Project Details
Description
A significant portion of lung cancer patients develop central nervous systems (CNS) metastasis at a certain time point of their disease courses. However, detection of small central nervous systems (CNS) lesions and effective drug delivery across the blood brain barrier (BBB) are challenging issues in biomedical researches. The structure of the BBB strictly regulates brain homeostasis and protects the brain from exogenous insults. The characteristics impedes efficient drug delivery from circulation and diminishes the likelihood of antibody-based molecular imaging for tumor detection. CNS metastasis occurs in most advanced-stage lung cancer patients at a certain time point in their disease courses. Current diagnosis of CNS metastasis predominantly relies on the gadolinium-enhanced magnetic resonance imaging (MRI). Nevertheless, detection for small brain tumors and leptomeningeal lesions can be difficult. Moreover, effective drug delivery into the CNS remains a challenging task and is an unmet clinical need. Monoclonal antibody-mediated targeted delivery has been explored by many investigators since its first discovery. Nevertheless, the size of antibody limits its tissue-penetration efficiency, with the reported cerebrospinal fluid (CSF)/serum partitioning being around 0.1%. Aptamers, also known as chemical antibodies, are small synthetic DNA or RNA oligonucleotides that fold into a three-dimensional structure with high binding affinity to targeted proteins. The small size of aptamer (6-30kDa) may facilitate its tissue penetration efficiency and is advantages in terms of targeted delivery. Whether aptamers can penetrate BBB and retain in brain tumors remains controversial. Our preliminary results suggest that DNA aptamers may penetrate BBB and accumulate in the brain. We are now developing mouse CNS tumor models for metastatic lung cancer and the preliminary results are promising. The current study aims to develop BBB-penetrating, lung cancer-targeting aptamers by in vivo SELEX using the CNS metastatic lung cancer model. The candidate aptamers will be fluorophore-labeled and evaluated for their tumor targeting and binding ability in vivo and in vitro. The study also aims to identify binding targets for these candidate BBB-penetrating, metastatic lung cancer-targeting aptamers. Targets identification will be explored by immunoprecipitation and MS/MS studies and verified by immunoprecipitation, immunoblotting and immunostaining. It is anticipated that by successful implementation of the goals proposed, BBB-penetrating, lung cancer-targeting aptamers be developed and their target proteins be identified. The aptamers may serve as molecular probes for imaging detection and/or guiding molecules for drug delivery. The results will contribute to a further understanding on CNS tumor targeting and drug delivery, and lead to a breakthrough in this currently puzzled research field.
Status | Finished |
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Effective start/end date | 8/1/20 → 7/31/21 |
Keywords
- Blood brain barrier
- Central nervous system
- Brain
- Leptomeningeal
- Aptamer
- Molecular imaging
- Drug delivery
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