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Liu T.,Washington State University | Wu L.Y.,Washington State University | Berkman C.E.,Washington State University | Berkman C.E.,Cancer Targeted Technology, Llc
Cancer Letters | Year: 2010

Prostate-specific membrane antigen (PSMA), an established enzyme-biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications. We aimed to determine the effects of PSMA-targeted photodynamic therapy (PDT) on cytoskeletal networks in prostate cancer cells. PSMA-targeted PDT resulted in rapid disruption of microtubules (α-/β-tubulin), microfilaments (actin), and intermediate filaments (cytokeratin 8/18) in the cytoplasm of LNCaP cells. The collapse of cytoplasmic microtubules and the later nuclear translocation of α-/β-tubulin were the most dramatic alternation. It is likely that these early changes of cytoskeletal networks are partly involved in the initiation of cell death. © 2010 Elsevier Ireland Ltd. Source


Liu T.,Washington State University | Wu L.Y.,Washington State University | Choi J.K.,Washington State University | Berkman C.E.,Washington State University | Berkman C.E.,Cancer Targeted Technology, Llc
International Journal of Oncology | Year: 2010

The limitation of specific delivery of photosensitizers to tumor sites, represents a significant shortcoming of photodynamic therapy (PDT) application at present. Prostate-specific membrane antigen (PSMA), a validated biomarker for prostate cancer, has attracted considerable attention as a target for imaging and therapeutic applications for prostate cancer. The present study focuses on the investigation of a PSMA inhibitor-conjugate of pyropheophorbide-a (Ppa-conjugate 2.1) for a targeted PDT application and the mechanism of its mediated-cell death in prostate cancer cells. Multiple fluorescence labeling methods were employed to monitor PDT-treated prostate cancer cells by confocal laser scanning microscopy. Our results demonstrate that Ppa-conjugate 2.1 mediated apoptosis is specific to PSMA+ (positive) LNCaP cells, but not PSMA- (negative) PC-3 cells. Furthermore, these results indicate that following PDT, the activation of caspase-8, -3, -9, cleavage of poly(ADP-ribose) polymerase (PARP) and DNA fragmentation is sequential. The appearance of cleaved ß-actin further supported involvement of caspase-3. Specific caspase inhibitor blocking studies reveal that the caspase-8/-3 cascade pathway plays a key role in apoptosis of LNCaP cells induced by Ppa-conjugate 2.1. The demonstrated selective targeting and efficacy of this agent suggests that targeted PDT could serve as an alternative treatment option for prostate cancer. Source


Liu T.,Washington State University | Nedrow-Byers J.R.,Washington State University | Hopkins M.R.,Washington State University | Berkman C.E.,Washington State University | Berkman C.E.,Cancer Targeted Technology, Llc
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Prostate-specific membrane antigen (PSMA), a type II transmembrane protein, has been becoming an active target for imaging and therapeutic applications for prostate cancer. Recently, the development of its various chemical inhibitor scaffolds has been explored to serve as carriers for therapeutic or diagnostic payloads targeted to PSMA-positive tumor cells. However, there have been few efforts to definitively determine the optimal length of linker between PSMA inhibitor cores and their payload molecules with regard to the affinity to PSMA and in vitro performance. In our present model study, three spacer-length varied fluorescent inhibitors (FAM-CTT-54, FAM-X-CTT-54 and FAM-PEG 8-CTT-54) were synthesized, and further enzymatic inhibition studies displayed linker length-dependent changes in: inhibitory potency (IC 50 = 0.41 nM, 0.35 nM, 1.93 nM), modes of binding (reversible, slowly reversible, irreversible), respectively. Furthermore, cell-labeling imaging revealed the spacer length-related change of fluorescence intensity (FAM-X-CTT-54 > FAM-PEG 8-CTT-54 > FAM-CTT-54). These results suggest that selection of linkers and their lengths will be important considerations in the development of next-generation prostate tumor-targeted imaging probes and therapeutic agents that specifically home to PSMA on tumor cells. © 2011 Elsevier Ltd. All rights reserved. Source


Patent
Cancer Targeted Technology, Llc and Washington State University | Date: 2014-03-14

Compounds of Marlush formula (I) described in the claims are useful in diagnostic methods for detecting and/or identifying cells presenting PSMA. Disclosed are also methods for preparing the compounds. Representative compounds according to the application are:


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2015

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