Small-Animal SPECT/CT of the Progression and Recovery of Rat Liver Fibrosis by Using an Integrin αvß3-targeting Radiotracer.

PURPOSE: To assess the potential utility of an integrin αvß3-targeting radiotracer, technetium 99m-PEG4-E[PEG4-cyclo(arginine-glycine-aspartic acid-D-phenylalanine-lysine)]2 ((99m)Tc-3PRGD2), for single photon emission computed tomography (SPECT)/computed tomography (CT) for monitoring of the progression and prognosis of liver fibrosis in a rat model. MATERIALS AND METHODS: All animal experiments were performed by following the protocol approved by the institutional animal care and use committee. (99m)Tc-3PRGD2 was prepared and longitudinal SPECT/CT was performed to monitor the progression (n = 8) and recovery (n = 5) of liver fibrosis induced in a rat model by means of thioacetamide (TAA) administration. The mean liver-to-background radioactivity per unit volume ratio was analyzed for comparisons between the TAA and control (saline) groups at different stages of liver fibrosis. Data were compared by using Student t and Mann-Whitney tests. Results:of SPECT/CT were compared with those of ex vivo biodistribution analysis (n = 5). RESULTS: Accumulation of (99m)Tc-3PRGD2 in the liver increased in proportion to the progression of fibrosis and TAA exposure time; accumulation levels were significantly different between the TAA and control groups as early as week 4 of TAA administration (liver-to-background ratio: 32.30 ± 3.39 vs 19.01 ± 3.31; P = .0002). Results of ex vivo immunofluorescence staining demonstrated the positive expression of integrin αvß3 on the activated hepatic stellate cells, and the integrin αvß3 levels in the liver corresponded to the results of SPECT/CT (R(2) = 0.75, P < .0001). (99m)Tc-3PRGD2 uptake in the fibrotic liver decreased after antifibrotic therapy with interferon α2b compared with that in the control group (relative liver-to-background ratio: 0.45 ± 0.05 vs 1.01 ± 0.05; P < .0001) or spontaneous recovery (relative liver-to-background ratio: 0.56 ± 0.06 vs 1.01 ± 0.05; P < .0001). CONCLUSION: (99m)Tc-3PRGD2 SPECT/CT was successfully used to monitor the progression and recovery of liver fibrosis and shows potential applications for noninvasive diagnosis of early stage liver fibrosis.

Serial in vivo imaging using a fluorescence probe allows identification of tumor early response to cetuximab immunotherapy.

Cetuximab is an antiepidermal growth factor receptor (EGFR) monoclonal antibody that has received the approval of the Food and Drug Administration (FDA) for cancer treatment. However, most clinical studies indicate that cetuximab can only elicit positive effects on a subset of cancer patients. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging of tumor vascular endothelial growth factor (VEGF) expression could be a biomarker for tumor early response to cetuximab therapy in preclinical wild-type and mutant tumor models of the KRAS gene. The treatment efficacy of cetuximab was determined in both HT-29 (wild-type KRAS) and HTC-116 (mutant KRAS) human colon cancer models. A VEGF-specific optical imaging probe (Dye755-Ran) was synthesized by conjugating ranibizumab (an anti-VEGF antibody Fab fragment) with a NIRF dye. Serial optical scans with Dye755-Ran were performed in HT-29 and HTC-116 xenograft models. By using longitudinal NIRF imaging, we were able to detect early tumor response on day 3 and day 5 after initiation of cetuximab treatment in the cetuximab-responsive HT-29 tumor model. Enzyme-linked immunosorbent assay (ELISA) confirmed that cetuximab treatment inhibited human VEGF expression in the KRAS wild-type HT-29 tumor but not in the KRAS mutant HCT-116 tumor. We have demonstrated that the antitumor effect of cetuximab can be noninvasively monitored by serial fluorescence imaging using Dye755-Ran. VEGF expression detected by optical imaging could serve as a sensitive biomarker for tumor early response to drugs that directly or indirectly act on VEGF.

The impact of corporate governance on the total factor productivity of pharmaceutical enterprises: a study based on the fsQCA method.

