Pre-clinical studies of EC2629, a highly potent folate- receptor-targeted DNA crosslinking agent.

Folate receptor (FR)-targeted small molecule drug conjugates (SMDCs) have shown promising results in early stage clinical trials with microtubule destabilizing agents, such as vintafolide and EC1456. In our effort to develop FR-targeted SMDCs with varying mechanisms of action, we synthesized EC2629, a folate conjugate of a DNA crosslinking agent based on a novel DNA-alkylating moiety. This agent was found to be extremely potent with an in vitro IC50 ~ 100× lower than folate SMDCs constructed with various microtubule inhibitors. EC2629 treatment of nude mice bearing FR-positive KB human xenografts led to cures in 100% of the test animals with very low dose levels (300 nmol/kg) following a convenient once a week schedule. The observed activity was not accompanied by any noticeable weight loss (up to 20 weeks post end of dosing). Complete responses were also observed against FR-positive paclitaxel (KB-PR) and cisplatin (KB-CR) resistant models. When evaluated against FR-positive patient derived xenograft (PDX) models of ovarian (ST070), endometrial (ST040) and triple negative breast cancers (ST502, ST738), EC2629 showed significantly greater anti-tumor activity compared to their corresponding standard of care treatments. Taken together, these studies thus demonstrated that EC2629, with its distinct DNA reacting mechanism, may be useful in treating FR-positive tumors, including those that are classified as drug resistant.

Variability in outcome after elective cerebral aneurysm repair in high-volume academic medical centers.

BACKGROUND AND PURPOSE: Unruptured intracranial aneurysm repair is the most commonly performed procedure for the prevention of hemorrhagic stroke. Despite efforts to regionalize care in high-volume centers, overall results have improved little. This study aims to determine the effectiveness in improving outcomes of previous efforts to regionalize unruptured intracranial aneurysm repair to high-volume centers and to recommend future steps toward that goal. METHODS: Using data obtained via the New York Statewide Planning and Research Cooperative System, this study included all patients admitted to any of the 10 highest volume centers in New York state between 2005 and 2010 with a principal diagnosis of unruptured intracranial aneurysm who were treated either by microsurgical or endovascular repair. Mixed-effects logistic regression was used to determine the degree to which hospital-level and patient-level variables contributed to observed variation in good outcome, defined as discharge to home, between hospitals. RESULTS: Of 3499 patients treated during the study period, 2692 (76.9%) were treated at the 10 highest volume centers, with 2198 (81.6%) experiencing a good outcome. Good outcomes varied widely between centers, with 44.6% to 91.1% of clipped patients and 75.4% to 92.1% of coiled patients discharged home. Mixed-effects logistic regression revealed that procedural volume accounts for 85.8% of the between-hospital variation in outcome. CONCLUSIONS: There is notable interhospital heterogeneity in outcomes among even the largest volume unruptured intracranial aneurysm referral centers. Although further regionalization may be needed, mandatory participation in prospective, adjudicated registries will be necessary to reliably identify factors associated with superior outcomes.

Evaluation of folate conjugate uptake and transport by the choroid plexus of mice.

PURPOSE: Because the choroid plexus (CP) is enriched in cell surface folate receptors, an investigation was initiated to evaluate whether folate receptor-mediated transcytosis might be exploited to deliver folate conjugates into the brain. METHODS: Balb/c mice were injected with radioactive and fluorescent conjugates of folate to measure and image their uptake by the CP. RESULTS: Retention of a radioactive folate conjugate, folate-diethylenetriaminepentaacetic acid (DTPA)-111In, into the brain of balb/c mice was observed, although repeated injections or prolonged release via an osmotic pump of the compound did not result in increased brain uptake. Uptake of an 125I-labeled anti-folate receptor antibody into the brain was very low, and no competition was observed with unlabeled antibody. Imaging of brain thin-sections and whole brain tissue from a mouse injected with folate-fluorescein revealed strong fluorescence in the CP, but virtually no where else in the brain. CONCLUSIONS: Both fluorescence and radioimaging results demonstrate specific uptake of small molecular weight folate conjugates into CP cells of the murine brain, but no significant transport of the molecules across the CSF. Furthermore, no uptake of larger folate-linked proteins by choroid plexus cells is observed, suggesting folate conjugate size may strongly influence access to CP folate receptors.

Synthesis and evaluation of taxol-folic acid conjugates as targeted antineoplastics.

A series of Taxol derivatives tethered at C2' and C-7 to glutamate and folate have been synthesized for evaluation as prodrugs which release Taxol via hydrolytic lability of their alpha-alkoxy and alpha-amino esters. The half-time for hydrolysis of these materials was determined in pH 7 and pH 5 buffer. The in vitro cytotoxicity has been assessed in cell culture against A-549 lung cancer, MCF-7 breast cancer, and HT-29 colon cancer. Selected agents were further screened for folate binding and competitive binding with free folic acid. One agent (54), further evaluated in animal studies was found to increase the lifespan in mice, but was less effective than Taxol itself.