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Published on: May 12, 2013
Water-absorbent polymer as a carrier for a discrete deposit of antisense oligodeoxynucleotides in the central nervous
M Bannai1, M Ichikawa, F Nishimura
1Department of Veterinary Physiology, Veterinary Medical Science, The University of Tokyo, 1-1-1 Bunkyo-ku, Tokyo 113, Japan.
Abstract:
One of the problems of introducing antisense oligodeoxynucleotides (ODN) into the central nervous system (CNS) is their rapid disappearance from the target site due to their dispersion and diffusion, which results in poor uptake and/or retention in cells (M. Morris, A.B. Lucion, Antisense oligonucleotides in the study of neuroendocrine systems, J. Neuroendocrinol. 7 (1995) 493-500; S. Ogawa, H.E. Brown, H.J. Okano, D.W. Pfaff, Cellular uptake of intracerebrally administrated oligodeoxynucleotides in mouse brain, Regul. Pept. 59 (1995) 143-149) [2,5]. Recently, we adapted a new method using water-absorbent polymer (WAP; internally cross-linked starch-grafted-polyacrylates) as a carrier for antisense ODN. The polymer forms a hydro-gel after absorbing water which is chemically and biologically inert. In these studies, the polymer (powder-form) is fully swollen by physiological saline containing antisense ODN (0.2 micromol/ml) to make 80-fold volume gel. Hydro-gel (1 microliter) is injected into the target site, and water solutes are assumed to be diffused stoichiometrically into CNS from the surface of the gel. Histological studies indicate that 24 h after the injection, antisense ODN (5'biotinylated-S-oligos of 15 mer) are distributed to within 800 micrometer from the edge of the area where the gel is located and then gradually disappear from this area within days, but still remain within 300-micrometer distance 7 days later. Antisense ODN are effectively incorporated by all the cell types examined, i.e., neurons, astrocytes and microglias, and suppress the synthesis of the target protein. This method can be adapted to slow delivery of antisense ODN and other water soluble substances into the CNS.
Insights
A novel water-absorbent polymer hydrogel effectively delivers antisense oligodeoxynucleotides (ODN) into the central nervous system (CNS). This method enhances ODN retention and cellular uptake, enabling sustained protein synthesis suppression in neurons, astrocytes, and microglias.
Area of Science:
- Neuroscience
- Biomaterials Science
- Drug Delivery Systems
Background:
- Introducing antisense oligodeoxynucleotides (ODN) into the central nervous system (CNS) is challenging due to rapid dispersion and poor cellular uptake.
- Existing methods struggle with efficient and sustained delivery of ODN to target sites within the CNS.
- Effective delivery is crucial for modulating gene expression and protein synthesis in neurological research and therapeutics.
Purpose of the Study:
- To evaluate a novel water-absorbent polymer (WAP) hydrogel as a carrier for sustained antisense ODN delivery into the CNS.
- To assess the distribution, retention, and cellular incorporation of antisense ODN delivered via WAP hydrogel.
- To determine the efficacy of WAP-mediated ODN delivery in suppressing target protein synthesis in CNS cells.
Main Methods:
- Antisense ODN were incorporated into a WAP hydrogel formed by swelling the polymer in physiological saline.
- The WAP hydrogel containing ODN was stereotaxically injected into the target site in the CNS.
- Histological analysis and cell type examination were performed at various time points post-injection to assess ODN distribution, retention, and cellular uptake.
Main Results:
- Antisense ODN were distributed up to 800 micrometers from the injection site 24 hours post-injection, with sustained presence within 300 micrometers at 7 days.
- The WAP hydrogel facilitated effective incorporation of ODN into neurons, astrocytes, and microglias.
- Suppression of target protein synthesis was observed in cells treated with WAP-delivered antisense ODN.
Conclusions:
- Water-absorbent polymer hydrogels offer a promising strategy for the slow and sustained delivery of antisense ODN into the CNS.
- This method overcomes the limitations of rapid dispersion and poor retention associated with conventional ODN administration.
- The WAP hydrogel system is adaptable for delivering other water-soluble therapeutic agents to the CNS.
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