The pharmaceutical industry is an important industry for the national economy and the people's livelihood, which is not only beneficial to the people's livelihood, but also has huge commercial value. How to promote the development of Chinese pharmaceutical industry is an urgent problem to be solved. In this study, 47 listed pharmaceutical companies are taken as cases, and Qualitative Comparative Analysis of Fuzzy Sets (fsQCA) is used to analyze the influence of five antecedent conditions on the total factor productivity of pharmaceutical enterprises from the perspective of corporate governance, and to explore the composition to Total Factor Productivity (TFP) improvement. The results are as follows. First, single corporate governance factor does not constitute the necessary condition to improve the TFP of pharmaceutical enterprises. Second, there are three configurations of high TFP of pharmaceutical enterprises, among these, two configurations belong to regulatory constraints type and one configuration belongs to the active board type. There is only one configurations to low TFP of pharmaceutical enterprises: the passive board. Based on the perspective of configuration, this paper discusses how corporate governance drives TFP improvement in pharmaceutical enterprises, which can provide systematic thinking and practical guidance for each company to promote its TFP improvement according to its own corporate structure.

Development of a Wilms' tumor antigen-specific T-cell receptor for clinical trials: engineered patient's T cells can eliminate autologous leukemia blasts in NOD/SCID mice.

BACKGROUND: The Wilms' tumor antigen (WT1) is an attractive target for immunotherapy of leukemia. In the past, we isolated and characterized the specificity and function of a WT1-specific T-cell receptor. The goal of this translational study was to develop a safe and efficient WT1-T-cell receptor retroviral vector for an adoptive immunotherapy trial with engineered T cells. DESIGN AND METHODS: We generated a panel of retroviral constructs containing unmodified or codon-optimized WT1-T-cell receptor alpha and beta genes, linked via internal ribosome entry sites or 2A sequences, with or without an additional inter-chain disulfide bond in the T-cell receptor constant domains. These constructs were functionally analyzed in vitro, and the best one was tested in an autologous primary leukemia model in vivo. RESULTS: We identified a WT1-T-cell receptor construct that showed optimal tetramer staining, antigen-specific cytokine production and killing activity when introduced into primary human T cells. Fresh CD34(+) cells purified from a patient with leukemia were engrafted into NOD/SCID mice, followed by adoptive immunotherapy with patient's autologous T cells transduced with the WT1-T-cell receptor. This therapeutic treatment evidently decreased leukemia engraftment in mice and resulted in a substantial improvement of leukemia-free survival. CONCLUSIONS: This is the first report that patient's T cells, engineered to express the WT1-T-cell receptor, can eliminate autologous leukemia progenitor cells in an in vivo model. This study provides a firm basis for the planned WT1-T-cell receptor gene therapy trial in leukemia patients.

IL15 can reverse the unresponsiveness of Wilms' tumor antigen-specific CTL in patients with prostate cancer.

PURPOSE: The Wilms' tumor antigen 1 (WT1) is overexpressed in several leukemias and solid tumors, but there is currently limited information regarding its role in prostate cancer. This study aimed to investigate WT1 expression in prostate cancer, and to determine the number and function of WT1-specific T cells in the peripheral blood of patients. EXPERIMENTAL DESIGN: Immunohistochemistry was used to assess WT1 expression in cancer tissues. Human leukocyte antigen A2 (HLA-A2) tetramers served to detect WT1-specific T cells, and peptide-specific stimulation was used to assess T-cell function in vitro. RESULTS: Immunohistochemistry of tissue arrays comprising 36 cancer and 8 normal prostate samples revealed nuclear WT1 staining in 39% of cancer samples, but not in normal prostate tissues. Tetramer analysis revealed a low frequency of WT1-specific T cells in 20 of 38 HLA-A2-positive patients. In vitro stimulation with WT1 peptide plus interleukin 2(IL2) and interleukin 7 (IL7) did not lead to an accumulation of WT1-specific T cells in any of the patient samples, although all patients were able to generate T-cell responses against Melan-A/MART1 control peptide. Stimulation with WT1 peptide in the presence of interleukin 15 (IL15), a cytokine that was shown to reverse tolerance of murine tumor-specific T cells, was able to restore the expansion and IFNgamma production of WT1-specific T cells in a subgroup of prostate cancer patients. CONCLUSION: The observation that IL15 can restore the function of WT1-specific T cells that were unresponsive to IL2 has implications for vaccination and immunotherapeutic strategies that aim to enhance WT1-specific T cell immunity in patients.

Smart strategies to overcome tumor hypoxia toward the enhancement of cancer therapy.

