The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Kazuki N. Sugahara - One of the best experts on this subject based on the ideXlab platform.
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new P32 gc1qr ligands for targeted tumor drug delivery
ChemBioChem, 2016Co-Authors: Lauri Paasonen, Shweta Sharma, Gary B. Braun, Venkata Ramana Kotamraju, Thomas D.y. Chung, Zhi-gang She, Kazuki N. SugaharaAbstract:Cell surface P32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind P32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to P32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant P32 and, when injected intravenously, homed to P32-expressing breast tumors in mice. This compound provides a lead for the development of P32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.
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New P32/gC1qR Ligands for Targeted Tumor Drug Delivery.
Chembiochem : a European journal of chemical biology, 2016Co-Authors: Lauri Paasonen, Shweta Sharma, Gary B. Braun, Venkata Ramana Kotamraju, Thomas D.y. Chung, Zhi-gang She, Kazuki N. Sugahara, Marjo Yliperttula, Maurizio PellecchiaAbstract:Cell surface P32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind P32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to P32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant P32 and, when injected intravenously, homed to P32-expressing breast tumors in mice. This compound provides a lead for the development of P32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.
Valentina Fogal - One of the best experts on this subject based on the ideXlab platform.
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A novel small molecule inhibitor of P32 mitochondrial protein overexpressed in glioma.
Journal of translational medicine, 2017Co-Authors: Venkata Mahidhar Yenugonda, Valentina Fogal, Natsuko Nomura, Valentina L. Kouznetsova, Igor F. Tsigelny, Elmar Nurmemmedov, Santosh Kesari, Ivan BabicAbstract:The mitochondrial protein P32 is a validated therapeutic target of cancer overexpressed in glioma. Therapeutic targeting of P32 with monoclonal antibody or P32-binding LyP-1 tumor-homing peptide can limit tumor growth. However, these agents do not specifically target mitochondrial-localized P32 and would not readily cross the blood–brain barrier to target P32-overexpressing gliomas. Identifying small molecule inhibitors of P32 overexpressed in cancer is a more rational therapeutic strategy. Thus, in this study we employed a pharmacophore modeling strategy to identify small molecules that could bind and inhibit mitochondrial P32. A pharmacophore model of C1q and LyP-1 peptide association with P32 was used to screen a virtual compound library. A primary screening assay for inhibitors of P32 was developed to identify compounds that could rescue P32-dependent glutamine-addicted glioma cells from glutamine withdrawal. Inhibitors from this screen were analyzed for direct binding to P32 by fluorescence polarization assay and protein thermal shift. Affect of the P32 inhibitor on glioma cell proliferation was assessed by Alamar Blue assay, and affect on metabolism was examined by measuring lactate secretion. Identification of a hit compound (M36) validates the pharmacophore model. M36 binds directly to P32 and inhibits LyP-1 tumor homing peptide association with P32 in vitro. M36 effectively inhibits the growth of P32 overexpressing glioma cells, and sensitizes the cells to glucose depletion. This study demonstrates a novel screening strategy to identify potential inhibitors of mitochondrial P32 protein overexpressed in glioma. High throughput screening employing this strategy has potential to identify highly selective, potent, brain-penetrant small molecules amenable for further drug development.
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Mitochondrial P32 is upregulated in Myc expressing brain cancers and mediates glutamine addiction
Oncotarget, 2014Co-Authors: Valentina Fogal, Ivan Babic, Ying Chao, Sandra Pastorino, Rajesh Mukthavaram, Pengfei Jiang, Yoon-jae Cho, Sandeep C. Pingle, John R. Crawford, David PiccioniAbstract:Metabolic reprogramming is a key feature of tumorigenesis that is controlled by oncogenes. Enhanced utilization of glucose and glutamine are the best-established hallmarks of tumor metabolism. The oncogene c-Myc is one of the major players responsible for this metabolic alteration. However, the molecular mechanisms involved in Myc-induced metabolic reprogramming are not well defined. Here we identify P32, a mitochondrial protein known to play a role in the expression of mitochondrial respiratory chain complexes, as a critical player in Myc-induced glutamine addiction. We show that P32 is a direct transcriptional target of Myc and that high level of Myc in malignant brain cancers correlates with high expression of P32. Attenuation of P32 expression reduced growth rate of glioma cells expressing Myc and impaired tumor formation in vivo. Loss of P32 in glutamine addicted glioma cells induced resistance to glutamine deprivation and imparted sensitivity to glucose withdrawal. Finally, we provide evidence that P32 expression contributes to Myc-induced glutamine addiction of cancer cells. Our findings suggest that Myc promotes the expression of P32, which is required to maintain sufficient respiratory capacity to sustain glutamine metabolism in Myc transformed cells.
