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Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

ABSTRACT: Rationale: The dual-targeted drug delivery system was designed for enhancing permeation of the blood-brain barrier (BBB) and providing an anti-glioma effect. As transferrin receptor (TfR) is over-expressed by the brain capillary endothelial (hCMEC/D3) and glioma cells, a mouse monoclonal antibody, RI7217, with high affinity and selectivity for TfR, was used to study the brain targeted drug delivery system. Muscone, an ingredient of traditional Chinese medicine (TCM) musk, was used as the "guide" drug to probe the permeability of the BBB for drug delivery into the cerebrospinal fluid. This study investigated the combined effects of TCM aromatic resuscitation and modern receptor-targeted technology by the use of muscone/RI7217 co-modified docetaxel (DTX) liposomes for enhanced drug delivery to the brain for anti-glioma effect. Methods: Cellular drug uptake from the formulations was determined using fluorescence microscopy and flow cytometry. The drug penetrating ability into tumor spheroids were visualized using confocal laser scanning microscopy (CLSM). In vivo glioma-targeting ability of formulations was evaluated using whole-body fluorescent imaging system. The survival curve study was performed to evaluate the anti-glioma effect of the formulations. Results: The results showed that muscone and RI7217 co-modified DTX liposomes enhanced uptake into both hCMEC/D3 and U87-MG cells, increased penetration to the deep region of U87-MG tumor spheroids, improved brain targeting in vivo and prolonged survival time of nude mice bearing tumor. Conclusion: Muscone and RI7217 co-modified DTX liposomes were found to show improved brain targeting and enhanced the efficacy of anti-glioma drug treatment in vivo.

SUBMITTER: Kang S

PROVIDER: S-EPMC7150489 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

Kang Shuangming S Duan Wenjuan W Zhang Shangqian S Chen Dawei D Feng Jianfang J Qi Na N

Theranostics 20200304 10

<b>Rationale</b>: The dual-targeted drug delivery system was designed for enhancing permeation of the blood-brain barrier (BBB) and providing an anti-glioma effect. As transferrin receptor (TfR) is over-expressed by the brain capillary endothelial (hCMEC/D3) and glioma cells, a mouse monoclonal antibody, RI7217, with high affinity and selectivity for TfR, was used to study the brain targeted drug delivery system. Muscone, an ingredient of traditional Chinese medicine (TCM) musk, was used as the ...[more]

PMID: 32292496

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Project description:Key pointsThe blood-brain barrier (BBB) is an important and dynamic structure which contributes to homeostasis in the central nervous system. BBB permeability changes occur in health and disease but measurement of BBB permeability in humans is not straightforward. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can be used to model the movement of gadolinium contrast into the brain, expressed as the influx constant Ki . Here evidence is provided that Ki as measured by DCE-MRI behaves as expected for a marker of overall BBB leakage. These results support the use of DCE-MRI for in vivo studies of human BBB permeability in health and disease.AbstractBlood-brain barrier (BBB) leakage can be measured using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as the influx constant Ki . To validate this method we compared measured Ki with biological expectations, namely (1) higher Ki in healthy individual grey matter (GM) versus white matter (WM), (2) GM/WM cerebral blood volume (CBV) ratio close to the histologically established GM/WM vascular density ratio, (3) higher Ki in visibly enhancing multiple sclerosis (MS) lesions versus MS normal appearing white matter (NAWM), and (4) higher Ki in MS NAWM versus healthy individual NAWM. We recruited 13 healthy individuals and 12 patients with MS and performed whole-brain 3D DCE-MRI at 3 T. Ki and CBV were calculated using Patlak modelling for manual regions of interest (ROI) and segmented tissue masks. Ki was higher in control GM versus WM (P = 0.001). CBV was higher in GM versus WM (P = 0.005, mean ratio 1.9). Ki was higher in visibly enhancing MS lesions versus MS NAWM (P = 0.002), and in MS NAWM versus controls (P = 0.014). Bland-Altman analysis showed no significant difference between ROI and segmentation methods (P = 0.638) and an intra-class correlation coefficient showed moderate single measure consistency (0.610). Ki behaves as expected for a compound marker of permeability and surface area. The GM/WM CBV ratio measured by this technique is in agreement with the literature. This adds evidence to the validity of Ki measured by DCE-MRI as a marker of overall BBB leakage.

Dataset Information

Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

Publications

Muscone/RI7217 co-modified upward messenger DTX liposomes enhanced permeability of blood-brain barrier and targeting glioma.

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