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Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers., Hyperthermia used as an adjuvant with chemotherapy is highly promising in the treatment of certain cancers. Currently, the small molecule drugs used in combination with hyperthermia were not designed for this application. Herein, we report the evaluation of a chlorambucil and a ruthenium compound modified with a long fluorous chain, which exhibit thermoresponsive activity in colorectal adenocarcinoma xenografts in athymic mice in combination with mild hyperthermia (42 °C). Intraperitoneal injection of the derivatives followed by local hyperthermia showed a synergistic tumor growth reduction by 79% and 90% for the chlorambucil and ruthenium-based derivatives, respectively, with the latter exhibiting a higher synergy in combination with hyperthermia compared to the monotherapies. Histological analysis shows that both derivatives in combination with hyperthermia significantly decrease the number of proliferating tumor cells.

Angiogenesis, the formation of new blood vessels, is involved in many pathological processes like cancer, ischemic disease, atherosclerosis, and chronic inflammation [1]. Inhibition of angiogenesis in cancer is a novel strategy to stop tumor growth/progression. in the angiogenic cascade different cell surface receptors are expressed at the endothelium of the new vasculature. The avb3-integrin is such a receptor which is associated with angiogenesis. The non-invasive in vivo detection of this integrin would allow one to be able to monitor angiogenesis and to be able to follow the effect of anti-angiogenic therapies. Several studies have used the tripeptide sequence arginineglycine- aspartic acid (RGD) conjugated with a radiolabel to image the expression of this integrin with nuclear imaging methods [2,3]. In this study, we aim to non-invasively image the expression of avb3 in tumor bearing mice with Magnetic Resonance Imaging (MRI). Therefore, we developed and used MR-detectable and fluorescent liposomes[4], which carry over 300 RGD-moieties per liposome. The in vivo MRI findings were validated with ex vivo fluorescence microscopy. Material and Methods Paramagnetic and fluorescent liposomes were prepared as described previously [4]. The cyclic RGD and control RAD-peptide were conjugated to maleimide-PEG-DSPE incorporated in the liposomes. The specificity of the liposomes was determined on HUVEC with MRI and fluorescence microscopy. Tumor bearing mice were anesthetized with an isoflurane/airmixture and an infusion line was put into the tail vein. Next, the mice were placed in a 6.3 T MRI scanner. A T1-map and a T1-weighted image were generated before the contrast agent was injected and at 5 time points after the contrast agent was injected. Next, the mice were euthanized and the tumor was dissected and frozen in isopentane. Sections of tissue (10-lm thickness) were prepared and fluorescence microscopy was performed. Results Both MRI and fluorescence microscopy revealed a strong association of the RGD-liposomes to avb3 expressing HUVEC, while RADliposomes did not. MRI on tumor bearing mice howed contrast enhancement of the tumor after injecting the contrast agent, both for RGD-liposomes and RAD-liposomes. Fluorescence microscopy revealed a distinct difference between tumors of mice that were injected with RGD-liposomes or RAD-liposomes. In case of RADliposomes a diffuse pattern of fluorescence was found around tumor blood vessels in the tumor tissue. This can be ascribed to extravasation of the liposomes in the tumor tissue. In contrast, RGD-liposomes were exclusively found was associated with blood vessels. Conclusions: This study demonstrates that molecular MR imaging of angiogenesis is possible by using a targeted contrast agent specific for the avb3-intergin.

Photodynamic therapy (PDT) is an effective clinical treatment for a number of different cancers. PDT can induce hypoxia and inflammation, pro-angiogenic side effects, which may counteract its angio-occlusive mechanism. The combination of PDT with anti-angiogenic drugs offers a possibility for improved anti-tumour outcome. We used two tumour models to test the effects of the clinically approved angiostatic tyrosine kinase inhibitors sunitinib, sorafenib and axitinib in combination with PDT, and compared these results with the effects of bevacizumab, the anti-VEGF antibody, for the improvement of PDT. Best results were obtained from the combination of PDT and low-dose axitinib or sorafenib. Molecular analysis by PCR revealed that PDT in combination with axitinib suppressed VEGFR-2 expression in tumour vasculature. Treatment with bevacizumab, although effective as monotherapy, did not improve PDT outcome. In order to test for tumour vessel normalization effects, axitinib was also applied prior to PDT. The absence of improved PDT outcome in these experiments, as well as the lack of increased oxygenation in axitinib-treated tumours, suggests that vascular normalization did not occur. The current data imply that there is a future for certain anti-angiogenic agents to further improve the efficacy of photodynamic anti-cancer therapy.

Silica particles as a nanoparticulate carrier material for contrast agents have received considerable attention the past few years, since the material holds great promise for biomedical applications. A key feature for successful application of this material in vivo is biocompatibility, which may be significantly improved by appropriate surface modification. In this study, we report a novel strategy to coat silica particles with a dense monolayer of paramagnetic and PEGylated lipids. The silica nanoparticles carry a quantum dot in their center and are made target-specific by the conjugation of multiple alphavbeta3-integrin-specific RGD-peptides. We demonstrate their specific uptake by endothelial cells in vitro using fluorescence microscopy, quantitative fluorescence imaging, and magnetic resonance imaging. The lipid-coated silica particles introduced here represent a new platform for nanoparticulate multimodality contrast agents.