Hypoxia, as a typical factor in a tumor microenvironment, plays a vital role in tumor treatment resistance, tumor invasion and migration. Hypoxia inducible factor (HIF), as the vital response element of hypoxia, mediates these untoward effects through a series of downstream reactions. Cancer treatments such as photodynamic therapy (PDT), radiotherapy (RT) and chemotherapy are severely hindered by hypoxia and HIF, back, however, could be intelligently manipulated through nanocomposite materials for their great potentiality to combine different functions. Herein, we reviewed the smart strategies in emerging research studies to overcome hypoxia toward the enhancement of tumor therapy.

Small-animal SPECT/CT imaging of cancer xenografts and pulmonary fibrosis using a 99mTc-labeled integrin αvß6-targeting cyclic peptide with improved in vivo stability.

ABSTRACT: Integrin αvß6 is expressed at an undetectable level in normal tissues, but is remarkably upregulated during many pathological processes, especially in cancer and fibrosis. Noninvasive imaging of integrin αvß6 expression using a radiotracer with favorable in vivo pharmacokinetics would facilitate disease diagnosis and therapy monitoring. Through disulfide-cyclized method, we synthesized in this study, a new integrin αvß6-targeted cyclic peptide (denoted as cHK), and radiolabeled it with 99mTc. The ability of the resulting radiotracer 99mTc-HYNIC-cHK to detect integrin αvß6 expression in pancreatic cancer xenografts and idiopathic pulmonary fibrosis was evaluated using small-animal single-photon emission computed tomography (SPECT)/computed tomography (CT). 99mTc-HYNIC-cHK showed significantly improved in vivo metabolic stability compared to the linear peptide-based radiotracer 99mTc-HYNIC-HK. 99mTc-HYNIC-cHK exhibited similar biodistribution properties to 99mTc-HYNIC-HK, but the tumor-to-muscle ratio was significantly increased (2.99 ± 0.87 vs. 1.82 ± 0.27, P < 0.05). High-contrast images of integrin αvß6-positive tumors and bleomycin-induced fibrotic lungs were obtained by SPECT/CT imaging using 99mTc-HYNIC-cHK. Overall, our studies demonstrate that 99mTc-HYNIC-cHK is a promising SPECT radiotracer for the noninvasive imaging of integrin αvß6 in living subjects.

Noninvasive small-animal imaging of galectin-1 upregulation for predicting tumor resistance to radiotherapy.

Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). Herein, we investigated whether near-infrared fluorescence (NIRF) imaging and positron-emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or 64Cu, and NIRF and PET imaging using the resulting probes (Dye-αGal-1 and 64Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-αGal-1) were performed in 4T1 breast cancer-bearing mice treated with several rounds of sorafenib. Radiotherapy was performed in vitro and in vivo to identify the role of galectin-1 in radioresistance. NIRF and PET imaging both revealed significantly increased upregulation of galectin-1 in the hypoxic tumors after sorafenib treatment, which was verified by ex vivo biodistribution, western blotting, and enzyme-linked immunosorbent assays. Galectin-1 specific inhibition by thiodigalactoside dramatically improved the efficacy of radiotherapy, and overcame sorafenib-induced radiotherapy resistance. Taken together, galectin-1 is a key mediator of tumor resistance to radiotherapy. Targeted molecular imaging allows for real-time, noninvasive, and quantitative detection of the dynamic changes in galectin-1 levels in vivo; this introduces the possibility of early detection of tumor resistance to therapies.

Chemotherapy-Induced Macrophage Infiltration into Tumors Enhances Nanographene-Based Photodynamic Therapy.

Increased recruitment of tumor-associated macrophages (TAM) to tumors following chemotherapy promotes tumor resistance and recurrence and correlates with poor prognosis. TAM depletion suppresses tumor growth, but is not highly effective due to the effects of tumorigenic mediators from other stromal sources. Here, we report that adoptive macrophage transfer led to a dramatically enhanced photodynamic therapy (PDT) effect of 2-(1-hexyloxyethyl)-2-devinyl pyropheophor-bide-alpha (HPPH)-coated polyethylene glycosylated nanographene oxide [GO(HPPH)-PEG] by increasing its tumor accumulation. Moreover, tumor treatment with commonly used chemotherapeutic drugs induced an increase in macrophage infiltration into tumors, which also enhanced tumor uptake and the PDT effects of GO(HPPH)-PEG, resulting in tumor eradication. Macrophage recruitment to tumors after chemotherapy was visualized noninvasively by near-infrared fluorescence and single-photon emission CT imaging using F4/80-specific imaging probes. Our results demonstrate that chemotherapy combined with GO(HPPH)-PEG PDT is a promising strategy for the treatment of tumors, especially those resistant to chemotherapy. Furthermore, TAM-targeted molecular imaging could potentially be used to predict the efficacy of combination therapy and select patients who would most benefit from this treatment approach. Cancer Res; 77(21); 6021-32. ©2017 AACR.

