title: High efficiency diffusion molecular retention tumor targeting.
abstract: Here we introduce diffusion molecular retention (DMR) tumor targeting, a technique that employs PEG-fluorochrome shielded probes that, after a peritumoral (PT) injection, undergo slow vascular uptake and extensive interstitial diffusion, with tumor retention only through integrin molecular recognition. To demonstrate DMR, RGD (integrin binding) and RAD (control) probes were synthesized bearing DOTA (for (111) In(3+)), a NIR fluorochrome, and 5 kDa PEG that endows probes with a protein-like volume of 25 kDa and decreases non-specific interactions. With a GFP-BT-20 breast carcinoma model, tumor targeting by the DMR or i.v. methods was assessed by surface fluorescence, biodistribution of [(111)In] RGD and [(111)In] RAD probes, and whole animal SPECT. After a PT injection, both probes rapidly diffused through the normal and tumor interstitium, with retention of the RGD probe due to integrin interactions. With PT injection and the [(111)In] RGD probe, SPECT indicated a highly tumor specific uptake at 24 h post injection, with 352%ID/g tumor obtained by DMR (vs 4.14%ID/g by i.v.). The high efficiency molecular targeting of DMR employed low probe doses (e.g. 25 ng as RGD peptide), which minimizes toxicity risks and facilitates clinical translation. DMR applications include the delivery of fluorochromes for intraoperative tumor margin delineation, the delivery of radioisotopes (e.g. toxic, short range alpha emitters) for radiotherapy, or the delivery of photosensitizers to tumors accessible to light.
authors.affiliation: Department of Radiology, Center for Translational Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Guo
authors.forename: Hushan
authors.initials: H
authors.lastname: Yuan
authors.forename: Hoonsung
authors.initials: H
authors.lastname: Cho
authors.forename: Darshini
authors.initials: D
authors.lastname: Kuruppu
authors.forename: Kimmo
authors.initials: K
authors.lastname: Jokivarsi
authors.forename: Aayush
authors.initials: A
authors.lastname: Agarwal
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
authors.forename: Lee
authors.initials: L
authors.lastname: Josephson
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004058:Diffusion; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D007267:Injections; D016023:Integrins / Q000378:metabolism; D051379:Mice; D057054:Molecular Imaging; D064847:Multimodal Imaging; D009369:Neoplasms / Q000175:diagnosis / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D014018:Tissue Distribution; D014057:Tomography, X-Ray Computed; D014183:Transplantation, Heterologous
chemical_list: D005456:Fluorescent Dyes; D016023:Integrins; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols