Recent advances towards overcoming the blood-brain barrier.

The blood-brain barrier (BBB) is a protective element of the neurovascular unit (NVU) surrounded by astrocytes, pericytes, extracellular matrix, and the tight junctional complex, which play a fundamental role in brain homeostasis. Due to its impeccable structural architecture, the BBB is referred to as the brain's gatekeeper, a near-impenetrable barrier to therapeutics. This review summarises the significant strides that have been made in the last 5 years towards circumventing the BBB and developing efficient drug delivery systems. Challenges associated with several CNS disorders related to BBB failure and exploitation of this unique NVU component for targeted treatment of brain-related disorders are also discussed.

Syphilis mimetic nanoparticles for cuproptosis-based synergistic cancer therapy via reprogramming copper metabolism.

Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M-Cu-MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.

Current approaches to facilitate improved drug delivery to the central nervous system.

Although many pharmaceuticals have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been effectively administered. It is due to the fact that the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSF) restrict them from crossing the brain to exert biological activity. This article reviews the current approaches aiming to improve penetration across these barriers for effective drug delivery to the CNS. These issues are summarized into direct systemic delivery and invasive delivery, including the BBB disruption and convection enhanced delivery. Furthermore, novel drug delivery systems used at the nanoscale, including polymeric nanoparticles, liposomes, nanoemulsions, dendrimers, and micelles are discussed. These nanocarriers could contribute to a breakthrough in the treatment of many different CNS diseases. However, further broadened studies are needed to assess the biocompatibility and safety of these medical devices.

Biodistribution Analysis of an Anti-EGFR Antibody in the Rat Brain: Validation of CSF Microcirculation as a Viable Pathway to Circumvent the Blood-Brain Barrier for Drug Delivery.

Cerebrospinal fluid (CSF) microcirculation refers to CSF flow through brain or spinal parenchyma. CSF enters the tissue along the perivascular spaces of the penetrating arteries where it mixes with the interstitial fluid circulating through the extracellular space. The potential of harnessing CSF microcirculation for drug delivery to deep areas of the brain remains an area of controversy. This paper sheds additional light on this debate by showing that ABT-806, an EGFR-specific humanized IgG1 monoclonal antibody (mAb), reaches both the cortical and the deep subcortical layers of the rat brain following intra-cisterna magna (ICM) injection. This is significant because the molecular weight of this mAb (150 kDa) is highest among proteins reported to have penetrated deeply into the brain via the CSF route. This finding further confirms the potential of CSF circulation as a drug delivery system for a large subset of molecules offering promise for the treatment of various brain diseases with poor distribution across the blood-brain barrier (BBB). ABT-806 is the parent antibody of ABT-414, an antibody-drug conjugate (ADC) developed to engage EGFR-overexpressing glioblastoma (GBM) tumor cells. To pave the way for future efficacy studies for the treatment of GBM with an intra-CSF administered ADC consisting of a conjugate of ABT-806 (or of one of its close analogs), we verified in vivo the binding of ABT-414 to GBM tumor cells implanted in the cisterna magna and collected toxicity data from both the central nervous system (CNS) and peripheral tissues. The current study supports further exploration of harnessing CSF microcirculation as an alternative to systemic delivery to achieve higher brain tissue exposure, while reducing previously reported ocular toxicity with ABT-414.

Brain-targeted co-delivery of ß-amyloid converting enzyme 1 shRNA and epigallocatechin-3-gallate by multifunctional nanocarriers for Alzheimer's disease treatment.

Progressive memory loss and cognitive dysfunction are hallmark clinical features of Alzheimer's disease (AD). As a possible treatment for AD, we developed an epigallocatechin-3-gallate (EGCG) and ß-site amyloid precursor protein (APP) cleaving enzyme 1 antisense (BACE1-AS) shRNA-encoded plasmid. The plasmid was loaded on to RVG29 peptide-targeted multifunctional nanoparticles (NPs) (REGS-PN). The polymeric NPs were characterized by flow cytometry, biocompatibility assay, pharmacokinetic analysis, Western blot analysis, and the Morris water maze (MWM) test. The differences in plasma and brain NP accumulation following intravenous administration showed a significantly longer circulation time for EGS-PN and REGS-PN in the blood stream. In contrast, free EGCG was rapidly eliminated from the circulation. REGS-PM successfully travelled through the blood-brain barrier and was present at a higher concentration in the brain compared with both non-targeted NPs and free EGCG. REGS-PN administration to APPswe/PS1dE9 double transgenic mice (APP/PS1 mice) resulted in downregulation of the key enzyme in amyloid-ß formation (BACE1) and amyloid beta, indicating synergistic therapeutic activity. The MWM test revealed that simultaneous delivery of a therapeutic gene and EGCG (REGS-PN) remarkably improved the spatial learning and memory capabilities of APP/PS1 mice as well as wild type mice compared with the free EGCG-treated group. With these results, we propose that co-delivery of a therapeutic gene (shRNA) and EGCG in a multifunctional nanocarrier could achieve higher therapeutic concentrations in the brain and could be an excellent strategy for AD treatment.

Current approaches to enhance CNS delivery of drugs across the brain barriers.

Although many agents have therapeutic potentials for central nervous system (CNS) diseases, few of these agents have been clinically used because of the brain barriers. As the protective barrier of the CNS, the blood-brain barrier and the blood-cerebrospinal fluid barrier maintain the brain microenvironment, neuronal activity, and proper functioning of the CNS. Different strategies for efficient CNS delivery have been studied. This article reviews the current approaches to open or facilitate penetration across these barriers for enhanced drug delivery to the CNS. These approaches are summarized into three broad categories: noninvasive, invasive, and miscellaneous techniques. The progresses made using these approaches are reviewed, and the associated mechanisms and problems are discussed.