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mitochondrial cell surface protein P32 gc1qr as a molecular target in tumor cells and tumor stroma
Cancer Research, 2008Co-Authors: Valentina Fogal, Lianglin Zhang, Stan Krajewski, Erkki RuoslahtiAbstract:A tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as P32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for P32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-P32 antibodies showed that P32-positive cell lines expressed P32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total P32 expression in the cells. Like the LyP-1 peptide, P32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant P32 expression was common in human cancers and the P32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish P32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make P32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]
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Mitochondrial/cell-surface protein P32/gC1qR as a molecular target in tumor cells and tumor stroma.
Cancer research, 2008Co-Authors: Valentina Fogal, Lianglin Zhang, Stan Krajewski, Erkki RuoslahtiAbstract:A tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as P32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for P32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-P32 antibodies showed that P32-positive cell lines expressed P32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total P32 expression in the cells. Like the LyP-1 peptide, P32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant P32 expression was common in human cancers and the P32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish P32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make P32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]
Dongchon Kang - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial P32 c1qbp is a critical regulator of dendritic cell metabolism and maturation
Cell Reports, 2018Co-Authors: Kazuhito Gotoh, Mikako Yagi, Takeshi Uchiumi, Daiki Setoyama, Takafumi Morisaki, Katsuhiko Sasaki, Ko Igami, Soichi Mizuguchi, Yoshinori Fukui, Dongchon KangAbstract:Summary Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that P32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in P32-deficient DCs. We also found that P32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via P32-dependent PDH activity. P32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that P32 may serve as a therapeutic target for DC-related autoimmune diseases.
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Mitochondrial P32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation
Cell reports, 2018Co-Authors: Kazuhito Gotoh, Mikako Yagi, Takeshi Uchiumi, Daiki Setoyama, Takafumi Morisaki, Katsuhiko Sasaki, Ko Igami, Soichi Mizuguchi, Yoshinori Fukui, Dongchon KangAbstract:Summary Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that P32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in P32-deficient DCs. We also found that P32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via P32-dependent PDH activity. P32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that P32 may serve as a therapeutic target for DC-related autoimmune diseases.
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Mitochondrial P32/C1qbp Is a Critical Regulator of Dendritic Cell Metabolism and Maturation
Elsevier, 2018Co-Authors: Kazuhito Gotoh, Mikako Yagi, Takeshi Uchiumi, Daiki Setoyama, Takafumi Morisaki, Katsuhiko Sasaki, Ko Igami, Soichi Mizuguchi, Yoshinori Fukui, Dongchon KangAbstract:Summary: Dendritic cell (DC) maturation induced by Toll-like receptor agonists requires activation of downstream signal transduction and metabolic changes. The endogenous metabolite citrate has recently emerged as a modulator of DC activation. However, the metabolic requirements that support citrate production remain poorly defined. Here, we demonstrate that P32/C1qbp, which functions as a multifunctional chaperone protein in mitochondria, supports mitochondrial metabolism and DC maturation. Metabolic analysis revealed that the citrate increase induced by lipopolysaccharide (LPS) is impaired in P32-deficient DCs. We also found that P32 interacts with dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase [PDH] complex) and positively regulates PDH activity in DCs. Therefore, we suggest that DC maturation is regulated by citrate production via P32-dependent PDH activity. P32-null mice administered a PDH inhibitor show decreased DC maturation and ovalbumin-specific IgG production in vivo, suggesting that P32 may serve as a therapeutic target for DC-related autoimmune diseases. : Although mitochondrial metabolic pathways are essential for DC activation, the precise molecular mechanism remains poorly understood. Gotoh et al. show that mitochondrial P32/C1qbp supports dendritic cell metabolism and maturation. In addition, mitochondrial P32 and pyruvate dehydrogenase activity are necessary for DC maturation in vitro and in vivo. Keywords: dendritic cell, mitochondria, P32/C1qbp, citrate, pyruvate dehydrogenas
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cardiomyocyte specific loss of mitochondrial P32 c1qbp causes cardiomyopathy and activates stress responses
Cardiovascular Research, 2017Co-Authors: Toshiro Saito, Mikako Yagi, Takeshi Uchiumi, Rie Amamoto, Daiki Setoyama, Yuichi Matsushima, Dongchon KangAbstract:Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial P32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of P32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic P32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial P32/C1qbp in the heart. Methods and results We investigated the role of P32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against P32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of P32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by P32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific P32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the P32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in P32-deficient compared with control myocytes, AMPKɑ was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the P32-deficient hearts. Conclusion These findings support a key role for mitochondrial P32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.
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Cardiomyocyte-specific loss of mitochondrial P32/C1qbp causes cardiomyopathy and activates stress responses.
