Event Abstract

Back to Event

Convection-enhanced delivery as a method of delivering therapeutic agents in the brain of laboratory animals

Dimitrios Giakoumettis1*, Anastasia S. Tsingotzidou2, Aristeidis Kritis3 and Nicolas Foroglou4
  • 1 Neurosurgical Resident, Greece
  • 2 Aristotle University, Veterinary School, Greece
  • 3 Aristotle University, Medical School, Greece
  • 4 Aristotle University, A' Neurosurgical Clinic,, Greece

Background Malignant gliomas are known to be the most common pathology of brain tumors and come from the brain cells which constitute neuroglia, that is to say astrocytes, oligodendrocytes ependymal cells and microglia. The worldwide incidence rate of primary malignant glioma according to Central Brain Tumor Registry of the United States was 3.4 per 100,000 population for 2008-2012 (1). Despite surgical and medical advancements the 5-year survival rate for malignant gliomas is 6% and for the most aggressive form of them glioblastoma multiform 3.4%. Dealing with malignant gliomas remains challenging and median survival ranges from 6 months to 24 months(2). Therefore there is a need for novel therapeutic strategies and techniques such as convection enhanced delivery (CED). It is a new technique of delivering a drug directly to targeted sites. Small or large molecules can be distributed in significant volumes of brain tissue bypassing blood-brain barrier avoiding systemic side effects. The main objective of CED is to achieve diffuse homogenous distribution of the agent throughout the tumor and into the adjacent area of tumor cell-infiltrated brain parenchyma. Methods-Material Delivery of therapeutic agents in the brain can be achieved by two main routes. The first is systemic delivery and the second is local delivery. Even though systemic delivery routes are not the most efficient approach for achieving high drug concentrations in Central Nervous System (CNS), they are convenient and well accepted by laboratory animals and patients. There are three routinely used procedures for systemic delivery: the intravenous injection, the intraperitoneal injection and the oral gavage. Local delivery procedure includes intratumoral bolus injection, surgical implantation of drug-loaded polymer matrices in the brain, intraarterial injection and convection enhanced delivery (3). In our establishment Wistar rats with implanted C6 glioma cell line in the brain underwent under general anesthesia a surgical operation for CED, 7 days after the cell implantation. A skin incision was made and bregma, coronal and sagital sutures were recognized. At the same coordinates of cell implantation, which is at 2 mm in front of coronal suture, 2 mm right to sagital suture and 3 mm depth, CED was performed. In order to perform CED a control rate syringe pump, a system of catheters, syringes of 22G and winged infusion set (butterfly needles) of 27G are needed. A drug was then infused through our system with a specific rate and duration in order to be infused in the extracellular matrix. Specifically the butterfly needle was inserted inside the brain parenchyma at the aforementioned coordinates and was left there inert for 3’. Then the infusion started at the specific rates of: • 0,1 μl/min for 5 min, • 0,2 μl/min for 5 min, • 0,5 μl/min for 5 min, • 0,8 μl/min for 7,5 min. At the end of the infusion the needle remained again inert for 3’ and was removed afterwards. The animal recovered under heat light and was given orally analgesic medication. Discussion CED is performed in our establishment and various drugs are being tested. At this time being a plant extract is being tested and the results of its effectiveness are expected in a couple of months. Malignant gliomas are the most deadly form of brain cancer with poor prognosis and median survival less than 2 years. Despite surgical therapy, radiotherapy and chemotherapy they remain a formidable foe. Thus it is imperative that new methods and new chemotherapeutic agents for their treatment must be developed over the years. Malignant gliomas are a very aggressive form of brain cancer which is characterized by its infiltration rate as well by tumor center necrosis and neovascularization. Although they partially disrupt the blood-brain barrier (4), it seems that the intravenous chemotherapeutic agents have little effect on the glioma, probably due to the fact that the chemotherapeutic agents are not specific for brain gliomas and target all of neuroglia. Furthermore it is well known that every intravenous agent has its systematic side-effects due to its metabolization through the liver or the kidneys. Besides its side-effects, it must be taken into consideration that intravenous injection of chemotherapy is a procedure that is not well tolerated by many patients, as each session demands the patient to visit a chemotherapy center and be punctured every time. On the other hand administration of the agents per os has its disadvantages. Although the route of administration is easier, the bioavailability of the drugs diminishes as it passes through the gastrointestinal tract before it enters the systematic circulation. CED seems to be promising enough because it is a method that bypasses the blood stream and targets specific areas of the brain (5). The chemotherapeutic agent is administered right to the center of the tumor and due to the rate and duration of administration it is diffused in the extracellular matrix without compromising healthy cells. However this technique is not perfect and has some problems that need to be addressed. Firstly, there are no special catheters that can be inserted in the brain without causing brain shifting or reflux. Secondly, the rate of infusion differs according to the physical characteristics of each brain tumor which are yet to be documented. In that way no one can truly foretell the spatial distribution of the chemotherapeutic agent or the amount of drug that had a reflux (6, 7). Last but not least the composition of the drug plays the most important role. The administration via CED is documented in the literature to have a wide variety of size or composition of the agents, such as nanoparticles, macromolecules, immunotoxins, liposomes or even vectors and bacteriophages (8) which can be used in the future for gene therapy (9-11). Although CED seems a very promising method of drug administration targeting specific areas bypassing the blood-brain barrier and avoiding any systematic side-effects, its failure to deal with malignant gliomas is only due to the nature of the disease. Nevertheless, it is in our belief that a combined approach of gene therapy with CED will be an answer to gliomas, but their benefits are yet to come.

