Improving In Vivo Brain Delivery of Monoclonal Antibody Using Novel Cyclic Peptides

Many proteins can be used to treat brain diseases; however, the presence of the blood–brain barrier (BBB) creates an obstacle to delivering them into the brain. Previously, various molecules were delivered through the paracellular pathway of the BBB via its modulation, using ADTC5 and HAV6 peptides. This study goal was to design new cyclic peptides with N-to-C terminal cyclization for better plasma stability and modulation of the BBB. Cyclic HAVN1 and HAVN2 peptides were derived from a linear HAV6 peptide. Linear and N-to-C terminal cyclic ADTHAV peptides were designed by combining the sequences of ADTC5 and HAV6. These novel cyclic peptides were used to deliver an IRdye800CW-labeled IgG monoclonal antibody into the brain. Cyclic HAVN1 and HAVN2 peptides deliver IgG into the brain, while the parent linear HAV6 peptide does not. Cyclic and linear ADTHAV and ADTC5 peptides enhanced brain delivery of IgG mAb, in which cyclic ADTHAV peptide was better than linear ADTHAV (p = 0.07). Cyclic ADTHAV and ADTC5 influenced the distribution of IgG mAb in other organs while HAV6, HAVN1 and HAVN2 did not. In summary, the novel cyclic peptides are generally better BBB modulators than their linear counterparts for delivering IgG mAb into the brain.

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Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood–brain barrier permeability for drug delivery to the brain in a non-human primate

Journal of Controlled Release ◽

10.1016/j.jconrel.2021.06.009 ◽

2021 ◽

Author(s):

Keisuke Tachibana ◽

Yosuke Hashimoto ◽

Keisuke Shirakura ◽

Yoshiaki Okada ◽

Ryuichi Hirayama ◽

...

Keyword(s):

Drug Delivery ◽

Monoclonal Antibody ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Safety And Efficacy ◽

Barrier Permeability ◽

Blood Brain Barrier Permeability ◽

Brain Barrier Permeability ◽

The Brain ◽

Human Primate

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The Potential Roles of Blood–Brain Barrier and Blood–Cerebrospinal Fluid Barrier in Maintaining Brain Manganese Homeostasis

Nutrients ◽

10.3390/nu13061833 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1833

Author(s):

Shannon Morgan McCabe ◽

Ningning Zhao

Keyword(s):

Cerebrospinal Fluid ◽

Blood Brain Barrier ◽

Blood Circulation ◽

Critical Role ◽

Systemic Circulation ◽

Brain Parenchyma ◽

Brain Barrier ◽

Blood Brain ◽

The Brain

Manganese (Mn) is a trace nutrient necessary for life but becomes neurotoxic at high concentrations in the brain. The brain is a “privileged” organ that is separated from systemic blood circulation mainly by two barriers. Endothelial cells within the brain form tight junctions and act as the blood–brain barrier (BBB), which physically separates circulating blood from the brain parenchyma. Between the blood and the cerebrospinal fluid (CSF) is the choroid plexus (CP), which is a tissue that acts as the blood–CSF barrier (BCB). Pharmaceuticals, proteins, and metals in the systemic circulation are unable to reach the brain and spinal cord unless transported through either of the two brain barriers. The BBB and the BCB consist of tightly connected cells that fulfill the critical role of neuroprotection and control the exchange of materials between the brain environment and blood circulation. Many recent publications provide insights into Mn transport in vivo or in cell models. In this review, we will focus on the current research regarding Mn metabolism in the brain and discuss the potential roles of the BBB and BCB in maintaining brain Mn homeostasis.

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Lipid Nanoparticles Improve the Uptake of α-Asarone Into the Brain Parenchyma: Formulation, Characterization, In Vivo Pharmacokinetics, and Brain Delivery

AAPS PharmSciTech ◽

10.1208/s12249-020-01832-8 ◽

2020 ◽

Vol 21 (8) ◽

Author(s):

Prakash Ramalingam ◽

Palanivel Ganesan ◽

D. S. Prabakaran ◽

Pardeep K. Gupta ◽

Sriramakamal Jonnalagadda ◽

...

Keyword(s):

Lipid Nanoparticles ◽

Brain Parenchyma ◽

Brain Delivery ◽

The Brain ◽

In Vivo Pharmacokinetics

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Pharmacological Modulation of Blood–Brain Barrier Permeability by Kinin Analogs in Normal and Pathologic Conditions

Pharmaceuticals ◽

10.3390/ph13100279 ◽

2020 ◽

Vol 13 (10) ◽

pp. 279

Author(s):

Dina Sikpa ◽

Lisa Whittingstall ◽

Martin Savard ◽

Réjean Lebel ◽

Jérôme Côté ◽

...

