, acrylate-endcapped urethane-based poly(ε-caprolactone) (AUP-PCL) toward the fabrication of MNs. Physico-chemical characterization (¹H-NMR, evaluation of swelling, gel fraction) of the developed polymer was performed and confirmed successful acrylation of PCL-diol. Subsequently, AUP-PCL, and commercially available PCL-based microneedle arrays were fabricated for comparative evaluation of the constructs. Hydrocortisone was chosen as model drug. To enhance the drug release efficiency of the MNs, Brij®35, a nonionic surfactant was exploited. The thermal properties of the MNs were evaluated via differential scanning calorimetry. Compression testing of the arrays confirmed that the MNs stay intact upon applying a load of 7 N, which correlates to the standard dermal insertion force of MNs. The drug release profile of the arrays was evaluated, suggesting that the developed PCL arrays can offer efficient drug delivery for up to two days, while the AUP-PCL arrays can provide a release up to three weeks. Finally, the insertion of MN arrays into skin samples was performed, followed by histological analysis demonstrating the AUP-PCL MNs outperforming the PCL arrays upon providing pyramidical-shaped perforations through the epidermal layer of the skin.