This is revised submission requesting renewal funds for an ongoing project in anticancer drug development. It is focused on the use of gadolinium(III) texaphyrin cores as carriers to bring Pt agents directly to tumor sites. Gadolinium(III) texaphyrins are a class of expanded porphyrins developed by the P.I. that have a clinically validated ability to localize selectively in tumors. By conjugating a Pt anticancer agent to texaphyrin and controlling the nature of the platinum species employed, we expect to produce new drug leads that i) provide for an increased intracellular delivery of platinum, ii) circumvent DNA repair mechanisms, and iii) enhance wild- type p53 function, thus overcoming three key determinants of cisplatin resistance. We now have in hand a lead texaphyrin-platinum agent (conjugate 3) that shows no resistance between ovarian A2780 and its isogenic platinum resistant partner (2780CP) in cell culture. We have also completed an in vivo, multidose toxicity study of this lead system and have confirmed that, relative to analogous FDA-approved Pt agents, it is capable of delivering approximately twice the dose of Pt to balb/c mice without engendering toxic symptoms. To develop this project further we will pursue the following specific aims: 1) Study the in vitro properties of our lead system, conjugate 3;2) carry out in vivo efficacy studies of this lead system and new agents we prepare;3) determine toxicity, drug distribution;quantify the ability of promising conjugates to localize within the tumor and form Pt DNA adducts, and 4) synthesize new conjugates, including those based on Pt(IV) centers. The net result of this effort will be one or more agents in advanced preclinical testing that addresses the all- important problem of platinum drug resistance.
This ongoing project involves the synthesis and study of small molecule systems that carry platinum-type anticancer agents directly to the tumor. This is expected to limit the toxic side effects and increase efficacy. This approach looks particularly promising for the treatment of Pt-resistant ovarian cancer.
|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|
|Du, Yan; Lim, Byung Joon; Li, Bingling et al. (2014) Reagentless, ratiometric electrochemical DNA sensors with improved robustness and reproducibility. Anal Chem 86:8010-6|
|Thiabaud, Grégory; Arambula, Jonathan F; Siddik, Zahid H et al. (2014) Photoinduced reduction of Pt(IV) within an anti-proliferative Pt(IV)-texaphyrin conjugate. Chemistry 20:8942-7|
|Lee, Min Hee; Park, Nayoung; Yi, Chunsik et al. (2014) Mitochondria-immobilized pH-sensitive off-on fluorescent probe. J Am Chem Soc 136:14136-42|
|Barkey, Natalie M; Preihs, Christian; Cornnell, Heather H et al. (2013) Development and in vivo quantitative magnetic resonance imaging of polymer micelles targeted to the melanocortin 1 receptor. J Med Chem 56:6330-8|
|Preihs, Christian; Arambula, Jonathan F; Magda, Darren et al. (2013) Recent developments in texaphyrin chemistry and drug discovery. Inorg Chem 52:12184-92|
|Hargrove, Amanda E; Ellington, Andrew D; Anslyn, Eric V et al. (2011) Chemical functionalization of oligodeoxynucleotides with multiple boronic acids for the polyvalent binding of saccharides. Bioconjug Chem 22:388-96|
|Devoille, Aline M J; Richardson, Patricia; Bill, Nathan L et al. (2011) Selective anion binding by a cofacial binuclear zinc complex of a Schiff-base pyrrole macrocycle. Inorg Chem 50:3116-26|
|Arambula, Jonathan F; Sessler, Jonathan L; Siddik, Zahid H (2011) Overcoming biochemical pharmacologic mechanisms of platinum resistance with a texaphyrin-platinum conjugate. Bioorg Med Chem Lett 21:1701-5|
|Preihs, Christian; Magda, Darren; Sessler, Jonathan L (2011) Crown ether functionalized texaphyrin monomers and dimers. J Porphyr Phthalocyanines 15:539-546|
Showing the most recent 10 out of 33 publications