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Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

ABSTRACT: Targeted therapy of Parkinson's disease is an important challenge because of the blood-brain barrier limitation. Here, we propose a natural killer cell membrane biomimetic nanocomplex (named BLIPO-CUR) delivered via the meningeal lymphatic vessel (MLV) route to further the therapeutic efficacy of Parkinson's disease. The membrane incorporation enables BLIPO-CUR to target the damaged neurons, thus improving their therapeutic efficacy through clearing reactive oxygen species, suppressing the aggregation of α-synuclein, and inhibiting the spread of excess α-synuclein species. Compared with the conventional intravenous injection, this MLV administration can enhance the delivered efficiency of curcumin into the brain by ~20 folds. The MLV route administration of BLIPO-CUR enhances the treatment efficacy of Parkinson's disease in mouse models by improving their movement disorders and reversing neuron death. Our findings highlight the great potential of MLV route administration used as targeted delivery of drugs to the brain, holding a great promise for neurodegenerative disease therapy.

SUBMITTER: Liu J

PROVIDER: S-EPMC10076012 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

Liu Jing J Gao Duyang D Hu Dehong D Lan Siyi S Liu Yu Y Zheng Hairong H Yuan Zhen Z Sheng Zonghai Z

Research (Washington, D.C.) 20230130

Targeted therapy of Parkinson's disease is an important challenge because of the blood-brain barrier limitation. Here, we propose a natural killer cell membrane biomimetic nanocomplex (named BLIPO-CUR) delivered via the meningeal lymphatic vessel (MLV) route to further the therapeutic efficacy of Parkinson's disease. The membrane incorporation enables BLIPO-CUR to target the damaged neurons, thus improving their therapeutic efficacy through clearing reactive oxygen species, suppressing the aggre ...[more]

PMID: 37040500

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Project description:Targeted therapy via the patient-friendly oral route remains the holy grail of chemotherapy for cancer. Herein we report a yeast-derived platform for targeted oral delivery of cisplatin (CDDP) that is one of the most effective drugs for chemotherapy of various types of cancers. Methods: The optimal conditions were first established to fabricate yeast microcapsules (YCs) with desirable loading capability. Then, CDDP-derived precursor nanoparticles (PreCDDP) were prepared and packaged into YC to produce orally deliverable PreCDDP/YC. The physiochemical properties, in vitro drug release profiles, in vitro antitumor activity, oral targeting capability, in vivo pharmacokinetics, and in vivo efficacy of the YC-based biomimetic delivery system were examined. Results: YCs obtained under the optimized condition showed desirable loading efficiency for quantum dots that were used as a model nanocargo. In vitro experiments demonstrated rapid endocytosis and prolonged retention of YC in macrophages. By electrostatic force-mediated self-deposition, PreCDDP was efficiently loaded into YC. PreCDDP/YC showed potent cytotoxicity in different tumor cells, indicating that PreCDDP loaded in YC maintained its antitumor activity after intracellular release. As compared to CDDP and PreCDDP, orally administered PreCDDP/YC displayed significantly higher bioavailability. Post oral delivery, YC could accumulate in A549 human lung carcinoma xenografts in mice, achieving by monocyte/macrophage-mediated translocation via the lymphatic system. Through this targeting effect, orally administered PreCDDP/YC showed desirable efficacy in A549 xenograft-bearing mice, which was comparable to that of free CDDP administered by intravenous injection. Orally administered free CDDP, however, did not afford antitumor effects. Furthermore, oral treatment with PreCDDP/YC displayed better safety than free CDDP administered via the oral or intravenous route. Conclusions: This biomimetic approach can serve as an effective strategy to develop targeted oral chemotherapies based on CDDP or its derivatives.

Project description:Rationale: Meningeal lymphatic vessels (MLVs) are essential for the clearance of subdural hematoma (SDH). However, SDH impairs their drainage function, and the pathogenesis remains unclear. Herein, we aimed to understand the pathological mechanisms of MLV dysfunction following SDH and to test whether atorvastatin, an effective drug for SDH clearance, improves meningeal lymphatic drainage (MLD). Methods: We induced SDH models in rats by injecting autologous blood into the subdural space and evaluated MLD using Gadopentetate D, Evans blue, and CFSE-labeled erythrocytes. Whole-mount immunofluorescence and transmission electron microscopy were utilized to detect the morphology of MLVs. Phosphoproteomics, western blot, flow cytometry, and in vitro experiments were performed to investigate the molecular mechanisms underlying dysfunctional MLVs. Results: The basal MLVs were detected to have abundant valves and play an important role in draining subdural substances. Following SDH, these basal MLVs exhibited disrupted endothelial junctions and dilated lumen, leading to impaired MLD. Subsequent proteomics analysis of the meninges detected numerous dephosphorylated proteins, primarily enriched in the adherens junction, including significant dephosphorylation of ERK1/2 within the meningeal lymphatic endothelial cells (LECs). Subdural injection of the ERK1/2 kinase inhibitor PD98059 resulted in dilated basal MLVs and impaired MLD, resembling the dysfunctional MLVs observed in SDH. Moreover, inhibiting ERK1/2 signaling severely disrupted intercellular junctions between cultured LECs. Finally, atorvastatin was revealed to protect the structure of basal MLVs and accelerate MLD following SDH. However, these beneficial effects of atorvastatin were abolished when combined with PD98059. Conclusion: Our findings demonstrate that SDH induces ERK1/2 dephosphorylation in meningeal LECs, leading to disrupted basal MLVs and impaired MLD. Additionally, we reveal a beneficial effect of atorvastatin in improving MLD.

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Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

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Delivery of Biomimetic Liposomes via Meningeal Lymphatic Vessels Route for Targeted Therapy of Parkinson's Disease.

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