Drug Delivery and Translational Research最新文献

Sustainable systems are designed to promote lasting viability and resilience while reducing negative effects on the environment, society, and economy. Like many others, the drug delivery field is facing the challenges of the global environmental crisis. Despite its rapid growth and significant funding, there has been a noticeable slowdown in the rate of advancement, impacting the economy, society, and environment. This paper delves into sustainable strategies for drug delivery research, including reducing pill burden through controlled release systems, use of bio-degradable/absorbable polymers, reduction in excipient requirements and use of functional excipients, clinically viable drug delivery system designs, non-invasive/self-administration technologies, and use of relevant in vitro and in vivo tools and computational approaches. When adopted, these strategies can help researchers create widely available, reasonably priced, and ecologically friendly drug delivery systems, thereby advancing sustainable healthcare for all. The manuscript also advocates for funding policies that support sustainable drug delivery research. It underscores the need to integrate sustainability principles into drug delivery research to achieve the broader agenda of global sustainability and well-being, such as SDG 3 (Good Health and Well-being), SDG 7 (Affordable and Clean Energy), SDG 9 (Industry, Innovation, and Infrastructure), and SDG 12 (Responsible Consumption and Production).

Glioblastoma (GBM), a highly aggressive brain tumor, poses significant treatment challenges due to its highly immunosuppressive microenvironment and the brain immune privilege. Immunotherapy activating the immune system and T lymphocyte infiltration holds great promise against GBM. However, the brain's low immunogenicity and the difficulty of crossing the blood-brain barrier (BBB) hinder therapeutic efficacy. Recent advancements in immune-actuated particles for targeted drug delivery have shown the potential to overcome these obstacles. These particles interact with the BBB by rapidly and reversibly disrupting its structure, thereby significantly enhancing targeting and penetrating delivery. The BBB targeting also minimizes potential long-term damage. At GBM, the particles demonstrated effective chemotherapy, chemodynamic therapy, photothermal therapy (PTT), photodynamic therapy (PDT), radiotherapy, or magnetotherapy, facilitating tumor disruption and promoting antigen release. Additionally, components of the delivery system retained autologous tumor-associated antigens and presented them to dendritic cells (DCs), ensuring prolonged immune activation. This review explores the immunosuppressive mechanisms of GBM, existing therapeutic strategies, and the role of nanomaterials in enhancing immunotherapy. We also discuss innovative particle-based approaches designed to traverse the BBB by mimicking innate immune functions to improve treatment outcomes for brain tumors.

Glaucoma is an optic neuropathy in which progressive degeneration of retinal ganglion cells and the optic nerve leads to irreversible visual loss. Glaucoma is one of the leading causes of blindness. The pathogenesis of glaucoma is determined by different pathogenetic mechanisms, including increased intraocular pressure, mechanical stress, excitotoxicity, resistance to aqueous drainage and oxidative stress. Topical formulations are often used in glaucoma treatment, whereas surgical measures are used in acute glaucoma cases. For most patients, long-term glaucoma treatments are given. Poor patient compliance and low bioavailability are often associated with topical therapy, which suggests that sustained-release, long-acting drug delivery systems could be beneficial in managing glaucoma. This review summarizes the eye's physiology, the pathogenesis of glaucoma, current treatments, including both pharmacological and nonpharmacological interventions, and recent advances in long-acting drug delivery systems for the treatment of glaucoma.

Parkinson's disease (PD) is the most prominent and highly prevalent chronic neuro-degenerative disease generally recognized by classical motor symptoms which are linked with genetic mutation, Lewy bodies, and subsequently selective loss of nigrostriatal dopaminergic neurons. The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier protect the central nervous system against toxins and are the most significant barriers to effective brain drug delivery in managing Parkinsonism. In recent years, intranasal delivery has attracted remarkable attention for brain targeting as the drug can be administered to the brain directly from the nose employing the trigeminal and olfactory pathways. For brain targeting through nasal delivery, several advanced and promising formulation techniques have been investigated globally. Nanoemulsions are regarded as an innovative carrier approach for PD, where these provide targeted administration and enhanced bioavailability of neurotherapeutics. This manuscript provides deeper insight into the pathophysiology of PD, various drug delivery strategies to overcome BBB, and the potential role of nanoemulsions via the intranasal route. Various research findings on the intranasal administration of nanoemulsions and their pivotal applications in the treatment of PD have also been embarked. The potential role of phytoconstituents and surface-modified nanoemulsions for the effective treatment of PD has also been reflected along with current challenges and future perspectives in this avenue.

