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Published on: January 19, 2018
Tumor endothelial cell-specific drug delivery system using apelin-conjugated liposomes
Hiroki Kawahara1, Hisamichi Naito, Kazuhiro Takara
1Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Background:
A drug delivery system specifically targeting endothelial cells (ECs) in tumors is required to prevent normal blood vessels from being damaged by angiogenesis inhibitors. The purpose of this study was to investigate whether apelin, a ligand for APJ expressed in ECs when angiogenesis is taking place, can be used for targeting drug delivery to ECs in tumors.
Methods And Results:
Uptake of apelin via APJ stably expressed in NIH-3T3 cells was investigated using TAMRA (fluorescent probe)-conjugated apelin. Both long and short forms of apelin (apelin 36 and apelin 13) were taken up, the latter more effectively. To improve efficacy of apelin- liposome conjugates, we introduced cysteine, with its sulfhydryl group, to the C terminus of apelin 13, resulting in the generation of apelin 14. In turn, apelin 14 was conjugated to rhodamine-encapsulating liposomes and administered to tumor-bearing mice. In the tumor microenvironment, we confirmed that liposomes were incorporated into the cytoplasm of ECs. In contrast, apelin non-conjugated liposomes were rarely found in the cytoplasm of ECs. Moreover, non-specific uptake of apelin-conjugated liposomes was rarely detected in other normal organs.
Conclusions:
ECs in normal organs express little APJ; however, upon hypoxic stimulation, such as in tumors, ECs start to express APJ. The present study suggests that apelin could represent a suitable tool to effectively deliver drugs specifically to ECs within tumors.
Insights
Apelin targets APJ receptors on tumor endothelial cells (ECs) for precise drug delivery. This method enhances drug accumulation in tumors while minimizing damage to normal blood vessels, improving therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Molecular Biology
- Oncology
Background:
- Targeted drug delivery to tumor endothelial cells (ECs) is crucial to avoid damaging normal vasculature with angiogenesis inhibitors.
- Apelin, a ligand for the APJ receptor, is expressed in ECs during angiogenesis, making it a potential targeting agent.
Purpose of the Study:
- To investigate the potential of apelin for targeted drug delivery specifically to ECs within tumors.
- To evaluate apelin's efficacy in directing therapeutic agents to tumor neovasculature.
Main Methods:
- Investigated apelin uptake in NIH-3T3 cells expressing APJ using fluorescently labeled apelin.
- Developed apelin 14 by modifying apelin 13 with cysteine for improved liposome conjugation.
- Administered rhodamine-encapsulating liposomes conjugated with apelin 14 to tumor-bearing mice.
Main Results:
- Both long and short forms of apelin were internalized by cells expressing APJ, with apelin 13 being more effective.
- Apelin 14-conjugated liposomes were effectively incorporated into the cytoplasm of ECs in the tumor microenvironment.
- Apelin-conjugated liposomes showed minimal non-specific uptake in normal organs, indicating high tumor specificity.
Conclusions:
- Endothelial cells (ECs) in normal tissues express low levels of APJ, but its expression increases in tumors due to hypoxia.
- Apelin serves as a promising targeting molecule for the specific delivery of drugs to ECs within tumors.
- This targeted approach minimizes off-target effects and enhances therapeutic efficacy.
