Cell microencapsulation technology for drug delivery in the CNS
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1
University of the Basque Country (UPV/EHU), Paseo de la Universidad n°7, Laboratory of Pharmacy and Pharmaceutical Technology, Spain
The brain can be damaged by a wide range of conditions including infections, hypoxia, poisoning, stroke, chronic degenerative diseases, and acute trauma. Some of the most problematic forms of brain damage are those associated with chronic neurodegenerative diseases or acute brain trauma as a result of contusive or penetrating injury. In these cases, damage results in the loss of specific populations of neurons and the development of defined psychiatric or neurological symptoms. Current treatments for these problems are designed to pharmacologically modify disease symptoms; however there are not yet any therapies that fully restore lost function or slow ongoing neurodegeneration in the brain.
Several strategies have been proposed to provide brain protection, repair and recovery including delivery of neuroprotective compounds to prevent cellular degeneration, tissue engineering, cell replacement and cell transplantation approaches to replace loss cells, and methods to enhance plasticity by promoting the intrinsic capacity of the brain to regenerate and reorganize (1). Cell microencapsulation is a cell-based drug delivery technology in which cells secreting therapeutically active agents are enclosed into selectively permeable materials that have been shaped into polymeric structures, and are protected from immune rejection by an artificial, semipermeable membrane (Figure 1).
Many studies have demonstrated the pre-clinical feasibility of encapsulation as a means of delivering factors to the CNS including the use of primary chromaffin cells for pain, PC12 cells for Parkinson’s Disease (PD), genetically-engineered cells secreting trophic factors for PD, Huntington’s (HD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS), and encapsulated endostatin releasing cells for brain tumor therapy (2- 4). More recent studies suggest that neurotrophic factor-secreting cells immobilized in alginate capsules might be useful for preventing the degeneration of neurons in several CNS disorders.
To demonstrate the proof of principle in PD, we implanted alginate-poly-L-lysinealginate microcapsules containing immobilized Fischer rat 3T3 fibroblasts transfected to produce GDNF into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats (5). Results demonstrated that rats implanted with microencapsulated GDNF secreting cells showed a decrease in apomorphine-induced rotations by 84, 64, 84, 60 and 52% (2, 5, 8, 16 and 24 weeks respectively) with respect to the value before implantation and with respect to the value obtained from the empty microcapsulated implanted-group at each time point (Figure 2).
Recently, we have studied the effects of a continuous release of VEGF using cell microencapsulation technology in AD. The histological and behavioural effects of a sustained release of VEGF on APP/Ps1 transgenic mice were evaluated. Results showed that VEGF secreted by encapsulated cells was functional in vivo. Neuronal loss in the cortex was reduced which supports the neuroprotective role of VEGF.
In addition, a reduced caspase activation was observed. The latter is important because caspase-3 activation is involved in the cytotoxic effect of beta-amyloid on brain neurons and microvascular endothelial cells, and it is increased in brains of patients with AD (9). Results obtained in the behaviour test suggest that reducing the neuronal lost in the cortex may be sufficient to improve some cognitive functions such as spatial memory. Our preliminary data indicates that continuous VEGF delivery in the cortex could be a useful therapy to improve AD symptoms and cell encapsulation technology a potential approach for the continuous long term delivery of therapeutic products for the treatment of AD.
References
1. Orive G, Anitua E, Pedraz JL, Emerich D. Advances in biomaterials for promoting brain repair and regeneration. Nature Rev Neurosci 10: 682-692 (2009).
2. Aebischer P, et al. Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients. Nature Med 2: 696- 699 (1996).
3. Zurn AD, et al. Evaluation of an intrathecal immune response in amyotrophic lateral sclerosis patients implanted with encapsulated genetically-engineered xenogeneic cells. Cell Transpl 9: 471-484 (2000).
4. Orive G, et al. Cell encapsulation: promise and progress. Nat Med 9: 104-107 (2003).
5. Grandoso L, et al. Striatal implantation of encapsulated glial cell-line derived neurotrophic factor secreting cells improves behavioral abnormalities in a unilateral rat model of Parkinson's disease. Int J Pharm 343: 69-78 (2007).
Conference:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU, Brussels, Belgium, 11 Feb - 12 Feb, 2010.
Presentation Type:
Oral Presentation
Topic:
Presentations
Citation:
Orive
G,
Hernández
RM and
Pedraz
JL
(2010). Cell microencapsulation technology for drug delivery in the CNS.
Front. Pharmacol.
Conference Abstract:
Pharmacology and Toxicology of the Blood-Brain Barrier: State of the Art, Needs for Future Research and Expected Benefits for the EU.
doi: 10.3389/conf.fphar.2010.02.00022
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Received:
11 Mar 2010;
Published Online:
11 Mar 2010.
*
Correspondence:
Gorka Orive, University of the Basque Country (UPV/EHU), Paseo de la Universidad n°7, Laboratory of Pharmacy and Pharmaceutical Technology, Vitoria-Gasteiz, Spain, gorka.orive@ehu.es