The aim of this study was to assess the critical quality attributes of parenteral nanoemulsion formulations by measuring several physicochemical parameters and linking them to their in vitro performance, illustrating how simplistic and routinely used approaches are insufficient for understanding a potential nanomedicine. Physicochemical characterization should encompass size and size distribution through at least two orthogonal techniques, such as dynamic light scattering (DLS) and electron microscopy, with added value from analytical ultracentrifugation. In vitro toxicity assessment was performed using three different assays to determine mitochondrial activity (WST-1), membrane integrity (lactate dehydrogenase release (LDH) assay), and cell viability (propidium iodide (PI) staining). Special focus was placed on estimating appropriate incubation times for relevant results in biological investigations. All formulations had an average diameter of around 100 nm. Conclusions regarding in vitro safety were assay-dependent: LDH and PI-based assays showed good correlation, while the WST-1 assay indicated that the non-PEGylated formulation altered mitochondrial activity more significantly compared to the PEGylated ones. The study underlined that the selection of appropriate cytotoxicity assays should be based on the possible mechanism of cellular perturbation. Alternatively, different aspects of cellular toxicity should be tested. Additionally, there is a need for well-designed controls to overcome nanoparticle scattering effects and avoid potentially false high toxicity results, which was demonstrated. Combining orthogonal, well-designed physicochemical and biological assays in a standardized manner as an initial step in the reliable preclinical characterization of nanomedicines is suggested. This represents a key aspect of new methodologies in nanomedicine characterization.

Cancer, particularly skin cancer, is a major cause of mortality worldwide, with melanoma being one of the most aggressive and challenging to treat types. Current therapeutic options, such as dacarbazine (DTIC), have limitations due to dose-related toxicities like liver toxicity. Therefore, there is a need for new and effective treatments for melanoma. Dihydroartemisinin (DHA), derived from artemisinin compounds known for their anti-malarial properties, has shown promise as an anti-cancer agent. However, the clinical use of DHA faces challenges such as low solubility and toxicity, which limit its therapeutic efficacy. To overcome these challenges, we developed an exosomal formulation of DHA to enhance its anti-cancer activity and reduce metastasis. Exosomes, biological vesicles, contain many biological macromolecules such as DNA, RNAs, and many other proteins, involved in intercellular communication, were isolated and loaded with DHA using the sonication method. The loaded exosomes were characterized for size (90-103 nm), polydispersity index (PDI: 0.119-0.123), and zeta potential (-23 to -28 mV). In vitro studies demonstrated the efficacy of DHA-loaded exosomes through cytotoxicity and apoptosis assays. The molecular mechanism of action was further elucidated using immunoblotting analysis, focusing on key proteins involved in apoptosis and metastasis regulation, including Bax, Bcl-2, survivin, and MMP-9. Furthermore, we observed a significant improvement in oral bioavailability (2.8-fold) with the exosomal formulation and enhanced in vivo anti-cancer activity of DHA. Notably, treatment with Exo-DHA resulted in strong enhancement of tumor growth suppression and reduced melanoma cell metastasis compared to free DHA.

Glioblastoma presents a significant treatment challenge due to the blood-brain barrier (BBB) hindering drug delivery, and the overexpression of matrix metalloproteinases (MMPs), which promotes tumor invasiveness. This study introduces a novel nanostructured lipid carrier (NLC) system designed for the delivery of batimastat, an MMP inhibitor, across the BBB and into the glioblastoma microenvironment. The NLCs were functionalized with epidermal growth factor (EGF) and a transferrin receptor-targeting construct to enhance BBB penetration and entrapment within the tumor microenvironment. NLCs were prepared by ultrasonicator-assisted hot homogenization, followed by surface functionalization with EGF and the construct though carbodiimide chemistry. The construct was successfully conjugated with an efficiency of 81%. Two functionalized NLC formulations, fMbat and fNbat, differing in the surfactant amount, were characterized. fMbat had a size of 302 nm, a polydispersity index (PDI) of 0.298, a ζ-potential (ZP) of -27.1 mV and an 85% functionalization efficiency (%FE), whereas fNbat measured 285 nm, with a PDI of 0.249, a ZP of -28.6 mV and a %FE of 92%. Both formulations achieved a drug loading of 0.42 μg/mg. In vitro assays showed that fNbat was cytotoxic and failed to cross the BBB, while fMbat showed cytocompatibility at concentrations 10 times higher than the drug's IC50. Additionally, fMbat inhibited MMP-2 activity between 11 and 62% across different cell lines and achieved a three-fold increase in BBB penetration upon functionalization. Our results suggest that the fMbat formulation has potential for enhancing GB treatment by overcoming current drug delivery limitations and may be combined with other therapeutic strategies for improved outcomes.

