title: Synthesis and Evaluation of Folate-Conjugated Phenanthraquinones for Tumor-Targeted Oxidative Chemotherapy.
abstract: Almost all cells are easily killed by exposure to potent oxidants. Indeed, major pathogen defense mechanisms in both animal and plant kingdoms involve production of an oxidative burst, where host defense cells show an invading pathogen with reactive oxygen species (ROS). Although cancer cells can be similarly killed by ROS, development of oxidant-producing chemotherapies has been limited by their inherent nonspecificity and potential toxicity to healthy cells. In this paper, we describe the targeting of an ROS-generating molecule selectively to tumor cells using folate as the tumor-targeting ligand. For this purpose, we exploit the ability of 9,10-phenanthraquinone (PHQ) to enhance the continuous generation of H2O2in the presence of ascorbic acid to establish a constitutive source of ROS within the tumor mass. We report here that incubation of folate receptor-expressing KB cells in culture with folate-PHQ plus ascorbate results in the death of the cancer cells with an IC50of ~10 nM (folate-PHQ). We also demonstrate that a cleavable spacer linking folate to PHQ is significantly inferior to a noncleavable spacer, in contrast to most other folate-targeted therapeutic agents. Unfortunately, no evidence for folate-PHQ mediated tumor regression in murine tumor models is obtained, suggesting that unanticipated impediments to generation of cytotoxic quantities of ROSin vivoare encountered. Possible mechanisms and potential solutions to these unanticipated results are offered.
authors.affiliation: International Center for Trans-disciplinary Research, School of Environmental Affairs, Universidad Metropolitana, San Juan, Puerto Rico ; Department of Chemistry, University of Puerto Rico, Humacao, Puerto Rico.
authors.forename: Ajay
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana ; Department of Chemistry, Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology, Indore, Simrol Campus, Madhya Pradesh, India.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Chelvam
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Mahalingam
authors.initials: M
authors.lastname: Sakkarapalayam
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Guo
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Chemistry, University of Puerto Rico, Humacao, Puerto Rico.
authors.forename: Pedro
authors.initials: P
authors.lastname: Sanchez-Cruz
authors.affiliation: Department of Chemistry, University of Puerto Rico, Humacao, Puerto Rico.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Piñero
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
authors.affiliation: Department of Chemistry, University of Puerto Rico, Humacao, Puerto Rico.
authors.forename: Antonio E
authors.initials: AE
authors.lastname: Alegria
keywords: Cancer; Folate Receptor; Reactive Oxygen Species