Inhibiting Metastasis and Preventing Tumor Relapse by Triggering Host Immunity with Tumor-Targeted Photodynamic Therapy Using Photosensitizer-Loaded Functional Nanographenes.

Effective cancer therapy depends not only on destroying the primary tumor but also on conditioning the host immune system to recognize and eliminate residual tumor cells and prevent metastasis. In this study, a tumor integrin αvß6-targeting peptide (the HK peptide)-functionalized graphene oxide (GO) was coated with a photosensitizer (HPPH). The resulting GO conjugate, GO(HPPH)-PEG-HK, was investigated whether it could destroy primary tumors and boost host antitumor immunity. We found that GO(HPPH)-PEG-HK exhibited significantly higher tumor uptake than GO(HPPH)-PEG and HPPH. Photodynamic therapy (PDT) using GO(HPPH)-PEG suppressed tumor growth in both subcutaneous and lung metastatic mouse models. Necrotic tumor cells caused by GO(HPPH)-PEG-HK PDT activated dendritic cells and significantly prevented tumor growth and lung metastasis by increasing the infiltration of cytotoxic CD8+ T lymphocytes within tumors as evidenced by in vivo optical and single-photon emission computed tomography (SPECT)/CT imaging. These results demonstrate that tumor-targeted PDT using GO(HPPH)-PEG-HK could effectively ablate primary tumors and destroy residual tumor cells, thereby preventing distant metastasis by activating host antitumor immunity and suppressing tumor relapse by stimulation of immunological memory.

Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis.

Tumor relapse after initial regression post-chemotherapy is a major challenge in cancer treatment, as it usually leads to local-regional recurrence or inoperable distant metastasis. M2 macrophages diminish the tumor-inhibitory effect of chemotherapy and correlate with distant metastasis and poor prognosis. In this study, we investigated whether molecular imaging of M2 macrophages could serve as an early biomarker for tumor relapse after chemotherapy and tumor lymph node metastasis in preclinical mouse models. Methods: We developed M2 macrophage-targeted probes for near-infrared fluorescence (NIRF) imaging and single-photon emission computed tomography (SPECT) using an anti-CD206 monoclonal antibody. The specific targeting capacity and potential applications of the NIRF and SPECT probes were investigated in subcutaneous tumor and lymph node metastasis models of 4T1 murine breast cancer. Results: M2 macrophage infiltration was significantly increased in the 4T1 tumors that later underwent relapse but not in non-relapsing 4T1 tumors after cyclophosphamide treatment. Through NIRF imaging and SPECT using our synthesized probes, the infiltration of M2 macrophages in relapsing tumors and tumor lymph node metastasis could be sensitively detected. Importantly, early prediction of tumor relapse by molecular imaging of M2 macrophages resulted in an effective eradication of tumors upon combination with additional radiotherapy. Conclusion: Our findings demonstrate that M2 macrophage-targeted imaging allows for noninvasively predicting post-chemotherapy tumor relapse and sensitively detecting the metastatic lymph nodes in vivo. This imaging strategy could provide a better understanding of cancer progression, enable early prediction of tumor resistance, and have implications on the rational design of cancer therapeutics.

Generation of tumor-specific T-cell therapies.

Antigen-specific tumor immunotherapy remains an attractive strategy for the treatment of malignancies. In this review we will discuss why, despite the identification of large numbers of T cell recognised tumor antigens, effective immunotherapy remains a formidable challenge. Effective strategies are needed to deal with the tolerogenic properties of many tumor antigens, and with the immunocompromised status of patients. We discuss different methods of generating tumor-specific T cells which are currently being evaluated in clinical practice, such as vaccination and adoptive transfer of tumor antigen-specific T cells. Finally, we shall discuss novel strategies in development, such as the adoptive transfer of T cell receptor (TCR) gene modified T cells to establish antigen-specific immunity in patients with leukemia and solid cancers. The transfer of validated high avidity TCRs, isolated from 'non-tolerant' repertoires or produced by in vitro affinity maturation, can serve to equip patient T cells with new anti-tumor specificities that are not naturally present in the autologous repertoire. TCR transfer into CD4(+) and CD8(+) T cells can serve to harness the function of both helper and cytotoxic T cells for tumor elimination and establishment of long-term tumor immunity.

