Bypassing The Blood-brain Barrier Research Articles

Potentiation of Brain Bioavailability Using Thermoreversible Cubosomal Formulation.

The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 μg/mL), Cmax (368.07 ± 0.23 μg/mL), Tmax (4 h), and t1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

A technological comparison of freeze-dried poly-ɛ-caprolactone (PCL) and poly (lactic-co-glycolic acid) (PLGA) nanoparticles loaded with clozapine for nose-to-brain delivery

Clozapine (CZP) is an atypical antipsychotic, the most effective for the treatment of resistant schizophrenia. With the aim of overcome the limitations of current dosage forms (tablets or suspensions) and routes of administration (oral and intramuscular), this research project proposes nanocarrier systems for intranasal (IN) administration of CZP. In particular, the systems have been developed for the direct nose-to-brain (N2B) route, which allows the direct delivery of the drug to the central nervous system (CNS), bypassing the blood-brain barrier (BBB). This study focusses on the development and investigation of two distinct types of lyophilized polymeric nanoparticles (NPs) consisting of poly- ɛ -caprolactone (PCL) or poly (lactic-co-glycolic acid) (PLGA). The lyophilized formulations were cryoprotected with 5 % (w/v) d-maltose for PLGA-NPs and 25 % (w/v) d-maltose for PCL-NPs. The NPs showed a size of approximately 200 nm, suitable for reuptake from the olfactory nerve to reach the brain directly after the IN administration. In vitro release studies performed in artificial cerebrospinal fluid (aCSF) and simulated nasal fluid (SNF) showed that PLGA NPs released 100 % of the drug in 4 days in SNF, while in aCSF they released about 80 % in 20 days. On the contrary, PCL-NPs released the entire amount of drug within 24 h in both fluids. Furthermore, preliminary in vitro mucoadhesion studies were performed on NPs in liquid form (suspensions) to compare the possible variation in their mucoadhesive properties with respect to powdered NPs, which were tested directly on pig nasal mucosa tissue, where permeability was also assessed. CZP-loaded NPs showed some interactions with mucin in vitro, but no ex-vivo mucoadhesiveness was demonstrated. Furthermore, the results of permeation indicated that the use of CZP-PCL-NPs did not increase the effective permeation of CZP into the mucosa; however, a faster onset of permeation compared to free CZP and a controlled profile were demonstrated. Toxicity studies on primary human olfactory mucosa cells extracted from volunteer patients and on MDCKII cells were also done. Finally, stability studies were carried out under different conditions: suspensions stored at 4 and 25 °C for 3 months, in SNF at 35 °C and in aCSF at 37 °C; dry powders were instead stored at 25 °C with 50 % relative humidity for 8 months. All the results demonstrated a greater stability of NPs in powder form and the absence of aggregation phenomena under artificial physiological conditions.

Plant-Polyphenol-Mediated Synthesis of Magnetic Biocompatible Iron Oxide Nanoparticles for Diagnostic Imaging and Management of Neurodegenerative Diseases

<img src=” https://s3.amazonaws.com/production.scholastica/article/92424/large/prnano_992023ga.jpg?1705765455”> Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), and glioblastoma tumors (GB), represent a spectrum of disorders characterized by progressive neuronal degeneration. This gradual deterioration presents significant challenges in early diagnosis and treatment. As a solution, iron oxide nanoparticles (IONPs) have emerged as promising materials due to their diminutive size and inherent biocompatibility, which facilitates bypassing the blood-brain barrier (BBB), thereby serving as effective targeted nanocarriers for neuroprotective therapeutics, offering efficient delivery to the brain. Furthermore, IONPs demonstrate efficacy as T1/T2 contrast agents (CAs), offering a novel diagnostic tool for various NDDs, emphasizing GB. Despite the expanding potential of IONPs in the management of NDDs, a clear gap exists in developing environmentally sustainable synthesis methods. Such methods must adhere to ecological standards and enable the production of nanoparticles capable of efficiently crossing the BBB. This is essential for precisely delivering and monitoring therapeutic interventions in diseases such as AD, PD, and GB. This review systematically explores the potential of green-synthesized IONPs in the context of NDD treatment. In this review, we emphasize different functionalization techniques for IONPs, tackling how these functionalized IONPs can be effective therapeutic approaches for NDDs. Moreover, we discuss biosafety and biocompatibility by covering a range of in vitro biocompatibility studies to analyze the safety of green-synthesized IONPs for the human body. Furthermore, our thorough analysis discussed the current state of green-synthesized IONPs using plant extracts polyphenols, which also act as neuroprotective agents, as proved by studies mentioned in the review.

