DENDRIMER-BASED TARGETED THERAPY FOR THE TREATMENT OF CNS DISEASES
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Date
2016-03-18
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Johns Hopkins University
Abstract
Effective treatment of many CNS diseases remains a major challenge due to the lack of specificity for therapeutics to target pathological cells. Many nanoparticles offer promising approaches for controlled, sustained release of therapeutics, yet their applications are limited by the lack of knowledge on how they interact with pathological cells. Microglial cells play a key role in mediating the development of many CNS diseases. In this thesis, we investigated the mechanism for Polyamidoamine (PAMAM) dendrimers (dendrimers) to target microglial cells in different pathologies (e.g. malignant brain tumor, neuroinflammation) that are commonly observed in many CNS diseases. Building from this knowledge, we developed dendrimer-based therapeutics that can target microglia and improve therapeutic efficacy in CNS diseases.
We first determined the mechanism for dendrimers to target microglia in malignant brain tumor and neuroinflammation. In malignant brain tumor, we found systemically delivered dendrimers can target tumor and Tumor Associated Macrophages (TAMs) within 15 minutes and 4 hours respectively after administration. In the presence of neuroinflammation, dendrimers can cross the Blood-Brain Barrier (BBB) and selectively localize in ‘activated’ microglia at different stages of activation. Further ex vivo study revealed that, although these ‘activated’ microglial cells had impaired movement, they tended to take up dendrimers more rapidly and to a greater extent compared to the microglia under physiological conditions.
We then sought to investigate the physiochemical properties of dendrimer that can affect its intrinsic targeting to the CNS diseases. We found increase dendrimer size from generation 4 (G4) to generation 6 (G6) can increase its tumor uptake 100-fold, while still maintaining its intrinsic targeting to TAMs. Cationic dendrimers demonstrated the highest brain accumulation, following with neutral and anionic dendrimers, yet only neutral dendrimers were able to diffuse within the brain parenchyma and target ‘activated’ microglia.
Based on these design criteria, we formulated therapeutic dendrimer through covalently conjugating a glutamate carboxypeptidase II inhibitor (i.e. 2MPPA) to dendrimers (D-2MPPA), using disulfide bond as a linkage. When evaluated in a clinical translatable rabbit model of cerebral palsy, D-2MPPA demonstrated higher brain accumulation and specific glial cell-targeting compared with free 2MPPA. This targeted delivery efficiently inhibited glutamate excitotoxicity, attenuated neuroinflammation, and subsequently improved neurobehavior, with clinical significance.
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Keywords
Dendrimer, Drug delivery, Central Nervous System, Microglia, Neuroinflammation, Brain tumor.