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Distribution of 1,3-bis(2-chloroethyl)-1-nitrosourea and tracers in the rabbit brain after interstitial delivery by
J F Strasser1, L K Fung, S Eller
1Department of Chemical Engineering, Johns Hopkins University, Baltimore, Maryland, USA.
Abstract:
Intracranial tumors, such as glioblastoma multiforme and astrocytomas, are among the most aggressive and difficult to cure. In the present study, we evaluated the intracranial distribution of released agents during the first 3 days after implantation. Polymer implants containing [3H]-1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), [3H]dextran (MW 70,000) or [14C]iodoantipyrene (IAP) were implanted into the brains of rabbits; autoradiography was used to measure the distribution of radiolabels within the brain at 6, 24 and 72 hr after implantation. For all of the agents studied, the majority of the radioactivity was found within the region 1 to 2 mm from the surface of the polymer. Dextran, however, penetrated farther into the brain than either IAP or BCNU. The distribution of radiolabel on an anteroposterior axis was determined by examining serial coronal images: after 72 hr, significant radioactivity (< 2 S.D. above background) extended > 17 mm in animals with [3H]dextran implants and approximately mm in animals receiving [3H]BCNU or [14C]IAP. Concentration profiles were also measured on coronal images obtained at the implant site: radioactivity dropped to a 10% maximum value 1.7 mm from the surface of the pellet in [3H]dextran-treated animals and < 1.2 mm in [3H]BCNU or [14C]IAP-treated animals. Measured concentration profiles near the polymer were compared to mathematical models of drug diffusion and elimination. These results demonstrate that the majority of agents delivered into the brain by intracranially implanted polymers accumulates in the tissue within 1 to 2 mm of the implant, but that the size of the treated region depends on physicochemical properties of the agents.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Polymer implants release agents into the brain, but most accumulate near the implant site. Agent distribution depends on their properties, impacting the treated brain region size.
Area of Science:
- Neuroscience
- Biomedical Engineering
- Pharmacology
Background:
- Intracranial tumors like glioblastoma are aggressive and hard to treat.
- Effective drug delivery to the brain is crucial for treating these tumors.
Purpose of the Study:
- To evaluate the intracranial distribution of agents released from polymer implants.
- To understand how agent properties influence drug penetration in the brain.
Main Methods:
- Implanted polymer pellets containing radiolabeled agents ([3H]-BCNU, [3H]dextran, [14C]IAP) into rabbit brains.
- Used autoradiography to measure radiolabel distribution at 6, 24, and 72 hours post-implantation.
- Analyzed concentration profiles and compared them to mathematical diffusion models.
Main Results:
- Most agents concentrated within 1-2 mm of the polymer implant.
- [3H]dextran showed greater penetration ( >17 mm) compared to [3H]-BCNU and [14C]IAP (<1.2 mm).
- Radioactivity decreased to 10% of maximum at 1.7 mm for dextran and <1.2 mm for BCNU/IAP.
Conclusions:
- Intracranially delivered agents primarily accumulate near the polymer implant.
- The extent of the treated brain region is determined by the physicochemical properties of the delivered agents.
- Understanding these distribution patterns is key for optimizing drug delivery strategies for brain tumors.