Intranasal Delivery of Oncolytic Adenovirus XVir-N-31 via Optimized Shuttle Cells Significantly Extends Survival of Glioblastoma-Bearing Mice.

A glioblastoma (GBM) is an aggressive and lethal primary brain tumor with restricted treatment options and a dismal prognosis. Oncolytic virotherapy (OVT) has developed as a promising approach for GBM treatment. However, reaching invasive GBM cells may be hindered by tumor-surrounding, non-neoplastic cells when the oncolytic virus (OV) is applied intratumorally. Using two xenograft GBM mouse models and immunofluorescence analyses, we investigated the intranasal delivery of the oncolytic adenovirus (OAV) XVir-N-31 via virus-loaded, optimized shuttle cells. Intranasal administration (INA) was selected due to its non-invasive nature and the potential to bypass the blood-brain barrier (BBB). Our findings demonstrate that the INA of XVir-N-31-loaded shuttle cells successfully delivered OAVs to the core tumor and invasive GBM cells, significantly prolonged the survival of the GBM-bearing mice, induced immunogenic cell death and finally reduced the tumor burden, all this highlighting the therapeutic potential of this innovative approach. Overall, this study provides compelling evidence for the effectiveness of the INA of XVir-N-31 via shuttle cells as a promising therapeutic strategy for GBM. The non-invasive nature of the INA of OV-loaded shuttle cells holds great promise for future clinical translation. However, further research is required to assess the efficacy of this approach to ultimately progress in human clinical trials.

The Pharmacokinetics of Drugs Delivered to the Upper Nasal Space.

Pharmacokinetics (PK) includes how a drug is absorbed, distributed, metabolized and eliminated. The compartment providing this information is usuallythe plasma. This is as close to the tissue of interest that we can get, although biopsies may be obtained to give "tissue levels" of drugs. Ultimately, the goal of PK is to understand how long the drug is actually engaged with the target in the tissue of interest after a dose has been administered. Most drugs at some point in their development will have been administered intravenously (IV), which acts as the standard for 100% bioavailability. By comparing various routes of administration to IV, the percentage of drug delivered to the plasma, on a dose-normalized basis, can be calculated and is referred to as the "absolute bioavailability". As pharmacology has advanced and more drugs have become available, many older products have been reformulated to be given by routes other than those originally intended (often oral). As the drawbacks of oral (or IV) administration have become better appreciated, non-oral, non-IV formulations and methods of administration have become more popular. Nasal administration is one route that has historically been overlooked as an alternative to oral administration-particularly for products needing rapid and non-invasive access to the target tissue-mostly via the blood stream. But attention is now focused on nasal administration for direct access to the brain, as that has the potential to bypass the blood-brain-barrier (BBB), which not even IV administration can always achieve. Assessing PK for these drugs targeting the brain may require serial sampling of the cerebrospinal fluid (CSF), making PK assessments of CNS drugs more invasive and complex, but still possible in future product development. However, we are now seeing more drugs reformulated for nasal delivery to gain faster systemic levels than oral administration (especially in patients with known or suspected gastrointestinal dysmotility), while avoiding the use of needles. For example, in recent years several different formulations and delivery methods for an old drug, dihydroergotamine (DHE), have been developed and these show very different characteristics, suggesting that delivery to different parts of the nose may have very different PK profiles. This review summarizes the systemic PK of different nasal DHE options that have been, or are being, developed and suggests that delivery of drugs to the upper nasal space (UNS) may represent an optimal target. Further research is required to ascertain if this route could also be utilized for direct administration to the CNS (as an attractive alternative to intrathecal delivery) via the olfactory or trigeminal nerves-but already preclinical data (and some human data) suggest this is entirely possible.

Cerebral delivery of redox-responsive lenalidomide prodrug plus methotrexate for primary central nerve system lymphoma combination therapy.