The use of dissolving microneedle arrays (dMNA) for intradermal and transdermal drug delivery has been a growing trend in the field for the past decades. However, a lack of specific regulatory standards still hinders their clinical development and translation to market. It is also well-known that dMNA composition significantly impacts their performance, with each new formulation potentially presenting a challenge for developers, manufacturers and regulatory agencies. A systematic approach such as quality-by-design (QbD), which embeds quality from the very beginning of the product development process, allows the design and optimisation of a drug-loaded dMNA formulation with promising features. In this work, we defined the Quality Target Product Profile (QTPP) for lidocaine-loaded dMNA and optimised their composition through a sequential design of experiments (DoE) approach. The first step (DoE_1) confirmed the influence of all formulation components (PVP, PVA and sucrose) in the properties of the arrays and pre-optimised their settings for DoE_2. The array characterisation focused on previously defined critical quality attributes (drug content, dissolution time, mechanical strength, skin insertion and physical attributes). At its maximum desirability (85.15%), the optimised design space obtained in DoE_2 is predicted to produce Li-dMNA with high mechanical strength (< 10% needle height reduction), skin insertion (> 90% needle height) and Li-HCl loading (~ 5 mg), good physical attributes and dissolving in a maximum of 60 min. The flexible design space obtained allows for the production of dMNA that consistently meet the QTPP, reducing batch failure and end-product testing, which are common in the more rigid GMP approach. Overall, applying QbD principles to formulation development shows promise to increase product quality and facilitate translation of dMNA into the clinic.

Functionalization of polymer nanoparticles (NPs) with targeting peptides is of interest for drug delivery applications to enhance tumor accumulation and penetration. Herein, we evaluated the feasibility of two different methods for the attachment of a tumor-penetrating peptide LinTT1 (AKRGARSTA) to poly(ethylene glycol)-block-poly(ε-caprolactone) (PCL-PEG) NPs: (1) "post-conjugation" onto pre-formed nanoparticles, and (2) "pre-conjugation", the synthesis and purification of peptide-polymer conjugates and subsequent nanoprecipitation of the conjugates diluted with non-functionalized polymers. Conjugation of the labelled peptide via maleimide-thiol chemistry was verified by gel permeation chromatography (GPC) and fluorescence measurements. Characterization of NPs with respect to particle size, zeta potential, morphology and peptide content was performed, and their ability to bind to the target protein p32 was tested using a cell-free assay. Importantly, both methods resulted in NPs that were able to bind their target when methyl-terminated PCL-PEG used as the diluent polymer, but not when acid-terminated polymer was used. Moreover, peptide conjugation induced a morphological transformation from spheres to vesicles regardless of the conjugation method used. However, smaller and more homogeneous NPs were obtained by the pre-conjugation method.

Erastin, as an effective ferroptosis inducer, has received extensive attention in anti-tumor research. To develop an oral nanocarrier for high efficient loading hydrophobic erastin, here we prepared a fluoro-liposome (FA-3 F-LS) by the self-assembly of the folic acid modified fluorinated amphiphiles-FA-3 F conjugates. The hydrophobic component of three perfluorooctyl chains endows the FA-3 F-LSs with high stability to resist the harsh gastrointestinal tract condition. Folic acids conjugated on the surface of FA-3 F-LSs ensure the better tumor targeting and higher oral bioavailability (32.1%) of erastin-loaded FA-3 F-LSs (erastin@FA-3 F-LSs) than free erastin (8.98%). As targeted anti-tumor nanomedicines, erastin@FA-3 F-LSs effectively inhibited the tumor cell proliferation in vitro by inducing ferroptosis through enhancing the glutathione (GSH) depletion, lipid peroxidation and generation of reactive oxygen species. In vivo studies demonstrated that FA-3 F-LSs displayed excellent application potential as a tumor-targeted oral drug delivery nanocarrier to depress the tumor growth with the loaded chemotherapeutic agents.