Cardiovascular research, 2017Co-Authors: Toshiro Saito, Mikako Yagi, Takeshi Uchiumi, Rie Amamoto, Daiki Setoyama, Yuichi Matsushima, Dongchon KangAbstract:Aims Mitochondria are important organelles, dedicated to energy production. Mitochondrial P32/C1qbp, which functions as an RNA and protein chaperone, interacts with mitochondrial mRNA and is indispensable for mitochondrial function through its regulation of mitochondrial translation in cultured cell lines. However, the precise role of P32/C1qbp in vivo is poorly understood because of embryonic lethality in the systemic P32-deficient mouse. The goal of this study was to examine the physiological function of mitochondrial P32/C1qbp in the heart. Methods and results We investigated the role of P32 in regulating cardiac function in mice using a Cre-loxP recombinase technology against P32 with tamoxifen-inducible knockdown or genetic ablation during postnatal periods. Cardiomyocyte-specific deletion of P32 resulted in contractile dysfunction, cardiac dilatation and cardiac fibrosis, compared with hearts of control mice. We also found decreased COX1 expression, decreased rates of oxygen consumption and increased oxidative stress, indicating that these mice had cardiac mitochondrial dysfunction provoked by P32-deficiency at early stage. Next, we investigated lifespan in cardiac-specific P32-deficient mice. The mice died beginning at 12 months and their median lifespan was ∼14 months. Cardiac mitochondria in the P32-deficient mice showed disordered alignment, enlargement and abnormalities in their internal structure by electron microscopy. We observed that, in P32-deficient compared with control myocytes, AMPKɑ was constitutively phosphorylated and 4EBP-1 and ribosomal S6K were less phosphorylated, suggesting impairment of mammalian target of rapamycin signalling. Finally, we found that expression levels of mitokines such as FGF21 and of integrated stress response genes were significantly increased. Metabolic analysis demonstrated that the urea cycle was impaired in the P32-deficient hearts. Conclusion These findings support a key role for mitochondrial P32 protein in cardiac myocytes modulating mitochondrial translation and function, and thereby survival.
Erkki Ruoslahti - One of the best experts on this subject based on the ideXlab platform.
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mitochondrial cell surface protein P32 gc1qr as a molecular target in tumor cells and tumor stroma
Cancer Research, 2008Co-Authors: Valentina Fogal, Lianglin Zhang, Stan Krajewski, Erkki RuoslahtiAbstract:A tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as P32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for P32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-P32 antibodies showed that P32-positive cell lines expressed P32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total P32 expression in the cells. Like the LyP-1 peptide, P32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant P32 expression was common in human cancers and the P32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish P32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make P32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]
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Mitochondrial/cell-surface protein P32/gC1qR as a molecular target in tumor cells and tumor stroma.
Cancer research, 2008Co-Authors: Valentina Fogal, Lianglin Zhang, Stan Krajewski, Erkki RuoslahtiAbstract:A tumor homing peptide, LyP-1, selectively binds to tumor-associated lymphatic vessels and tumor cells in certain tumors and exhibits an antitumor effect. Here, we show that the protein known as P32 or gC1q receptor is the receptor for LyP-1. Various human tumor cell lines were positive for P32 expression in culture, and the expression was increased in xenograft tumors grown from the positive cell lines. Fluorescence-activated cell sorting analyses with anti-P32 antibodies showed that P32-positive cell lines expressed P32 at the cell surface. These cells bound and internalized LyP-1 peptide in proportion to the cell-surface expression level, which correlated with malignancy rather than total P32 expression in the cells. Like the LyP-1 peptide, P32 antibodies highlighted hypoxic areas in tumors, where they bound to both tumor cells and cells that expressed macrophage/myeloid cell markers and often seemed to be incorporated into the walls of tumor lymphatics. Significant P32 expression was common in human cancers and the P32 levels were often greatly elevated compared with the corresponding normal tissue. These results establish P32, particularly its cell-surface–expressed form, as a new marker of tumor cells and tumor-associated macrophages/myeloid cells in hypoxic/metabolically deprived areas of tumors. Its unique localization in tumors and its relative tumor specificity may make P32 a useful target in tumor diagnosis and therapy. [Cancer Res 2008;68(17):7210–8]
Lauri Paasonen - One of the best experts on this subject based on the ideXlab platform.
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new P32 gc1qr ligands for targeted tumor drug delivery
ChemBioChem, 2016Co-Authors: Lauri Paasonen, Shweta Sharma, Gary B. Braun, Venkata Ramana Kotamraju, Thomas D.y. Chung, Zhi-gang She, Kazuki N. SugaharaAbstract:Cell surface P32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind P32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to P32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant P32 and, when injected intravenously, homed to P32-expressing breast tumors in mice. This compound provides a lead for the development of P32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.
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New P32/gC1qR Ligands for Targeted Tumor Drug Delivery.
Chembiochem : a European journal of chemical biology, 2016Co-Authors: Lauri Paasonen, Shweta Sharma, Gary B. Braun, Venkata Ramana Kotamraju, Thomas D.y. Chung, Zhi-gang She, Kazuki N. Sugahara, Marjo Yliperttula, Maurizio PellecchiaAbstract:Cell surface P32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind P32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to P32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant P32 and, when injected intravenously, homed to P32-expressing breast tumors in mice. This compound provides a lead for the development of P32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.