Primary central nervous system lymphoma (PCNSL) is an extremely malignant CNS tumor with high incidence and mortality rates. Its chemotherapy in the clinic has been restricted owing to unsatisfactory drug distribution in the cerebral tissues. In this study, a redox-responsive prodrug of disulfide-lenalidomide-methoxy polyethylene glycol (LND-DSDA-mPEG) was successfully developed for the cerebral delivery of lenalidomide (LND), and methotrexate (MTX) via subcutaneous (s.c.) administration at the neck for combined anti-angiogenesis and chemotherapy on PCNSL. Both the subcutaneous xenograft tumor model and orthotopic intracranial tumor model demonstrated that the co-delivery of LND and MTX nanoparticles (MTX@LND NPs) may significantly inhibit the growth of lymphoma and effectively prevent liver metastasis by downregulating CD31 and VEGF expression. Moreover, an orthotopic intracranial tumor model further verified that through s.c. administration at the neck, redox-responsive MTX@LND NPs could bypass the blood-brain barrier (BBB), efficiently distribute into brain tissues, and effectively inhibit lymphoma growth in the brain, as detected by magnetic resonance imaging (MRI). Taken together, this biodegradable, biocompatible, and redox-responsive nano-prodrug with highly effective targeted delivery of LND and MTX in the brain through the lymphatic vasculature may provide a facile and feasible treatment strategy for PCNSL in the clinic.

Inactive Trojan Bacteria as Safe Drug Delivery Vehicles Crossing the Blood-Brain Barrier.

Escherichia coli K1 (EC-K1) can bypass the blood-brain barrier (BBB) and cause meningitis. Excitingly, we find the "dead EC-K1" can safely penetrate the BBB because they retain the intact structure and chemotaxis of the live EC-K1, while losing their pathogenicity. Based on this, we develop a safe "dead EC-K1"-based drug delivery system, in which EC-K1 engulf the maltodextrin (MD)-modified therapeutics through the bacteria-specific MD transporter pathway, followed by the inactivation via UV irradiation. We demonstrate that the dead bacteria could carry therapeutics (e.g., indocyanine green (ICG)) and together bypass the BBB after intravenous injection into the mice, delivering ∼3.0-fold higher doses into the brain than free ICG under the same conditions. What is more, all mice remain healthy even after 14 days of intravenous injection of ∼109 CFU of inactive bacteria. As a proof of concept, we demonstrate the developed strategy enables the therapy of bacterial meningitis and glioblastoma in mice.

Lipid-based Nanocarriers via Nose-to-Brain Pathway for Alzheimer's and Parkinson's Disease

Abstract: Neurodegenerative disorders are characterized by the progressive, irreversible deterioration of functions of the central nervous system, especially neurons, that lead to cognitive, motor, and intellectual impairment. Alzheimer's disease (AD) and Parkinson's disease (PD) are the most prevalent forms of neurodegenerative disorders and are predicted to be leading causes of mortality. Although conventional formulations are available for symptomatic treatment of AD and PD, many novel formulations and routes of administration are persistently studied for their better management and nose-to-brain delivery is one of them. This platform has been explored with various nanoformulations for targeted brain delivery. Lipid nanocarriers are known for bypassing the blood-brain barrier (BBB) through nasal delivery, and several drugs have been evaluated in the lipid carrier system. This review focuses on various lipid-based nanocarriers such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsions, nanoemulsions, micelles and cubosomes reported to treat and alleviate the symptoms of AD and PD via nasal route. It gives an overview of key findings of nasal lipid-based nanocarriers and their improved pharmacokinetic parameters and enhanced neuroprotection that may be utilized in the future to explore it commercially.

Feasibility of MRI-guided focused ultrasound-mediated intranasal delivery in a large animal model

Intranasal delivery provides non-invasive delivery of drugs from the nose to the brain bypassing the blood-brain barrier (BBB). We previously reported the focused ultrasound (FUS)-mediated intranasal delivery (FUSIN) of various agents in mice using FUS. However, no study has investigated the feasibility of FUSIN in large animals. The objective of this study was to investigate the feasibility of MR-guided FUS-mediated intranasal delivery in a large animal model. Pigs were used as the large animal model due to their clinical relevance to humans. Fluorescence-labeled albumin was mixed with an MRI contrast agent and administrated intranasally to the pig using a catheter. Followed by intravenous injection of microbubbles, FUS sonication was performed at two brain regions, the cortex and brainstem. T1-weighted MR images showed enhancement of MRI contrast agent at the olfactory region of the pig nose. Fluorescence imaging displayed enhanced fluorescence intensity at the FUS-targeted brain regions. These findings suggest that MR-guided FUS can achieve noninvasive and localized delivery of intranasally administered agents to the brain in large animals.