Enhanced Anti-Tumor Efficacy through a Combination of Integrin αvß6-Targeted Photodynamic Therapy and Immune Checkpoint Inhibition.

"Training" the host immune system to recognize and systemically eliminate residual tumor lesions and micrometastases is a promising strategy for cancer therapy. In this study, we investigated whether integrin αvß6-targeted photodynamic therapy (PDT) of tumors using a phthalocyanine dye-labeled probe (termed DSAB-HK) could trigger the host immune response, and whether PDT in combination with anti-PD-1 immune checkpoint inhibition could be used for the effective therapy of primary tumors and metastases. By near-infrared fluorescence imaging, DSAB-HK was demonstrated to specifically target either subcutaneous tumors in a 4T1 mouse breast cancer model or firefly luciferase stably transfected 4T1 (4T1-fLuc) lung metastatic tumors. Upon light irradiation, PDT by DSAB-HK significantly inhibited the growth of subcutaneous 4T1 tumors, and in addition promoted the maturation of dendritic cells and their production of cytokines, which subsequently stimulated the tumor recruitment of CD8(+) cytotoxic T lymphocytes. Furthermore, DSAB-HK PDT of the first tumor followed by PD-1 blockade markedly suppressed the growth of a second subcutaneous tumor, and also slowed the growth of 4T1-fLuc lung metastasis as demonstrated by serial bioluminescence imaging. Together, our results demonstrated the synergistic effect of tumor-targeted PDT and immune checkpoint inhibition for improving anti-tumor immunity and suppressing tumor growth/metastasis.

Molecular Imaging of Post-Src Inhibition Tumor Signatures for Guiding Dasatinib Combination Therapy.

UNLABELLED: Noninvasive, real-time, quantitative measurement of key biomarkers associated with cancer therapeutic interventions could provide a better understanding of cancer biology. We investigated in this study whether incorporating multiple molecular imaging approaches could be used to guide dasatinib anti-Src therapy and aid in the rational design of a combination therapy regimen. METHODS: Bioluminescence imaging, (18)F-FDG PET, integrin αvß3-targeted SPECT/CT, and vascular endothelial growth factor-targeted near-infrared fluorescence imaging were performed before and after dasatinib treatment in a tumor mouse model. RESULTS: There was no significant difference in the bioluminescence imaging signal or (18)F-FDG tumor uptake in dasatinib-treated tumors compared with the control tumors. However, the uptake of (99m)T-3PRGD2 (integrin αvß3-specific) and DyLight755-ranibizumab (vascular endothelial growth factor-specific) in the dasatinib-treated tumors was significantly lower than that in the control tumors. In vitro studies confirmed the antiangiogenic effects of dasatinib but indicated a lack of cytotoxicity. Dasatinib plus cytotoxic docetaxel elicited marked synergistic tumor growth inhibition in vivo. CONCLUSION: Visualization of post-Src inhibition tumor signatures through multiple imaging approaches facilitates sensitive and quantitative measurement of cancer biomarkers in vivo, thus aiding in the rational design of dasatinib combination therapy.

Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model.

Tumor-associated macrophages (TAMs) play essential roles in tumor invasion and metastasis, and contribute to drug resistance. Clinical evidence suggests that TAM levels are correlated with local tumor relapse, distant metastasis, and poor prognosis in patients. In this study, we synthesized a TAM-targeted probe (IRD-αCD206) by conjugating a monoclonal anti-CD206 antibody with a near-infrared phthalocyanine dye. We then investigated the potential application of the IRD-αCD206 probe to near-infrared fluorescence (NIRF) imaging and photoimmunotherapy (PIT) of tumors resistant to treatment with the kinase inhibitor sorafenib. Sorafenib treatment had no effect on tumor growth in a 4T1 mouse model of breast cancer, but induced M2 macrophage polarization in tumors. M2 macrophage recruitment by sorafenib-treated 4T1 tumors was noninvasively visualized by in vivo NIRF imaging of IRD-αCD206. Small-animal single-photon emission computed tomography (SPECT)/CT and intratumoral microdistribution analysis indicated TAM-specific localization of the IRD-αCD206 probe in 4T1 tumors after several rounds of sorafenib treatment. Upon light irradiation, IRD-αCD206 suppressed the growth of sorafenib-resistant tumors. In vivo CT imaging and ex vivo histological analysis confirmed the inhibition of lung metastasis in mice by IRD-αCD206 PIT. These results demonstrate the utility of the IRD-αCD206 probe for TAM-targeted diagnostic imaging and treatment of tumors that are resistant to conventional therapeutics.

