title: Noninvasive detection of passively targeted poly(ethylene glycol) nanocarriers in tumors.
abstract: The present studies noninvasively investigate the passive tumor distribution potential of a series of poly(ethylene glycol) (PEG) nanocarriers using a SkinSkan spectrofluorometer and an In Vivo Imaging System (IVIS) 100. Fluorescein conjugated PEG nanocarriers of varying molecular weights (10, 20, 30, 40, and 60 kDa) were prepared and characterized. The nanocarriers were administered intravenously to female balb/c mice bearing subcutaneous 4T1 tumors. Passive distribution was measured in vivo (λ(exc), 480 nm; λ(em), 515-520 nm) from the tumor and a contralateral skin site (i.e., control site). The signal intensity from the tumor was always significantly higher than that from the contralateral site. Trends in results between the two methods were consistent with tumor distribution increasing in a molecular weight-dependent manner (10 < 20 < 30 ≪ 40 ≪ 60 kDa). The 10 kDa nanocarrier was not detected in tumors at 24 h, whereas 40-60 kDa nanocarriers were detected in tumors for up to 96 h. The 30, 40, and 60 kDa nanocarriers showed 2.1, 5.3, and 4.1 times higher passive distribution in tumors at 24 h, respectively, as compared to the 20 kDa nanocarrier. The 60 kDa nanocarrier exhibited 1.5 times higher tumor distribution than 40 kDa nanocarrier at 96 h. Thus, PEG nanocarriers (40 and 60 kDa) with molecular weights close to or above the renal exclusion limit, which for globular proteins is ≥45 kDa, showed significantly higher tumor distribution than those below it. The hydrodynamic radii of PEG polymers, measured using dynamic light scattering (DLS), showed that nanocarriers obtained from polymers with hydrodynamic radii ≥8 nm exhibited higher tumor distribution. Ex vivo mass balance studies revealed that nanocarrier tissue distribution followed the rank order tumor > lung > spleen > liver > kidney > muscle > heart, thus validating the in vivo studies. The results of the current studies suggest that noninvasive dermal imaging of tumors provides a reliable and rapid method for the initial screening of nanocarrier tumor distribution pharmacokinetics.
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08854, United States.
authors.forename: Yashveer
authors.initials: Y
authors.lastname: Singh
authors.forename: Dayuan
authors.initials: D
authors.lastname: Gao
authors.forename: Zichao
authors.initials: Z
authors.lastname: Gu
authors.forename: Shike
authors.initials: S
authors.lastname: Li
authors.forename: Stanley
authors.initials: S
authors.lastname: Stein
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D003287:Contrast Media / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D005260:Female; D019793:Fluorescein / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D006207:Half-Life; D057446:Hydrodynamics; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008970:Molecular Weight; D049329:Nanostructures / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution; D051598:Whole Body Imaging
chemical_list: D003287:Contrast Media; D004337:Drug Carriers; D011092:Polyethylene Glycols; D019793:Fluorescein
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