期刊
MOLECULAR PHARMACEUTICS
卷 13, 期 11, 页码 3764-3772出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.6b00566
关键词
bacteriophage MS2; tumor targeting; antibody targeting; bioconjugation; PET imaging
资金
- DOD Breast Cancer Research Program [BC061995, W81XWH-14-0400]
- W. M. Keck Foundation
- Genentech Fellowship through the U.C. Berkeley Chemical Biology program
- DOD BCRP Grant [BC100159]
- Howard Hughes Medical Institute International Student Research Fellowship
- National Institutes of Health [1SI0RR022393-01]
- NIH [S10 RR023051]
- CDMRP [BC100159, 545196] Funding Source: Federal RePORTER
A variety of nanoscale scaffolds, including virus like particles (VLPs), are being developed for biomedical applications; however, little information is available about their in vivo behavior. Targeted nanoparticles are particularly valuable as diagnostic and therapeutic carriers because they Radiolabeled can increase the signal-to-background ratio of imaging agents, improve the efficacy of drugs, and reduce adverse effects by concentrating the therapeutic molecule in the region of interest. The genome-free capsid of bacteriophage MS2 has several features that make it well-suited for use in delivery applications, such as facile production and modification, the ability to display multiple copies of targeting ligands, and the capacity to deliver large payloads. Anti-EGFR antibodies were conjugated to MS2 capsids to construct nanoparticles targeted toward receptors overexpressed on breast cancer cells. The MS2 agents showed good stability in physiological conditions up to 2 days and specific binding to the targeted receptors in in vitro experiments. Capsids radiolabeled with Cu-64 isotopes were injected into mice possessing tumor xenografts, and both positron emission tomography computed tomography (PET/CT) and scintillation counting of the organs ex vivo were used to determine the localization of the agents. The capsids exhibit surprisingly long circulation times (10-15% ID/g in blood at 24 h) and moderate tumor uptake (2-5% ID/g). However, the targeting antibodies did not lead to increased uptake in vivo despite in vitro enhancements, suggesting that extravasation is a limiting factor for delivery to tumors by these particles.
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