Immunotherapy with CTL restricted by nonself MHC.

In the past years a number of target antigens recognized by cytotoxic T-lymphocytes (CTL) have been identified in human malignancies. In most cases, the CTL-recognized antigens did not arise from mutations, but were instead encoded by genes that were identical in normal and tumor cells. Gene expression in normal tissues may result in tolerance of high avidity CTL, leaving behind low avidity CTL that cannot provide effective immunity against tumors expressing the relevant target antigens. In this chapter we describe a strategy to circumvent immunological tolerance that can be used to generate high avidity CTL against self-proteins, including human tumor-associated antigens.

Recent Advances in Molecular Image-Guided Cancer Radionuclide Therapy.

Cancer-targeted radionuclide therapy is a promising approach for the treatment of a wide variety of malignancies, especially those resistant to conventional therapies. However, to improve the use of targeted radionuclide therapy for the management of cancer patients, the in vivo behaviors, dosimetry, and efficacy of radiotherapeutic agents need to be well characterized and monitored. Molecular imaging, which is a powerful tool for the noninvasive characterization and quantification of biological processes in living subjects at the cellular and molecular levels, plays an important role in the guidance of cancer radionuclide therapy. In this review, we introduce the radiotherapeutics for cancer-targeted therapy and summarize the most recent evidence supporting the use of molecular imaging to guide cancer radionuclide therapy.

A near-infrared phthalocyanine dye-labeled agent for integrin αvß6-targeted theranostics of pancreatic cancer.

Integrin αvß6 is widely upregulated in variant malignant cancers but is undetectable in normal organs, making it a promising target for cancer diagnostic imaging and therapy. Using streptavidin-biotin chemistry, we synthesized an integrin αvß6-targeted near-infrared phthalocyanine dye-labeled agent, termed Dye-SA-B-HK, and investigated whether it could be used for cancer imaging, optical imaging-guided surgery, and phototherapy in pancreatic cancer mouse models. Dye-SA-B-HK specifically bound to integrin αvß6 in vitro and in vivo with high receptor binding affinity. Using small-animal optical imaging, we detected subcutaneous and orthotopic BxPC-3 human pancreatic cancer xenografts in vivo. Upon optical image-guidance, the orthotopically growing pancreatic cancer lesions could be successfully removed by surgery. Using light irradiation, Dye-SA-B-HK manifested remarkable antitumor effects both in vitro and in vivo. (18)F-FDG positron emission tomography (PET) imaging and ex vivo fluorescence staining validated the observed decrease in proliferation of treated tumors by Dye-DA-B-HK phototherapy. Tissue microarray results revealed overexpression of integrin αvß6 in over 95% cases of human pancreatic cancer, indicating that theranostic application of Dye-DA-B-HK has clear translational potential. Overall, the results of this study demonstrated that integrin αvß6-specific Dye-SA-B-HK is a promising theranostic agent for the management of pancreatic cancer.

Molecular imaging of tumor-infiltrating macrophages in a preclinical mouse model of breast cancer.

Significant evidence has indicated that tumor-associated macrophages (TAMs) play a critical role in the proliferation, invasion, angiogenesis, and metastasis of a variety of human carcinomas. In this study, we investigated whether near-infrared fluorescence (NIRF) imaging using a macrophage mannose receptor (MMR; CD206)-targeting agent could be used to noninvasively visualize and quantify changes in TAMs in vivo. The CD206-targeting NIRF agent, Dye-anti-CD206, was prepared and characterized in vitro and in vivo. By using NIRF imaging, we were able to noninvasively image tumor-infiltrating macrophages in the 4T1 mouse breast cancer model. Importantly, longitudinal NIRF imaging revealed the depletion of macrophages in response to zoledronic acid (ZA) treatment. However, ZA alone did not lead to the inhibition of 4T1 tumor growth. We therefore combined anti-macrophage ZA therapy and tumor cytotoxic docetaxel (DTX) therapy in the mouse model. The results demonstrated that this combination strategy could significantly inhibit tumor growth as well as tumor metastasis to the lungs. Based on these findings, we concluded that CD206-targeted molecular imaging can sensitively detect the dynamic changes in tumor-infiltrating macrophages, and that the combination of macrophage depletion and cytotoxic therapy is a promising strategy for the effective treatment of solid tumors.