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.

• Authors: Hao-Han Pang, Pin-Yuan Chen, Kuo-Chen Wei, Chiun-Wei Huang, Yow-Ling Shiue, Chiung-Yin Huang, Hung-Wei Yang
• Journal: Theranostics (Theranostics) Vol. 9 Issue 6 Pg. 1752-1763 ( 2019) ISSN: 1838-7640 [Electronic] Australia
• PMID: 31037136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cell-Penetrating Peptides
• Drug Carriers
• Organometallic Compounds
• Virosomes
• Epirubicin
• gallium Ga 68 dotatate

Topics

• Animals
• Antineoplastic Agents (administration & dosage)
• Brain Neoplasms (diagnostic imaging, drug therapy)
• Cell Line, Tumor
• Cell-Penetrating Peptides (administration & dosage)
• Disease Models, Animal
• Drug Carriers (administration & dosage, pharmacokinetics)
• Epirubicin (administration & dosage)
• Humans
• Mice, Nude
• Optical Imaging
• Organometallic Compounds (administration & dosage)
• Positron-Emission Tomography
• Staining and Labeling (methods)
• Virosomes (administration & dosage, pharmacokinetics)