Neurodegenerative Diseases due to Neurotoxins passing through the Nose-to-Brain Pathway

Three neurodegenerative disorders- Alzheimer’s dementia (ALZ), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS)- share a common feature in their pathogenesis: evidence of mitochondrial dysfunction and reactive oxygen stress. Their pathologic classifications are based on the findings at autopsy based on patterns of protein aggregates in neurons and glial cells. This pathology supports the concept that neurotoxins are a major factor in the etiology of these disorders. There is value in exploring the similarities in the pathogenesis of ALS, Parkinson Disease and Alzheimer Dementia based on non-genetic etiologies. The nose to olfactory pathway feeds sensory input from the nasal cavity to the olfactory bulb and the entorhinal lobe. Another component of these pathways involves two branches of the trigeminal nerve with sensory input to the pons and midbrain. A key factor is their capacity to bypass the blood-brain barrier (BBB). The protection of the brain by the BBB diminishes with age and can be lost with damage from insults as with viral infections. The olfactory nerve is the only cranial nerve with direct exposure to the ambient environment and has a high rate of turnover of sensory receptors. The nasal cavity is being studied for drug delivery and can be used to deliver medications into the central nervous system (CNS. The nose-to-brain pathway may represent a critical avenue of exposure to oxidative neurotoxins. Neurotoxic mycotoxins are a major risk to humans. Neurotoxins may be amplified by the nose-to-brain pathway. The pathology shows similarities to prion disease. These neurotoxins are highly fat-soluble and tend to accumulate in mitochondria and synaptic vesicles. Neurotoxins in synaptic vesicles can migrate from neuron to neuron. There is evidence of chronic fungal infections in ALS patients that secret neurotoxic and immunotoxic mycotoxins leading to progressive immune suppression. The nose-to-olfactory pathway may amplify neurotoxins levels in the brain. If Parkinson Disease and ALZ are due to systemic poisonings, the source of neurotoxins may be episodic and lead to autoimmune disease.

Overcoming the Blood-Brain Barrier for Gene Therapy via Systemic Administration of GSH-Responsive Silica Nanocapsules.

CRISPR genome editing canpotentially treat the root causes of many genetic diseases, including central nervous system (CNS) disorders. However, the promise of brain-targeted therapeutic genome editing relies on the efficient delivery of biologics bypassing the blood-brain barrier (BBB), which represents a major challenge in the development of CRISPR therapeutics.Wecreated and screeneda library of glutathione (GSH)-responsive silica nanocapsules (SNCs) for brain targeted delivery of biologics via systemic administration. In vivo studies demonstrate that systemically delivered SNCs conjugated with glucose and rabies virus glycoprotein peptide under glycemic control can efficiently bypass the intact BBB, enabling brain-wide delivery of various biologics including CRISPR genome editors targeting different genes in both Ai14 reporter mice and wild-type mice. In particular, up to 28% neuron editing via systemic delivery of Cre mRNA in Ai14 mice, up to 6.1% amyloid precursor protein (App) gene editing (resulting in 19.1% reduction in the expression level of intact APP), and up to 3.9% tyrosine hydroxylase (Th) gene editing (resulting in 30.3% reduction in the expression level of TH) in wild-type mice are observed. This versatile SNC nanoplatform may offer a novel strategy for the treatment of CNS disorders including Alzheimer's, Parkinson's, and Huntington's disease.

Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy

Bacteria can bypass the blood-brain barrier (BBB), suggesting the possibility of employment of bacteria for combating central nervous system diseases. Herein, we develop a bacteria-based drug delivery system for glioblastoma (GBM) photothermal immunotherapy. The system, which we name as ‘Trojan bacteria’, consists of bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected bacteria bypass the BBB, targeting and penetrating GBM tissues. Upon 808 nm-laser irradiation, the photothermal effects produced by ICG allow the destruction of bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual bacteria are effectively eliminated from the body, supporting the potential therapeutic use of this system.

Nose to Brain Drug Delivery System

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. The nasal mucosa is nearby the brain, cerebrospinal fluid (CSF) and the drug concentrations can exceed plasma concentrations. a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.

Osmotic Pump-based Drug-delivery for In Vivo Remyelination Research on the Central Nervous System.

Demyelination has been identified in not only multiple sclerosis (MS), but also other central nervous system diseases such as Alzheimer's disease and autism. As evidence suggests that remyelination can effectively ameliorate the disease symptoms, there is an increasing focus on drug development to promote the myelin regeneration process. Thus, a region-selectable and result-reliable drug delivery technique is required to test the efficiency and specificity of these drugs in vivo. This protocol introduces the osmotic pump implant as a new drug delivery approach in the lysolecithin-induced demyelination mouse model. The osmotic pump is a small implantable device that can bypass the blood-brain barrier (BBB) and deliver drugs steadily and directly to specific areas of the mouse brain. It can also effectively improve the bioavailability of drugs such as peptides and proteins with a short half-life. Therefore, this method is of great value to the field of central nervous system myelin regeneration research.

