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Convection-Enhanced Delivery of a Virus-Like Nanotherapeutic Agent with Dual-Modal Imaging for Besiegement and Eradication of Brain Tumors.

ABSTRACT: Convection-enhanced delivery (CED) is a promising technique for infusing a therapeutic agent directly into the brain, bypassing the blood-brain barrier (BBB) with a pressure gradient to increase drug concentration specifically around the brain tumor, thereby enhancing tumor inhibition and limiting the systemic toxicity of chemotherapeutic agents. Herein, we developed a dual-imaging monitored virus-like nanotherapeutic agent as an ideal CED infusate, which can be delivered to specifically besiege and eradicate brain tumors. Methods: We report one-pot fabrication of green-fluorescence virus-like particles (gVLPs) in Escherichia coli (E. coli) for epirubicin (EPI) loading, cell-penetrating peptide (CPP) modification, and ⁶⁸Ga-DOTA labeling to form a positron emission tomography (PET)-fluorescence dual-imaging monitored virus-like nanotherapeutic agent (⁶⁸Ga-DOTA labeled EPI@CPP-gVLPs) combined with CED for brain tumor therapy and image tracking. The drug delivery, cytotoxicity, cell uptake, biodistribution, PET-fluorescence imaging and anti-tumor efficacy of the ⁶⁸Ga-DOTA labeled EPI@CPP-gVLPs were investigated in vitro and in vivo by using U87-MG glioma cell line and U87-MG tumor model. Results: The ⁶⁸Ga-DOTA-labeled EPI@CPP-gVLPs showed excellent serum stability as an ideal CED infusate (30-40 nm in size), and can be disassembled through proteolytic degradation of the coat protein shell to enable drug release and clearance to minimize long-term accumulation. The present results indicated that ⁶⁸Ga-DOTA-labeled EPI@CPP-gVLPs can provide a sufficiently high drug payload (39.2 wt% for EPI) and excellent detectability through fluorescence and PET imaging to accurately represent drug distribution during CED infusion. In vivo delivery of the ⁶⁸Ga-DOTA-labeled EPI@CPP-gVLPs through CED demonstrated that the median survival was prolonged to over 50 days when the mice received two administrations (once per week) compared with the control group (median survival: 26 days). Conclusion: The results clearly indicated that a combination of ⁶⁸Ga-DOTA-labeled EPI@CPP-gVLPs and CED can serve as a flexible and powerful synergistic treatment in brain tumors without evidence of systemic toxicity.

SUBMITTER: Pang HH

PROVIDER: S-EPMC6485197 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Convection-Enhanced Delivery of a Virus-Like Nanotherapeutic Agent with Dual-Modal Imaging for Besiegement and Eradication of Brain Tumors.

Pang Hao-Han HH Chen Pin-Yuan PY Wei Kuo-Chen KC Huang Chiun-Wei CW Shiue Yow-Ling YL Huang Chiung-Yin CY Yang Hung-Wei HW

Theranostics 20190228 6

Convection-enhanced delivery (CED) is a promising technique for infusing a therapeutic agent directly into the brain, bypassing the blood-brain barrier (BBB) with a pressure gradient to increase drug concentration specifically around the brain tumor, thereby enhancing tumor inhibition and limiting the systemic toxicity of chemotherapeutic agents. Herein, we developed a dual-imaging monitored virus-like nanotherapeutic agent as an ideal CED infusate, which can be delivered to specifically besiege ...[more]

PMID: 31037136

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Project description:Convection-enhanced delivery (CED) for the treatment of malignant gliomas is a technique that can deliver chemotherapeutic agents directly into the tumor and the surrounding interstitium through sustained, low-grade positive-pressure infusion. This allows for high local concentrations of drug within the tumor while minimizing systemic levels that often lead to dose-limiting toxicity. Diffuse intrinsic pontine gliomas (DIPGs) are universally fatal childhood tumors for which there is currently no effective treatment. In this report the authors describe CED of the topoisomerase inhibitor topotecan for the treatment of DIPG in 2 children. As part of a pilot feasibility study, the authors treated 2 pediatric patients with DIPG. Stereotactic biopsy with frozen section confirmation of glial tumor was followed by placement of bilateral catheters for CED of topotecan during the same procedure. The first patient underwent CED 210 days after initial diagnosis, after radiation therapy and at the time of tumor recurrence, with a total dose of 0.403 mg in 6.04 ml over 100 hours. Her Karnofsky Performance Status (KPS) score was 60 before CED and 50 posttreatment. Serial MRI initially demonstrated a modest reduction in tumor size and edema, but the tumor progressed and the patient died 49 days after treatment. The second patient was treated 24 days after the initial diagnosis prior to radiation with a total dose of 0.284 mg in 5.30 ml over 100 hours. Her KPS score was 70 before CED and 50 posttreatment. Serial MRI similarly demonstrated an initial modest reduction in tumor size. The patient subsequently underwent fractionated radiation therapy, but the tumor progressed and she died 120 days after treatment. Topotecan delivered by prolonged CED into the brainstem in children with DIPG is technically feasible. In both patients, high infusion rates (> 0.12 ml/hr) and high infusion volumes (> 2.8 ml) resulted in new neurological deficits and reduction in the KPS score, but lower infusion rates (< 0.04 ml/hr) were well tolerated. While serial MRI showed moderate treatment effect, CED did not prolong survival in these 2 patients. More studies are needed to improve patient selection and determine the optimal flow rates for CED of chemotherapeutic agents into DIPG to maximize safety and efficacy. Clinical trial registration no.: NCT00324844.

Dataset Information

Convection-Enhanced Delivery of a Virus-Like Nanotherapeutic Agent with Dual-Modal Imaging for Besiegement and Eradication of Brain Tumors.

Publications

Convection-Enhanced Delivery of a Virus-Like Nanotherapeutic Agent with Dual-Modal Imaging for Besiegement and Eradication of Brain Tumors.

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