Background-Invisible NIR fluorescent light can provide high sensitivity, high-resolution, and real-time image-guidance during oncologic surgery, but imaging systems that are presently available do not display this invisible light in the context of surgical anatomy. The FLARE™ imaging system overcomes this major obstacle.

SUMMARYNanoparticles (NPs) have the potential to revolutionize drug delivery, however, administering them to the human body without the need for intravenous injection remains a major challenge. In this study, a series of near-infrared (NIR) fluorescent NPs were systematically varied in chemical composition, shape, size, and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that NPs with hydrodynamic diameter (HD) less than ≈ 34 nm and a non-cationic surface charge translocate rapidly from lung to mediastinal lymph nodes. NPs of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings to drug delivery, air pollution, and carcinogenesis. KeywordsNanoparticles; nanomedicine; drug delivery; air pollution; lymph node uptake; biodistribution; renal clearance * Co-Senior Authors: Beth Israel Deaconess Medical Center 330 Brookline Avenue, Room SL-B05 Boston, MA 02215 Phone: 617-667-0692 Fax: 617-667-0981 jfrangio@bidmc.harvard.edu Harvard School of Public Health 665 Huntington Avenue Boston, MA 02115 Phone: 617-432-0127 Fax: 617-432-4710 atsuda@hsph.harvard.edu . AUTHOR CONTRIBUTIONS H.S.C., Y.A., J.H.L., S.H.K., A.M., N.I., and A.T. performed the experiments. H.S.C., M.G.B., M.S.B., A.T., and J.V.F. reviewed, analyzed, and interpreted the data. H.S.C., A.T., and J.V.F. wrote the paper. All authors discussed the results and commented on the manuscript. Nanoparticles (NPs) have been proposed as diagnostic, therapeutic, and theragnostic agents for a wide variety of human diseases. 1-3 Lung-based drug delivery of NPs is receiving increased attention due to the large surface area available and the minimal anatomical barriers limiting access to the body. 4 In this study, we explore whether it would be possible to administer NPs via the lung, and in so doing, attempt to define the key parameters that mediate lung to body NP translocation and subsequent elimination (i.e., clearance). COMPETING INTERESTS STATEMENTLung-administered NPs also have significant implications for air pollution. Recent toxicological studies have confirmed that nano-sized or ultrafine particles reach deep into the alveolar region of the lungs 5,6 and cause severe inflammation reactions due to their large surface areas per mass. 6 Inhalation of NPs is increasingly recognized as a major cause of adverse health effects, and has especially strong influence on the cardiovascular system and hemostasis, leading to increased cardiovascular morbidity and mortality. [6][7][8] The standard approach for studying the translocation of inhaled NPs and ultrafine air pollutants from the lungs to extrapulmonary compartments in animals is to perform postmortem analysis of tissues after inhalation of carbon-based particles, 9 radiotracers, 10 or neutron-activated metal particles. 11-13 Recently, Moller et al. reported that ultrafine NPs could pass from the lungs into bloodstream an...

Background and Aims Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown. Approach and Results We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8+) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4+ cells. We also found that under anti‐PD‐1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody. Conclusions We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.

BackgroundChemokines are involved in multiple aspects of pathogenesis and cellular trafficking in tumorigenesis. In this study, we report that the latest member of the C-X-C-type chemokines, CXCL17 (DMC/VCC-1), recruits immature myeloid-derived cells and enhances early tumor progression.Methodology/Principal FindingsCXCL17 was preferentially expressed in some aggressive types of gastrointestinal, breast, and lung cancer cells. CXCL17 expression did not impart NIH3T3 cells with oncogenic potential in vitro, but CXCL17-expressing NIH3T3 cells could form vasculature-rich tumors in immunodeficient mice. Our data showed that CXCL17-expressing tumor cells increased immature CD11b+Gr1+ myeloid-derived cells at tumor sites in mice and promoted CD31+ tumor angiogenesis. Extensive chemotactic assays proved that CXCL17-responding cells were CD11b+Gr1highF4/80− cells (∼90%) with a neutrophil-like morphology in vitro. Although CXCL17 expression could not increase the number of CD11b+Gr1+ cells in tumor-burdened SCID mice or promote metastases of low metastatic colon cancer cells, the existence of CXCL17-responding myeloid-derived cells caused a striking enhancement of xenograft tumor formation.Conclusions/SignificanceThese results suggest that aberrant expression of CXCL17 in tumor cells recruits immature myeloid-derived cells and promotes tumor progression through angiogenesis.