Drug Delivery and Translational Research最新文献

The blood-brain barrier (BBB) represents a major obstacle in the treatment of neurological disorders. While it plays a crucial role in protecting the central nervous system (CNS) from harmful xenobiotics, it also limits the entry of drugs already in systemic circulation. Intranasal drug delivery has emerged as an interesting, non-invasive strategy to bypass the BBB by exploiting the anatomical connections provided by the olfactory and trigeminal nerves, allowing direct transport from the nasal cavity to the brain. Nevertheless, drugs administered via this route face several challenges, including enzymatic degradation, mucociliary clearance and limited residence time on the nasal mucosa. This review examines the underlying mechanisms of nose-to-brain drug transport and details how recent advances in nanocarrier-based delivery systems, including lipid-based, polymeric-based, protein-based, and inorganic nanoparticles, can be engineered to enhance drug delivery to the brain. Recent preclinical advances demonstrate improved brain targeting, protection from degradation, and controlled release profiles. Finally, we summarize the current clinical progress and provide our perspective on the steps needed for successful clinical translation, emphasizing the importance of optimizing nanosystem performance across both the nasal cavity and brain compartments.

Alzheimer's disease (AD) is an incurable neurological disorder and the primary cause of dementia globally, yet therapeutic options remain limited by poor drug efficacy, low patient adherence, and the restrictive blood-brain barrier (BBB), which prevents over 98% of small molecules from reaching the brain. Piracetam (PIRA), a nootropic agent, and cannabidiol (CBD), a neuroprotective compound, have shown potential in addressing AD-related oxidative stress, inflammation, and neurotransmitter imbalance. However, both drugs exhibit short plasma half-lives, requiring frequent dosing that may reduce patient compliance. To address these challenges, we developed a sustained-release phospholipid phase-transition gel (PPTG) depot incorporating a PIRA-CBD nanoemulsion. A combination index study demonstrated potent synergy at a 1:5 CBD: PIRA ratio. Optimization of the nanoemulsion was carried out using a Box-Behnken design, which explored oil concentration (Capryol^® 90), Smix (Tween 20: Cremophor ELP), and stirring speed as key variables. A mean particle size of 137.8 nm, a PDI of 0.155, and a zeta potential of -7.587 mV were all observed in the formulation that was optimized. Upon subcutaneous injection, the PPTG showed excellent injectability and formed a stable depot in vivo, as confirmed by gamma scintigraphy. In vitro studies revealed sustained release of 90.538 ± 2.62% PIRA and 87.202 ± 2.16% CBD over 96 h, compared to rapid release from the drug solution. This study introduces a novel phospholipid-based phase-transition gel depot incorporating PIRA-CBD nanoemulsion, which provides sustained, targeted brain delivery to enhance therapeutic efficacy and improve patient compliance in Alzheimer's disease management.

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.

Monoclonal antibodies (mAbs) are promising therapeutic agents for neurological disorders due to their high specificity. However, their clinical application is significantly hindered by their poor transport across the blood-brain barrier (BBB) and their limited diffusion within the brain parenchyma. While significant efforts have been oriented to tackle the first barrier, the challenge of efficient brain diffusion remains largely underexplored. To address this, we have developed and evaluated two structurally distinct nanosystems for mAb delivery to the brain: PEGylated polyglutamic acid nanocapsules (PGA-PEG NCs) and PGAC14-based nanoassemblies (PGAC14 NAs). Both formulations encapsulated efficiently the model mAb bevacizumab (BVZ) while they exhibited different physicochemical properties. Namely, PGA-PEG NCs displayed a size of 80 nm and a neutral zeta potential, whereas PGAC14 NAs featured an ultra-small size of 40 nm and a negative surface charge. After assessing their diffusion capacity using immunofluorescence, we concluded that PGAC14 NAs exhibited the highest brain diffusion together with a favorable neuroinflammatory profile. This was likely driven by their small size and negative charge, along with a selective ability to interact with and deliver BVZ intracellularly to neuronal cells upon intraparenchymal administration. These findings provide key insights into optimizing nanocarrier design for improved mAb delivery to the brain.

Glioblastoma Multiforme is an aggressive and complex cancer affecting mostly elderly patients above the age of 60 years. Originally classified as the fourth stage of glioma, it has an abysmal prognosis along with limited therapeutic options. Surgical removal of tumors, radiotherapy, and chemotherapy are prevalent treatment strategies with numerous therapeutic obstacles, including undefined boundary of tumor mass leaving traces even after excision, chances of secondary cancer formation, and presence of blood-brain barrier. These blood-brain and blood-brain tumor barriers actively restrict the permeability of many molecules from blood circulation to enter the central nervous system. Therefore, many conventional antineoplastic drugs fail to reach the tumor periphery except temozolomide. Meanwhile, active stem cells in the tumor microenvironment, genetic mutation inducing tumor growth, and epigenetic pattern alteration make this cancer chemoresistant. Our review delineates the recent approaches to resensitize the existing clinical drugs through specifically designed nanoformulations. Nanoparticles with modified physiological characteristics and modified through technological parameters can reduce the tumor's stemness, which increases tumor cells' apoptosis rate. Moreover, these nanoparticles can efficiently traverse the blood-brain barrier and escape from endosomal degradation with minimum toxicological impact. Overall, this review discusses the cancer chemoresistance phenomena and related pathways and highlights the potential of nanoformulation in reversing chemoresistance. Also, the existing limitations of this unique approach and suggestions are discussed at the end of the article, which may facilitate the identification of new directions for advancement of the nanoparticle-mediated reversal of chemoresistance.

