The long-range goal of this project is to develop expanded porphyrin-based drugs for the treatment of human disease. To date, much of the focus has centered on the so-called texaphyrins. As the result of considerable effort, involving the P.l.'s group, the co-P.I. and other researchers at Pharmacyclics, Inc., a cadre of dedicated clinicians, and Cooperative Research and Development (clinical) support from the NCI, the gadolinium(lll) complex of a water solubilized texaphyrin, motexafin gadolinium (MGd; XcytrinZ(r)), has emerged as an agent with considerable promise in the area of cancer therapy, especially for non-small lung cancer (NSCLC). This agent, which is known to localize well to tumors, is currently the subject of more than a dozen ongoing clinical trials, including ones targeting metastatic brain tumors, non-Hodgkin's lymphoma, renal cell carcinoma, glioma, head and neck cancer, juvenile glioma, and NSCLC. In this context, MGd is being studied as both an adjuvant for radiation therapy and as a stand-alone chemotherapeutic, where it is being administered on its own or with other anticancer agents. Given this state of development, the goals for the upcoming funding period are two-fold: First, to support the clinical trials by continuing mechanistic studies of MGd and, second, to develop yet-improved drugs. Key questions we will address include: ? ? What are the relative effects of redox cycling, reactive oxygen species (ROS) production, and perturbations in zinc homeostasis in mediating the effect of MGd? Can analogues of MGd be generated that show improved chemical properties, including redox cycling capability? Do these systems lead to enhanced anti-cancer activity in vitro as judged by cellular assays and, if warranted, in vivo tumor regrowth studies? What are the factors that regulate the cellular- and sub-cellular localization of MGd and its analogues? Can these localization properties be exploited to generate carriers that deliver other active agents, including known oncology drugs, to cancer sites? Can approaches other than those based on MGd be used to modulate the intracellular concentrations of zinc ion and, if so, how are such perturbations reflected in anticancer activity? ? ? The proposed work will lead to progress in the anticancer area and provide a basis for rational drug design. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Stone, Helen B
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Austin
Schools of Arts and Sciences
United States
Zip Code
Jung, Hyo Sung; Verwilst, Peter; Sharma, Amit et al. (2018) Organic molecule-based photothermal agents: an expanding photothermal therapy universe. Chem Soc Rev 47:2280-2297
Lee, Min Hee; Sharma, Amit; Chang, Min Jung et al. (2018) Fluorogenic reaction-based prodrug conjugates as targeted cancer theranostics. Chem Soc Rev 47:28-52
Jung, Hyo Sung; Lee, Jae-Hong; Kim, Kyutae et al. (2017) A Mitochondria-Targeted Cryptocyanine-Based Photothermogenic Photosensitizer. J Am Chem Soc 139:9972-9978
Jung, Hyo Sung; Han, Jiyou; Shi, Hu et al. (2017) Overcoming the Limits of Hypoxia in Photodynamic Therapy: A Carbonic Anhydrase IX-Targeted Approach. J Am Chem Soc 139:7595-7602
Shin, Weon Sup; Han, Jiyou; Kumar, Rajesh et al. (2016) Programmed activation of cancer cell apoptosis: A tumor-targeted phototherapeutic topoisomerase I inhibitor. Sci Rep 6:29018
Thiabaud, Gregory; McCall, Rebecca; He, Guangan et al. (2016) Activation of Platinum(IV) Prodrugs By Motexafin Gadolinium as a Redox Mediator. Angew Chem Int Ed Engl 55:12626-31
Arambula, J F; McCall, R; Sidoran, K J et al. (2016) Targeting Antioxidant Pathways with Ferrocenylated N-Heterocyclic Carbene Supported Gold(I) Complexes in A549 Lung Cancer Cells. Chem Sci 7:1245-1256
Zhang, Huacheng; Lee, Juhoon; Lammer, Aaron D et al. (2016) Self-Assembled Pyridine-Dipyrrolate Cages. J Am Chem Soc 138:4573-9
Brown, Katherine A; Yang, Xiaoping; Schipper, Desmond et al. (2015) A self-assembling lanthanide molecular nanoparticle for optical imaging. Dalton Trans 44:2667-75
Lee, Min Hee; Kim, Jong Seung; Sessler, Jonathan L (2015) Small molecule-based ratiometric fluorescence probes for cations, anions, and biomolecules. Chem Soc Rev 44:4185-91

Showing the most recent 10 out of 51 publications