Gold Nanoclusters Doped with (64)Cu for CXCR4 Positron Emission Tomography Imaging of Breast Cancer and Metastasis.

As an emerging class of nanomaterial, nanoclusters hold great potential for biomedical applications due to their unique sizes and related properties. Herein, we prepared a (64)Cu doped gold nanocluster ((64)CuAuNC, hydrodynamic size: 4.2 ± 0.5 nm) functionalized with AMD3100 (or Plerixafor) for targeted positron emission tomography (PET) imaging of CXCR4, an up-regulated receptor on primary tumor and lung metastasis in a mouse 4T1 orthotopic breast cancer model. The preparation of targeted (64)CuAuNCs-AMD3100 (4.5 ± 0.4 nm) was done via one-step reaction with controlled conjugation of AMD3100 and specific activity, as well as improved colloid stability. In vivo pharmacokinetic evaluation showed favorable organ distribution and significant renal and fecal clearance within 48 h post injection. The expression of CXCR4 in tumors and metastasis was characterized by immunohistochemistry, Western blot, and reverse transcription polymerase chain reaction analysis. PET imaging with (64)CuAuNCs-AMD3100 demonstrated sensitive and accurate detection of CXCR4 in engineered tumors expressing various levels of the receptor, while competitive receptor blocking studies confirmed targeting specificity of the nanoclusters. In contrast to nontargeted (64)CuAuNCs and (64)Cu-AMD3100 alone, the targeted (64)CuAuNCs-AMD3100 detected up-regulated CXCR4 in early stage tumors and premetastatic niche of lung earlier and with greater sensitivity. Taken together, we believe that (64)CuAuNCs-AMD3100 could serve as a useful platform for early and accurate detection of breast cancer and metastasis providing an essential tool to guide the treatment.

Contrasting phylogeographic histories between broadly sympatric topminnows in the Fundulus notatus species complex.

Sympatrically distributed closely related species provide opportunities for studying evolutionary patterns of diversification. Such studies must account for historical contingencies in interpreting contemporary patterns of variation. Topminnows in the Fundulus notatus species complex are distributed sympatrically across much of the southern and Midwestern United States. Throughout most of their ranges F. olivaceus is often found in headwater stream habitats, and F. notatus is more typically distributed along the margins of larger river habitats. However, in some drainages, ecological associations of the respective species are reversed, with F. notatus populations isolated in headwater streams and F. olivaceus in downstream river habitats. Phylogeographic analyses of AFLP marker and multi-locus sequence data detected historical isolation in F. notatus consistent with pre-Pleistocene drainage patterns. Four F. notatus clades corresponded to (i) the Western Gulf Slope, (ii) the southwestern Ouachita Highlands, (iii) the Mobile Basin, and (iv) central Coastal Plain and Mississippi River Basin. In contrast, a relative lack of range-wide geographic structure in F. olivaceus is consistent with recent range expansion over much of the same geographic area. The southwestern Ouachita Highlands and Mobile Basin F. notatus clades corresponded to regions where ecological associations between the two species are reversed, providing evidence of the independent evolution of variation in contemporary habitat associations. Fundulus olivaceus from several drainages demonstrated introgression of mitochondrial DNA from F. notatus, but none of the sites in this study included individuals with hybrid ancestry in their nuclear genome. Phylogenetic analyses that included only nuclear loci supported the reciprocal monophyly of F. notatus, F. olivaceus and a third narrowly endemic species, Fundulus euryzonus, and supported a sister relationship between F. olivaceus and F. euryzonus.