Convection-enhanced drug delivery for glioblastoma: a review

Convection-enhanced delivery (CED) is a method of targeted, local drug delivery to the central nervous system (CNS) that bypasses the blood-brain barrier (BBB) and permits the delivery of high-dose therapeutics to large volumes of interest while limiting associated systemic toxicities. Since its inception, CED has undergone considerable preclinical and clinical study as a safe method for treating glioblastoma (GBM). However, the heterogeneity of both, the surgical procedure and the mechanisms of action of the agents studied-combined with the additional costs of performing a trial evaluating CED-has limited the field's ability to adequately assess the durability of any potential anti-tumor responses. As a result, the long-term efficacy of the agents studied to date remains difficult to assess. We searched PubMed using the phrase "convection-enhanced delivery and glioblastoma". The references of significant systematic reviews were also reviewed for additional sources. Articles focusing on physiological and physical mechanisms of CED were included as well as technological CED advances. We review the history and principles of CED, procedural advancements and characteristics, and outcomes from key clinical trials, as well as discuss the potential future of this promising technique for the treatment of GBM. While the long-term efficacy of the agents studied to date remains difficult to assess, CED remains a promising technique for the treatment of GBM.

Olfactory mucosa stem cells delivery via nasal route: a simple way for the treatment of Parkinson disease.

Finding a simple and effective way for transferring cells to the brain lesion site with minimum side effects mounts a challenge in cell therapy. Cell delivery via nasal route using the bypassing the blood-brain barrier (BBB) property is a simple and non-invasive strategy without serious complications such as trauma. Therefore, it is a suitable technique to treat neurodegenerative disorders like Parkinson's disease (PD). Olfactory ectomesenchymal stem cells (OE-MSCs) located in the lamina propria of olfactory mucosa could be differentiated into dopaminergic neurons under in vitro and in vivo conditions. Thus, OE-MSCs represent a good source of Parkinson's stem cell-based therapy. In this research, we studied thirty male rats (n = 10 in each group) in three control (Ctl), lesion (LE), and intranasal administration (INA) groups to investigate the therapeutic effect of intranasal injection of OE-MSCs in the Parkinson's animal models. To do so, we examined the homing variation of OE-MSCs in different brain regions such as olfactory bulb (OB), cortex, striatum (Str), hippocampus (HPC), and substantia nigra (SN). The results of real-time PCR and immunohistochemistry (IHC) analysis showed the expression of dopaminergic neuron markers such as PITX3, PAX2, PAX5 (as dopaminergic neurons markers), tyrosine hydroxylase (TH), and dopamine transporter (DAT) 2 months after INA of 1 × 106 OE-MSCs. The results confirmed that IN OE-MSCs delivery into the central nervous system (CNS) was powerful enough to improve the behavioral functions in the animal models of PD.

Inhibition of Tau aggregation with BSc3094 reduces Tau and decreases cognitive deficits in rTg4510 mice.

BackgroundOne of the major hallmarks of Alzheimer's disease (AD)is the aberrant modification and aggregation of the microtubule‐associated protein Tau . The extent of Tau pathology correlates with cognitive decline, strongly implicating Tau in the pathogenesis of the disease. Because the inhibition of Tau aggregation may be a promising therapeutic target, we tested the efficacy of BSc3094, an inhibitor of Tau aggregation, in reducing Tau pathology and ameliorating the disease symptoms in transgenic mice.MethodsMice expressing human Tau with the P301L mutation (line rTg4510) were infused with BSc3094 into the lateral ventricle using Alzet osmotic pumps connected to a cannula that was placed on the skull of the mice, thus bypassing the blood‐brain barrier (BBB) . The drug treatment lasted for 2 months, and the effect of BSc3094 on cognition and on reversing hallmarks of Tau pathology was assessed.ResultsBSc3094 significantly reduced the levels of Tau phosphorylation and sarkosyl‐insoluble Tau. In addition, the drug improved cognition in different behavioral tasks and reduced anxiety‐like behavior in the transgenic mice used in the study.ConclusionsOur in vivo investigations demonstrated that BSc3094 is capable of partially reducing the pathological hallmarks typically observed in Tau transgenic mice, highlighting BSc3094 as a promising compound for a future therapeutic approach for AD.