Brain abscess is a serious, life-threatening intracranial infection caused by inflammation and collection of infected material. Given the rise of multi-drug resistant strains and the widespread presence of bacteria, it is probable that the incidence of brain abscesses is expected to endure. The sequela of brain abscess constitutes a major source of morbidity and mortality. Brain abscess may cause permanent neurological damage, such as paresis, hydrocephalus, spasticity, mental deterioration and epileptic seizure. Current therapeutic approaches include surgical excision or drainage combined with prolonged antimicrobial treatment usually lasting 6-8 weeks. However, extended antimicrobial treatment may cause adverse side effects, such as nephrotoxicity, ototoxicity, and bone marrow suppression. As a result, it is essential to develop a novel approach to facilitate antibiotics delivery and shorten the therapeutic course clinically. Recently, focused ultrasound (FUS) has been demonstrated to have an ability to temporally open the brain blood barrier (BBB) and modulate the immune response in the brain tumor animal model or in naïve animals. In our study, we demonstrated the focused ultrasound treatment (3W acoustic power, 0.6 MPa peak negative pressure) to treat brain abscess by boosting immune response in CNS infection in the brain abscess animal model. The size of the brain abscess is reduced by 50 percent when the MRI scan is taken at 3 weeks post-treatment. The animals get better recovery after treatment. The use of low intensity FUS with systemic microbubble infusion to open the BBB by mechanical acoustic cavitation elicited an immediate immune response including elevations in proinflmmatory cytokine (IL-1, TNFα and IL-6) in the brain parenchyma surround the brain abscess. Furthermore, FUS exposure treatment also activated glial cells, potentially enhancing the encapsulation of brain abscesses and reducing the spread of bacteria to the adjacent brain parenchyma. Histological analysis also demonstrated that FUS can reduce neuron loss and blood vessel damage during brain abscess formation. Our findings indicate that the FUS system can achieve local reversible BBB opening, enhancing immunomodulation in an animal model of brain abscess.

Despite the rapid development of nanoparticle (NP)-based drug delivery systems, intravenous delivery of drugs to the brain remains a major challenge due to various biological barriers. To achieve therapeutic effects, NP-encapsulated drugs must avoid accumulation in off-target organs and selectively deliver to the brain, successfully cross the blood-brain barrier (BBB), and reach the target cells in the brain. Conjugating receptor-specific ligands to the surface of NPs is a promising technique for engineering NPs to overcome these barriers. Specifically, peptides as brain-targeting ligands have been of increasing interest given their ease of synthesis, low cytotoxicity, and strong affinity to target proteins. The success of peptides as targeting ligands is largely due to the diverse strategies of designing and modifying peptides with favorable properties, including membrane permeability and multi-receptor targeting. Here, we review the design and implementation of peptide-functionalized NP systems for neurological disease applications. We also explore advances in rational peptide design strategies for brain targeting, including using generative deep-learning models to computationally design new peptides.

Dementia includes a variety of neurodegenerative diseases that affect and target the brain's fundamental cognitive functions. It is undoubtedly one of the diseases that affects people globally. The ameliorating the disease is still not known; the symptoms, however, can be prevented to an extent. Dementia encompasses Alzheimer's disease, Parkinson's disease, Huntington's disease, Lewy body dementia, mixed dementia, and various other diseases. The aggregation of β-amyloid protein plaques and the formation of neurofibrillary tangles have been concluded as the foremost cause for the onset of the disease. As the cases climb, new neuroprotective methods are being developed in the form of new drug delivery systems that provide targeted delivery. Herbal drugs like Ashwagandha, Brahmi, and Cannabis have shown satisfactory results by not only treating the symptoms but have also been shown to reduce and ameliorate the formation of amyloid plaque formation. This article explores the intricate possibilities of drug delivery and the absolute use of herbal drugs to target neurodegenerative diseases. The various possibilities of nanotechnology currently available with new emerging techniques are also discussed.

The global prevalence of Parkinson's Disease (PD) is on the rise, driven by an ageing population and ongoing environmental conditions. To gain a better understanding of PD pathogenesis, it is essential to consider its relationship with the ageing process, as ageing stands out as the most significant risk factor for this neurodegenerative condition. PD risk factors encompass genetic predisposition, exposure to environmental toxins, and lifestyle influences, collectively increasing the chance of PD development. Moreover, early and precise PD diagnosis remains elusive, relying on clinical assessments, neuroimaging techniques, and emerging biomarkers. Conventional management of PD involves dopaminergic medications and surgical interventions, but these treatments often become less effective over time and do not address disease treatment. Challenges persist due to the blood-brain barrier's (BBB) impermeability, hindering drug delivery. Recent advancements in nanotechnology offer promising novel approaches for PD management. Various drug delivery systems (DDS), including nanosized polymers, lipid-based carriers, and nanoparticles (such as metal/metal oxide, protein, and carbonaceous particles), aim to enhance drug and gene delivery. These modifications seek to improve BBB permeability, ultimately benefiting PD patients. This review underscores the critical role of ageing in PD development and explores how age-related neuronal decline contributes to substantia nigra loss and PD manifestation in susceptible individuals. The review also highlights the advancements and ongoing challenges in nanotechnology-based therapies for PD.