Keyword(s):

Blood Brain Barrier ◽

Brain Barrier ◽

Brain Drug Delivery ◽

Blood Brain ◽

Brain Barrier Permeability ◽

Radiation Induced ◽

B2 Receptors ◽

Peptide Agonist ◽

The Brain

The blood–brain barrier (BBB) is a major obstacle to the development of effective diagnostics and therapeutics for brain cancers and other central nervous system diseases. Peptide agonist analogs of kinin B1 and B2 receptors, acting as BBB permeabilizers, have been utilized to overcome this barrier. The purpose of the study was to provide new insights for the potential utility of kinin analogs as brain drug delivery adjuvants. In vivo imaging studies were conducted in various animal models (primary/secondary brain cancers, late radiation-induced brain injury) to quantify BBB permeability in response to kinin agonist administrations. Results showed that kinin B1 (B1R) and B2 receptors (B2R) agonists increase the BBB penetration of chemotherapeutic doxorubicin to glioma sites, with additive effects when applied in combination. B2R agonist also enabled extravasation of high-molecular-weight fluorescent dextrans (155 kDa and 2 MDa) in brains of normal mice. Moreover, a systemic single dose of B2R agonist did not increase the incidence of metastatic brain tumors originating from circulating breast cancer cells. Lastly, B2R agonist promoted the selective delivery of co-injected diagnostic MRI agent Magnevist in irradiated brain areas, depicting increased vascular B2R expression. Altogether, our findings suggest additional evidence for using kinin analogs to facilitate specific access of drugs to the brain.

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Characterization of the Blood–Brain Barrier Integrity and the Brain Transport of SN-38 in an Orthotopic Xenograft Rat Model of Diffuse Intrinsic Pontine Glioma

Pharmaceutics ◽

10.3390/pharmaceutics12050399 ◽

2020 ◽

Vol 12 (5) ◽

pp. 399 ◽

Cited By ~ 2

Author(s):

Catarina Chaves ◽

Xavier Declèves ◽

Meryam Taghi ◽

Marie-Claude Menet ◽

Joelle Lacombe ◽

...

Keyword(s):

Blood Brain Barrier ◽

Diffuse Intrinsic Pontine Glioma ◽

Brain Barrier ◽

Brain Delivery ◽

Pontine Glioma ◽

Anticancer Drug Delivery ◽

Blood Brain ◽

The Brain

The blood–brain barrier (BBB) hinders the brain delivery of many anticancer drugs. In pediatric patients, diffuse intrinsic pontine glioma (DIPG) represents the main cause of brain cancer mortality lacking effective drug therapy. Using sham and DIPG-bearing rats, we analyzed (1) the brain distribution of 3-kDa-Texas red-dextran (TRD) or [14C]-sucrose as measures of BBB integrity, and (2) the role of major ATP-binding cassette (ABC) transporters at the BBB on the efflux of the irinotecan metabolite [3H]-SN-38. The unaffected [14C]-sucrose or TRD distribution in the cerebrum, cerebellum, and brainstem regions in DIPG-bearing animals suggests an intact BBB. Targeted proteomics retrieved no change in P-glycoprotein (P-gp), BCRP, MRP1, and MRP4 levels in the analyzed regions of DIPG rats. In vitro, DIPG cells express BCRP but not P-gp, MRP1, or MRP4. Dual inhibition of P-gp/Bcrp, or Mrp showed a significant increase on SN-38 BBB transport: Cerebrum (8.3-fold and 3-fold, respectively), cerebellum (4.2-fold and 2.8-fold), and brainstem (2.6-fold and 2.2-fold). Elacridar increased [3H]-SN-38 brain delivery beyond a P-gp/Bcrp inhibitor effect alone, emphasizing the role of another unidentified transporter in BBB efflux of SN-38. These results confirm a well-preserved BBB in DIPG-bearing rats, along with functional ABC-transporter expression. The development of chemotherapeutic strategies to circumvent ABC-mediated BBB efflux are needed to improve anticancer drug delivery against DIPG.

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Neutrophil affinity for PGP and HAIYPRH (T7) peptide dual-ligand functionalized nanoformulation enhances the brain delivery of tanshinone IIA and exerts neuroprotective effects against ischemic stroke by inhibiting proinflammatory signaling pathways

New Journal of Chemistry ◽

10.1039/c8nj04819c ◽

2018 ◽

Vol 42 (23) ◽

pp. 19043-19061

Author(s):

Yutao Li ◽

Chiying An ◽

Danan Han ◽

Yanxin Dang ◽

Xin Liu ◽

...

Keyword(s):

Ischemic Stroke ◽

Physicochemical Properties ◽

Signaling Pathways ◽

Blood Brain Barrier ◽

Tanshinone Iia ◽

Brain Barrier ◽

Brain Delivery ◽

Neuroprotective Effects ◽

The Poor ◽

The Brain

A great challenge to the therapy of ischemic stroke is the poor physicochemical properties and inability of the drug to cross the blood–brain barrier (BBB).