Catheter placement selection for convection-enhanced delivery of therapeutic agents to brain tumors

Background: Convection-enhanced delivery (CED) of therapeutic agents to brain tumors allows clinicians to bypass the blood-brain barrier (BBB) to infuse virus therapy, biological, or chemotherapy directly into a brain tumor through convection. However, the effectiveness of infusions via CED may depend on catheter placement. Methods: This study used diffusion maps from magnetic resonance imaging (MRI) of human brain tumors and computational fluid dynamics (CFD) simulations to assess therapy volume distribution percentages based on catheter placement locations. Results: The primary outcome showed differences in volume distribution based on the catheter placement location. Total tumor volume filled ranged from 144.40 mm3 to 317.98 mm3. Percent filled of tumor volume ranged from 2.87% to 6.32%. Conclusions: The selection of the location for catheter placement using the region with the highest volume filled may provide optimal therapeutic effect. The researchers conclude that CFD may provide guidance for catheter placement in CED of therapeutic agents.

Photosensitizer delivery by fibrin glue: potential for bypassing the blood-brain barrier.

Fibrin glue (FG) has potential as a delivery vehicle for photosensitizer directly to the resection cavity, so it may bypass the blood-brain barrier (BBB) and increase the concentration of successfully delivered photosensitizer. A specialized form of photodynamic therapy (PDT), photochemical internalization (PCI), which involves both photosensitizer and chemotherapeutic agent internalization, can locally inhibit the growth of cells. This will allow the reduction of recurrence of malignant gliomas around surgical resection. This study will look at the efficacy of FG loaded with drugs in mediating both PDT and PCI in inhibiting 3-dimensional tumor spheroid growth in vitro. Experiments were conducted on spheroids comprised of F98 glioma cells using photosensitizer AlPcS2a and chemotherapeutic drug bleomycin (BLM). At 2-, 24-, 48-, and 72-h increments, supernatant covering an FG layer within a well was collected and replaced by fresh medium, then added to spheroid-containing wells, which contained the respective chemicals for PDT and PCI. The wells were then exposed to light treatment from a diode laser, and after, spheroid growth was monitored for a period of 14days. Significant spheroid growth inhibition was observed in both PDT and PCI modalities, but was far greater in PCI. Additionally, complete growth suppression was achieved via PCI at the highest radiant exposure. Achieving a slow photosensitizer release, significant F98 spheroid inhibition was observed in FG-mediated PDT and PCI. The present study showed BLM-PCI was the most efficacious of the two modalities.

Recombinant BRICHOS chaperone domains delivered to mouse brain parenchyma by focused ultrasound and microbubbles are internalized by hippocampal and cortical neurons

The BRICHOS domain is found in human precursor proteins associated with cancer, dementia (Bri2) and amyloid lung disease (proSP-C). Recombinant human (rh) proSP-C and Bri2 BRICHOS domains delay amyloid-β peptide (Aβ) fibril formation and reduce associated toxicity in vitro and their overexpression reduces Aβ neurotoxicity in animal models of Alzheimer's disease. After intravenous administration in wild-type mice, rh Bri2, but not proSP-C, BRICHOS was detected in the brain parenchyma, suggesting that Bri2 BRICHOS selectively bypasses the blood-brain barrier (BBB). Here, our objective was to increase the brain delivery of rh proSP-C (trimer of 18 kDa subunits) and Bri2 BRICHOS (monomer to oligomer of 15 kDa subunits) using focused ultrasound combined with intravenous microbubbles (FUS + MB), which enables targeted and transient opening of the BBB. FUS + MB was targeted to one hemisphere of wild type mice and BBB opening in the hippocampal region was confirmed by magnetic resonance imaging. Two hours after FUS + MB brain histology showed no signs of tissue damage and immunohistochemistry showed abundant delivery to the brain parenchyma in 13 out of 16 cases given 10 mg/kg of proSP-C or Bri2 BRICHOS domains. The Bri2, but not proSP-C BRICHOS domain was detected also in the non-targeted hemisphere. ProSP-C and Bri2 BRICHOS domains were taken up by a subset of neurons in the hippocampus and cortex, and were detected to a minor extent in early endosomes. These results indicate that rh Bri2, but not proSP-C, BRICHOS, can be efficiently delivered into the mouse brain parenchyma and that both BRICHOS domains can be internalized by cell-specific mechanisms.