Joshua E. Collins

Morphologically controlled synthesis of colloidal upconversion nanophosphors and their shape-directed self-assembly

We report a one-pot chemical approach for the synthesis of highly monodisperse colloidal nanophosphors displaying bright upconversion luminescence under 980 nm excitation. This general method optimizes the synthesis with initial heating rates up to 100 °C/minute generating a rich family of nanoscale building blocks with distinct morphologies (spheres, rods, hexagonal prisms, and plates) and upconversion emission tunable through the choice of rare earth dopants. Furthermore, we employ an interfacial assembly strategy to organize these nanocrystals (NCs) into superlattices over multiple length scales facilitating the NC characterization and enabling systematic studies of shape-directed assembly. The global and local ordering of these superstructures is programmed by the precise engineering of individual NC’s size and shape. This dramatically improved nanophosphor synthesis together with insights from shape-directed assembly will advance the investigation of an array of emerging biological and energy-related nanophosphor applications.

Epigenetic modulation of endogenous tumor suppressor expression in lung cancer xenografts suppresses tumorigenicity

Epigenetic changes involved in cancer development, unlike genetic changes, are reversible. DNA methyltransferase and histone deacetylase inhibitors show antiproliferative effects in vitro, through tumor suppressor reactivation and induction of apoptosis. Such inhibitors have shown activity in the treatment of hematologic disorders but there is little data concerning their effectiveness in treatment of solid tumors. FHIT, WWOX and other tumor suppressor genes are frequently epigenetically inactivated in lung cancers. Lung cancer cell clones carrying conditional FHIT or WWOX transgenes showed significant suppression of xenograft tumor growth after induction of expression of the FHIT or WWOX transgene, suggesting that treatments to restore endogenous Fhit and Wwox expression in lung cancers would result in decreased tumorigenicity. H1299 lung cancer cells, lacking Fhit, Wwox, p16INK4a and Rassf1a expression due to epigenetic modifications, were used to assess efficacy of epigenetically targeted protocols in suppressing growth of lung tumors, by injection of 5‐aza‐2‐deoxycytidine (AZA) and trichostatin A (TSA) in nude mice with established H1299 tumors. High doses of intraperitoneal AZA/TSA suppressed growth of small tumors but did not affect large tumors (200 mm3); lower AZA doses, administered intraperitoneally or intratumorally, suppressed growth of small tumors without apparent toxicity. Responding tumors showed restoration of Fhit, Wwox, p16INKa, Rassf1a expression, low mitotic activity, high apoptotic fraction and activation of caspase 3. These preclinical studies show the therapeutic potential of restoration of tumor suppressor expression through epigenetic modulation and the promise of re‐expressed tumor suppressors as markers and effectors of the responses.

Peritoneal perfusion with oxygenated perfluorocarbon augments systemic oxygenation.

Background Despite maximal ventilatory support, many patients die from hypoxia in the setting of potentially reversible pulmonary failure. There remains a pressing need for additional pulmonary supportive care measures, especially techniques that do not require systemic anticoagulation. The objective of our experiments was to determine whether systemic oxygenation could be increased in a large animal, with induced hypoxia, by perfusing the abdominal cavity with oxygenated perfluorocarbons. Methods Fifteen pigs with a mean (± SD) weight of 45 ± 5 kg were intubated and rendered hypoxic by ventilating them with a blend of nitrogen and oxygen to achieve subatmospheric concentrations of inspired oxygen ranging from 18 to 10%, resulting in baseline mean Pao2 range of 65.9 ± 9.7 to 26.6 ± 2.8 mm Hg, respectively. Peritoneal perfusion was performed in eight animals with oxygenated perfluorocarbon and in seven control animals with oxygenated saline solution. Results The average increase in Pao2 with oxygenated perfluorocarbon perfusion, compared to oxygenated saline solution perfusion, ranged from 8.1 to 18.2 mm Hg. A common treatment effect was estimated across all fraction of inspired oxygen (Fio2) values, representing the average mean difference in oxygen uptake between oxygenated perfluorocarbon and saline solution, irrespective of the level of Fio2. This average was 12.8 mm Hg (95% confidence interval, 7.4 to 18.2; p < 0.001). The most clinically relevant results occurred at an Fio2 of 14%, resulting in a baseline mean Pao2 of 39.4 ± 5.0 mm Hg with oxygenated saline solution perfusion, and a mean Pao2 of 55.3 ± 7.6 mm Hg with oxygenated perfluorocarbon perfusion. This corresponded to an increase in arterial oxygen saturation from 73 to 89%. Conclusion These results of our principle experiments demonstrate that the peritoneal cavity can be used for gas exchange and, in our model, yielded clinically relevant increases in systemic arterial oxygen levels. This technique may have the potential for the supportive care of patients dying from hypoxia in the setting of reversible lung injury.

Infrared light utilized for photodynamic therapy by activation of rare earth phosphors for visible light generation.

Introduction: Photodynamic therapy (PDT) is a treatment for cancer requiring activation of a photosensitizer for light-mediated tumor cytotoxicity. PDT is limited by tissue penetration because visible light is required for photosensitizer activation. SunstonesTM are rare-earth phosphors which up-convert energy from infrared wavelengths to emit higher energy in the visible spectrum. We utilized this unique characteristic to generate light of appropriate intensity and wavelength for photosensitizer activation and subsequent tumor cell eradication. Methods: SunstonesTM with infrared absorption at 808 and 980nm and visible two-photon emission at 549.9 and 663.1nm were used. A murine NSCLC line was used to determine in vitro toxicity of SunstonesTM and dose response curves for SunstonesTM-mediated PDT. Human NSCLC cells were incubated with/without PhotofrinTM (photosensitizer). Experimental groups included: Infrared light treatment (IR), IR+PhotofrinTM, IR+SunstonesTM, and IR+SunstonesTM+PhotofrinTM. Groups were exposed to 2.5W of 808nm light and assayed for metabolic activity. Results: In vitro toxicity assays showed no significant toxicological side effects after 1 week incubation with SunstonesTM and demonstrated linear response in cytotoxicity as treatment times and infrared dose increased. IR+SunstonesTM+PhotofriTM group showed significantly decreased metabolic activity compared to control cells, cells treated with IR+SunstonesTM, and IR alone. Conclusion: SunstonesTM are nontoxic nanocrystals capable of activating photosensitizers for PDT. Future directions include conjugation of up-converters to a novel photosensitizer and managing the selective uptake of conjugate by tumor cells.