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Convection-enhanced delivery (CED) is a method enabling effective delivery of therapeutics into the brain by direct perfusion of large tissue volumes. The procedure requires the use of catheters and an optimized injection procedure. This protocol describes a methodology for CED of an antibody into a mouse brain.
Convection-enhanced delivery (CED) is a neurosurgical technique enabling effective perfusion of large brain volumes using a catheter system. Such an approach provides a safe delivery method by-passing the blood brain barrier (BBB), thus allowing treatment with therapeutics with poor BBB-permeability or those for which systemic exposure is not desired, e.g., due to toxicity. CED requires optimization of the catheter design, injection protocol, and properties of the infusate. With this protocol we describe how to perform CED of a solution containing up to 20 µg of an antibody into the caudate putamen of mice. It describes preparation of step catheters, testing them in vitro and performing the CED in mice using a ramping injection program. The protocol can be readily adjusted for other infusion volumes and can be used for injecting various tracers or pharmacologically active or inactive substances, including chemotherapeutics, cytokines, viral particles, and liposomes.
The blood brain barrier (BBB) forms a semipermeable border separating the central nervous system (CNS) from the blood circulation. Reaching the CNS with therapeutics is however necessary in context of various diseases, like brain tumors, Alzheimer’s disease (AD) or Parkinson’s disease (PD) among others1. This becomes important in the development of new therapies, especially if the tested drug exhibits poor BBB permeability or its systemic exposure can lead to dangerous toxicity1,2. Some of the clinically used antibodies display both of these features. A solution to this prob....
All methods described here have been approved by the Swiss Cantonal Veterinary Office under license number ZH246/15.
1. Preparation of the Step Catheters
This protocol enables preparation of step catheters (Figure 1) for use in the CED procedure in a laboratory environment. In order to control the catheters for leakage, reflux along the needle tract and clogging, we recommend performing injections of a dye, e.g., trypan blue solution, into an agarose block. Figure 3 depicts a cloud of trypan blue forming after injection of 1 µL at 0.5 µL/minute using a CED catheter (Figure 3A
Convection-enhanced delivery, or pressure-mediated drug infusion into the brain, was first proposed in the early 19903. This approach promises perfusion of large brain volumes behind the blood brain barrier in a controlled manner2. However, so far, only a few clinical trials have been performed using this approach, partially because CED in a clinical setup has shown to be technically demanding24,25. Recent developme.......
This work was supported by grants of the University of Zurich (FK-15-057), the Novartis Foundation for medical-biological Research (16C231) and Swiss Cancer Research (KFS-3852-02-2016, KFS-4146-02-2017) to Johannes vom Berg and BRIDGE Proof of Concept (20B1-1_177300) to Linda Schellhammer.
....Name | Company | Catalog Number | Comments |
10 μL syringe | Hamilton | 7635-01 | |
27 G blunt end needle | Hamilton | 7762-01 | |
Agarose | Promega | V3121 | |
Atipamezol | Janssen | ||
Bone wax | Braun | 1029754 | |
Buprenorphine | Indivior Schweiz AG | ||
Carprofen | Pfizer AG | ||
Dental drill bits, steel, size ISO 009 | Hager & Meisinger | 1RF009 | |
Ethanol 100% | Reuss-Chemie AG | 179-VL03K-/1 | |
Fentanyl | Helvepharm AG | ||
FITC-Dextran, 2000 kDa | Sigma Aldrich | FD2000S | |
Flumazenil | Labatec Pharma AG | ||
Formaldehyde | Sigma Aldrich | F8775-500ML | |
High viscosity cyanoacrylate glue | Migros | ||
Iodine solution | Mundipharma | ||
Medetomidin | Orion Pharma AG | ||
Microforge | Narishige | MF-900 | |
Midazolam | Roche Pharma AG | ||
Ophthalmic ointment | Bausch + Lomb | Vitamin A Blache | |
PBS | ThermoFischer Scientific | 10010023 | |
Polyclonal goat anti-rat IgG (H+L) antibody coupled with Alexa Fluor 647 | Jackson Immuno | ||
Scalpels | Braun | BB518 | |
Silica tubing internal diameter 0.1 mm, wall thickness of 0.0325 mm | Postnova | Z-FSS-100165 | |
Stereotactic frame for mice | Stoelting | 51615 | |
Stereotactic robot | Neurostar | Drill and Injection Robot | |
Succrose | Sigma Aldrich | S0389-500G | |
Topical tissue adhesive | Zoetis | GLUture | |
Trypan blue | ThermoFischer Scientific | 15250061 | |
Water | Bichsel | 1000004 |
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