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EXTH-02. THE BLOOD BRAIN BARRIER (BBB) PERMEABILITY IS ALTERED BY TUMOR TREATING FIELDS (TTFIELDS) IN VIVO

Neuro-Oncology ◽

10.1093/neuonc/noz175.336 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi82-vi82 ◽

Cited By ~ 2

Author(s):

Ellina Schulz ◽

Almuth F Kessler ◽

Ellaine Salvador ◽

Dominik Domröse ◽

Malgorzata Burek ◽

...

Keyword(s):

Brain Tumors ◽

Blood Brain Barrier ◽

Brain Barrier ◽

Dce Mri ◽

Tumor Treating Fields ◽

Blood Brain ◽

Vessel Structure ◽

Bbb Permeability ◽

The Brain

Abstract OBJECTIVE For glioblastoma patients Tumor Treating Fields (TTFields) have been established as adjuvant therapy. The blood brain barrier (BBB) tightly controls the influx of the majority of compounds from blood to brain. Therefore, the BBB may block delivery of drugs for treatment of brain tumors. Here, the influence of TTFields on BBB permeability was assessed in vivo. METHODS Rats were treated with 100 kHz TTFields for 72 h and thereupon i.v. injected with Evan’s Blue (EB) which directly binds to Albumin. To evaluate effects on BBB, EB was extracted after brain homogenization and quantified. In addition, cryosections of rat brains were prepared following TTFields application. The sections were stained for tight junction proteins Claudin-5 and Occludin and for immunoglobulin G (IgG) to assess vessel structure. Furthermore, serial dynamic contrast-enhanced DCE-MRI with Gadolinium contrast agent was performed before and after TTFields application. RESULTS TTFields application significantly increased the EB accumulation in the rat brain. In TTFields-treated rats, the vessel structure became diffuse compared to control cryosections of rat brains; Claudin 5 and Occludin were delocalized and IgG was found throughout the brain tissue. Serial DCE-MRI demonstrated significantly increased accumulation of Gadolinium in the brain, observed directly after 72 h of TTFields application. The effect of TTFields on the BBB disappeared 96 h after end of treatment and no difference in contrast enhancement between controls and TTFields treated animals was detectable. CONCLUSION By altering BBB integrity and permeability, application of TTFields at 100 kHz may have the potential to deliver drugs to the brain, which are unable to cross the BBB. Utilizing TTFields to open the BBB and its subsequent recovery could be a clinical approach of drug delivery for treatment of brain tumors and other diseases of the central nervous system. These results will be further validated in clinical Trials.

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Nose-to-Brain Delivery

Pharmaceutics ◽

10.3390/pharmaceutics12020138 ◽

2020 ◽

Vol 12 (2) ◽

pp. 138 ◽

Cited By ~ 2

Author(s):

Paolo Giunchedi ◽

Elisabetta Gavini ◽

Maria Cristina Bonferoni

Keyword(s):

Side Effects ◽

Blood Brain Barrier ◽

Neurological Diseases ◽

Systemic Administration ◽

Brain Barrier ◽

Brain Delivery ◽

Special Issue ◽

Drug Bioavailability ◽

Blood Brain ◽

The Brain

Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”.

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Boosting the Brain Delivery of Atazanavir through Nanostructured Lipid Carrier-Based Approach for Mitigating NeuroAIDS

Pharmaceutics ◽

10.3390/pharmaceutics12111059 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1059

Author(s):

Saif Ahmad Khan ◽

Saleha Rehman ◽

Bushra Nabi ◽

Ashif Iqubal ◽

Nida Nehal ◽

...

Keyword(s):

Targeted Delivery ◽

Drug Loading ◽

Entrapment Efficiency ◽

Fold Increase ◽

Pharmacokinetic Studies ◽

Nanostructured Lipid Carrier ◽

Brain Delivery ◽

The Brain

Atazanavir (ATZ) presents poor brain availability when administered orally, which poses a major hurdle in its use as an effective therapy for the management of NeuroAIDS. The utilization of nanostructured lipid carriers (NLCs) in conjunction with the premeditated use of excipients can be a potential approach for overcoming the limited ATZ brain delivery. Methods: ATZ-loaded NLC was formulated using the quality by design-enabled approach and further optimized by employing the Box–Behnken design. The optimized nanoformulation was then characterized for several in vitro and in vivo assessments. Results: The optimized NLC showed small particle size of 227.6 ± 5.4 nm, high entrapment efficiency (71.09% ± 5.84%) and high drug loading capacity (8.12% ± 2.7%). The release pattern was observed to be biphasic exhibiting fast release (60%) during the initial 2 h, then trailed by the sustained release. ATZ-NLC demonstrated a 2.36-fold increase in the cumulative drug permeated across the rat intestine as compared to suspension. Pharmacokinetic studies revealed 2.75-folds greater Cmax in the brain and 4-fold improvement in brain bioavailability signifying the superiority of NLC formulation over drug suspension. Conclusion: Thus, NLC could be a promising avenue for encapsulating hydrophobic drugs and delivering it to their target site. The results suggested that increase in bioavailability and brain-targeted delivery by NLC, in all plausibility, help in improving the therapeutic prospects of atazanavir.

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