Preclinical Evaluation of Novel All-in-one Formulations of 5-Fluorouracil and Folinic Acid with Reduced Toxicity Profiles - Supplementary Data

Objectives: 5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations persist with the administration of these drugs in combination including phlebitis and catheter blockages, which are associated with reduced efficacy and/or quality of life for patients. We have previously reported novel all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating beta-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid.Methods: We performed toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared to 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared to dose-matched sequential administration of 5-FU:folinic acid.Results: Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by tissue distribution and pharmacokinetics of 5-FU, but was generally better tolerated as determined by weight loss, hematological and other clinical parameters. Compared to 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, equivalent to enhanced efficacy of Fluorodex compared to 5-FU:folinic acid against human carcinoma tumour models in mice was observed.Conclusions: These novel all-in-one formulations represent a superior injectable form of 5- FU that allows co-delivery of folinic acid. This should translate to improved patient tolerability with potential for enhanced efficacy

Challenge-led interdisciplinary research in practice: Program design, early career research, and a dialogic approach to building unlikely collaborations

Challenge-led interdisciplinary research is a relatively new way of bringing together disciplinary expertise in response to complex societal and environmental problems. Common difficulties include how to define \u27interdisciplinary research\u27; how to improve the participation and flourishing of early-career researchers; and how to manage projects with disparate teams of researchers while deepening external collaborations. This article reports from a major initiative of this type. It interrogates qualitative data generated from program evaluation among participating researchers, identifying insights on beneficial structural (program design) and \u27soft\u27 infrastructure (human capital) variables, as well as on-going barriers and tensions. Notwithstanding the difficulties of communicating and collaborating across epistemic domains, the program in question exceeded expectations in building interdisciplinary research and early research careers\u27though not necessarily in ways initially imagined. Staggered funding pools meant it was acceptable in early phases for low-cost projects to \u27fail safely\u27, while strict funding guidelines on distal interdisciplinarity compelled unlikely and novel researcher combinations and projects. Moreover, such program design features \u27granted permission\u27 to early-career researchers to approach more senior, crossfaculty researchers as potential collaborators, hence building leadership capacity. Human capital variables included a dialogic approach to project development (\u27curating\u27 projects as they evolve), inclusive program leadership, and promotion of the benefits of a collaborative rather than competitive research culture. Distal interdisciplinarity not only nourishes novel and unlikely research projects that respond to complex problems; with good program design and meaningful relationships it can, we argue, also build research careers differently from an early phase

Understanding the assistive technology needs of people over 55: The future of mobility aids

Objective: To understand mobility issues not adequately serviced by assistive technology (AT). Methods: A two-stage mixed-methods research project that forms the basis of future AT design and manufacture. Stage 1: a focus group comprising 46 participants (people aged 55 years or older with mobility issue/s) and their support networks. Stage 2: a sample of 413 people over 55 completed a purpose-designed survey informed by stage 1, regarding mobility issues and perceived desirability of suggested AT mobility aids. Results: Two core themes emerged: (a) functionality issues relating to existing AT designs and (b) identified mobility issues encountered during activities of daily living that could potentially be resolved by developing new AT. Importance was placed on certain features of AT mobility aids with cost, transportability and aesthetics being primary issues. Conclusion: Consulting end-users and their networks ensures valuable insight into how future AT can better address and target mobility needs

Preclinical evaluation of novel, all-in-one formulations of 5-fluorouracil and folinic acid with reduced toxicity profiles

Objectives: 5-Fluorouracil (5-FU) in combination with its synergistic biomodulator folinic acid maintains a pivotal position in cancer chemotherapy. However, clinical limitations persist with the administration of these drugs in combination including phlebitis and catheter blockages, which are associated with reduced efficacy and/or quality of life for patients. We have previously reported novel all-in-one, pH neutral, parenteral 5-FU and folinic acid formulations (termed Fluorodex) incorporating beta-cyclodextrins. Fluorodex maintains potency while overcoming the accepted incompatibility of 5-FU and folinic acid.Methods: We performed toxicological, pharmacokinetic and biodistribution, and efficacy evaluations of Fluorodex compared to 5-FU:folinic acid using several administration routes and schedules in two rodent models. These were compared to dose-matched sequential administration of 5-FU:folinic acid.Results: Fluorodex showed bioequivalence to 5-FU:folinic acid as assessed by tissue distribution and pharmacokinetics of 5-FU, but was generally better tolerated as determined by weight loss, hematological and other clinical parameters. Compared to 5-FU:folinic acid, Fluorodex was also associated with reduced phlebitis using a rabbit ear vein model. Furthermore, equivalent to enhanced efficacy of Fluorodex compared to 5-FU:folinic acid against human carcinoma tumour models in mice was observed.Conclusions: These novel all-in-one formulations represent a superior injectable form of 5- FU that allows co-delivery of folinic acid. This should translate to improved patient tolerability with potential for enhanced efficacy

Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma

Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by (213)Bi-labeled plasminogen activator inhibitor type 2 (alpha-PAI-2) in multiple carcinoma models. Here, we present preclinical toxicologic and efficacy assessment of alpha-PAI-2 in mice, using both single and multiple-dose schedules, administered by an i.p. route. We also present novel data showing that human PAI-2 inhibited murine uPA and was specifically endocytosed by murine fibroblast cells. This diminishes potential problems associated with species specificity of the targeting reagent in toxicologic assessments as human alpha-PAI-2 should interact with any uPA-expressing host cells. In this model, single bolus doses up to 36 mCi/kg alpha-PAI-2 did not reach the maximum tolerated dose (MTD). The MTD for a multiple fractionated (once daily for 5 days) administration schedule was determined to lie between 4.8 and 6.0 mCi/kg/d x 5. Comparison of the tumor growth rates and survival using sub-MTD single and multiple-dose schedules in an orthotopic human breast carcinoma xenograft murine model indicated that 4.8 mCi/kg/d x 5 was the most efficacious schedule. In conclusion, we have determined a safe dose and schedule of alpha-PAI-2 administration in mice, thus confirming that it is an efficacious therapeutic modality against tumor growth. This will allow detailed safety evaluation in a second species and for the initiation of human studies. [Mol Cancer Ther 2007;6(1):203-11]