We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.

Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-kappaB and NF-kappaB-regulated gene products, leading to inhibition of proliferation and angiogenesis.

Purpose: To develop and validate an optical imaging nanoprobe for the discrimination of epidermal growth factor (EGF) receptor (EGFR)^overexpressing tumors from surrounding normal tissues that also expresses EGFR. Experimental Design: Near-infrared (NIR) quantum dots (QD) were coupled to EGF using thiol-maleimide conjugation to create EGF-QD nanoprobes. In vitro binding affinity of these nanoprobes and unconjugated QDs was evaluated in a panel of cell lines, with and without anti-EGFR antibody pretreatment. Serial optical imaging of HCT116 xenograft tumors was done after systemic injection of QD and EGF-QD. Results: EGF-QD showed EGFR-specific binding in vitro. In vivo imaging showed three distinct phases, tumor influx (f3 min), clearance (f60 min), and accumulation (1-6 h), of EGF-QD nanoprobes. Both QD and EGF-QD showed comparable nonspecific rapid tumor influx and clearance followed by attainment of an apparent dynamic equilibrium at f60 min. Subsequently (1-6 h), whereas QD concentration gradually decreased in tumors, EGF-QDs progressively accumulated in tumors. On delayed imaging at 24 h, tumor fluorescence decreased to near-baseline levels for both QD and EGF-QD. Ex vivo whole-organ fluorescence, tissue homogenate fluorescence, and confocal microscopic analyses confirmed tumor-specific accumulation of EGF-QD at 4 h. Immunofluorescence images showed diffuse colocalization of EGF-QD fluorescence within EGFR-expressing tumor parenchyma compared with patchy perivascular sequestration of QD. Conclusion: These results represent the first pharmacokinetic characterization of a robust EGFR imaging nanoprobe. The measurable contrast enhancement of tumors 4 h after systemic administration of EGF-QD and its subsequent normalization at 24 h imply that this nanoprobe may permit quantifiable and repetitive imaging of EGFR expression.One of the most promising biological targets for cancer therapy is the epidermal growth factor (EGF) receptor (EGFR), a transmembrane glycoprotein that controls pleiotropic biological phenomena, including proliferation, angiogenesis, tissue invasion, and metastasis (1, 2). Although EGFR is ubiquitously expressed in normal tissues, it is preferentially overexpressed on the surface of many tumors and downstream signaling from this receptor renders them resistant to standard therapies (3,4). Targeted therapies that selectively inhibit this receptor have found widespread clinical applicability (4) but there are few reliable methods to predict response to therapy or gauge treatment response over time (5). Noninvasive imaging techniques that can discriminate between EGFR-overexpressing tumors and surrounding normal tissues that also express EGFR may facilitate repetitive and quantitative imaging of EGFR during a course of treatment.Although several studies have been reported on the imaging of EGFR expression, they predominantly use radiolabeled probes (6 -11). Alternatively, optical imaging using fluorescent techniques (12 -14) offers a convenient means of mapping molecular profiles noninv...

Purpose Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathological response to therapy due to resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays and the mechanism of their radioresistance was investigated. We characterize the transcription factor nuclear factor-κB (NF-κB) activation as a mechanism of inducible radioresistance in colorectal cancer and use curcumin, the active ingredient in the yellow spice turmeric to overcome this resistance. Results Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-κB activity in a dose- and time-dependent manner while curcumin suppressed this radiation-induced NF-κB activation via inhibition of radiation-induced phosphorylation and degradation of IκBα, inhibition of IKK activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-κB regulated gene products (Bcl-2, Bcl-xL, inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions Our results suggest that transient inducible NF-κB activation provides a pro-survival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the anti-tumor effects of radiation therapy.