Folate receptor-targeted fluorescent paramagnetic bimodal liposomes for tumor imaging
Nan Ding1,2, Yao Lu1, Robert J Lee3, Chang Yang1, Lei Huang1, Jian Liu1, Guangya Xiang1,4
1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA; 4Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China
The first three authors contributed equally to this work.
Rationale and objective: Receptor-targeted delivery of imaging and therapeutic agents can lead to enhanced efficacy for both. Multimodality imaging offers unique advantages over traditional single modality imaging. Tumor marker folate receptor (FR)-targeted fluorescent paramagnetic bimodal liposomes were synthesized to co-deliver paramagnetic and fluorescence agents for magnetic resonance (MR) and optical bimodal imaging contrast enhancement.
Materials and methods: Fluorescent and paramagnetic bimodal liposomes were synthesized with a mean diameter of 136 nm and a low polydispersity index. The liposomes incorporated folate-PEG3350-CHEMS for FR targeting, Gd(III)[N,N-Bis-stearylamidomethyl-N’-amidomethyl]diethylenetriamine tetraacetic acid (Gd-DTPA-BSA) for MR contrast, and calcein for fluorescence. To determine the specificity and efficiency of delivery, the liposomes were evaluated in FR-positive KB and HeLa cells and FR-negative A549 cells, which were analyzed by fluorescence microscopy, magnetic resonance imaging (MRI), and flow cytometry (FCM).
Results: FR-specific and efficient cellular uptake of the FR-targeted bimodal liposomes was confirmed by fluorescence microscopy and by FCM. The mean fluorescence intensity (MFI) of KB cells treated with FR-targeted liposomes was 45× that of cells treated with nontargeted liposomes, and 18× that of cells treated with FR-targeted liposomes and excess folic acid (FA). The MFI of HeLa cells treated with targeted liposomes was 33× that of nontargeted liposomes, and was 16× that of the mixture of targeted liposomes and free FA. In contrast, the MFI of A549 cells treated with FR-targeted liposomes was nearly the same as those treated with nontargeted liposomes. The T1-weighted MR images of HeLa and KB cells incubated with FR-targeted liposomes had much higher signal intensity than those treated with nontargeted liposomes or free Gd-DTPA. Furthermore, the FR-targeting effect could be blocked by excess free FA.
Conclusion: FR-targeted fluorescent paramagnetic bimodal liposomes provided a novel platform for bimodal tumor imaging and theranostic delivery.
Keywords: folate receptor, tumor targeting, MRI, fluorescence, bimodal liposomes
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