Figure 1
Image
Figure 2
Image
Figure 3
Image

References

1. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-Oncology. 2015 October 1, 2015;17(suppl 4):iv1-iv62.
2. Gupta T, Sarin R. Poor-prognosis high-grade gliomas: evolving an evidence-based standard of care. Lancet Oncol. 2002 Sep;3(9):557-64.
3. Sheleg SV, Korotkevich EA, Zhavrid EA, Muravskaya GV, Smeyanovich AF, Shanko YG, et al. Local chemotherapy with cisplatin-depot for glioblastoma multiforme. J Neurooncol. 2002 Oct;60(1):53-9.
4. Wolburg H, Noell S, Fallier-Becker P, Mack AF, Wolburg-Buchholz K. The disturbed blood-brain barrier in human glioblastoma. Mol Aspects Med. 2012 Oct-Dec;33(5-6):579-89.
5. Groothuis DR, Benalcazar H, Allen CV, Wise RM, Dills C, Dobrescu C, et al. Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res. 2000 Feb 21;856(1-2):281-90.
6. Ian F. Parney, Sandeep Kunwar, Michael McDermott, Mitchel Berger, Michael Prados, Soonmee Cha, et al. Neuroradiographic changes following convection-enhanced delivery of the recombinant cytotoxin interleukin 13—PE38QQR for recurrent malignant glioma. Journal of Neurosurgery. 2005;102(2):267-75.
7. Rosenbluth KH, Luz M, Mohr E, Mittermeyer S, Bringas J, Bankiewicz KS. Design of an in-dwelling cannula for convection-enhanced delivery. J Neurosci Methods. 2011 Mar 15;196(1):118-23.
8. Ksendzovsky A, Walbridge S, Saunders RC, Asthagiri AR, Heiss JD, Lonser RR. Convection-enhanced delivery of M13 bacteriophage to the brain. J Neurosurg. 2012 Aug;117(2):197-203.
9. Brem H. Polymers to treat brain tumours. Biomaterials. 1990 Nov;11(9):699-701.
10. Emerich DF, Winn SR, Bartus RT. Injection of chemotherapeutic microspheres and glioma. IV: Eradicating tumors in rats. Cell Transplant. 2002;11(1):47-54.
11. Emerich DF, Winn SR, Snodgrass P, LaFreniere D, Agostino M, Wiens T, et al. Injectable chemotherapeutic microspheres and glioma II: enhanced survival following implantation into deep inoperable tumors. Pharm Res. 2000 Jul;17(7):776-81.

Keywords: glioblastoma multiforme (GBM), Convection enhanced delivery, malignant glioma, brain tumors, Wistar Rats

Conference: SAN2016 Meeting, Corfu, Greece, 6 Oct - 9 Oct, 2016.

Presentation Type: Poster Presentation in SAN2016 Conference

Topic: Posters

Citation: Giakoumettis D, Tsingotzidou AS, Kritis A and Foroglou N (2016). Convection-enhanced delivery as a method of delivering therapeutic agents in the brain of laboratory animals. Conference Abstract: SAN2016 Meeting. doi: 10.3389/conf.fnhum.2016.220.00044

Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.

The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.

Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.

For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.

Received: 01 Aug 2016; Published Online: 01 Aug 2016.

* Correspondence: Mr. Dimitrios Giakoumettis, Neurosurgical Resident, Thessaloniki, Greece, dgiakoumettis@gmail.com