Research > Focus C > Work Packages C01
Summary
In order to prioritize the preclinical development of drugs & biologicals (and combinations thereof) according to their pharmacological characteristics, we will screen potentially effective drug candidates for their brain accessibility and confirm blood-brain-barrier permeation in vivo and over time using microdialysis. Drug candidates with insufficient brain access will be subject to drug-delivery development using cell-penetrating liposomes for packaging, which will be re-evaluated for their brain accessibility. Final efficacy evaluation of promising drugs and drug delivery candidates will be based on the UNITE Core Collection of orthotopic preclinical models of different molecular subgroups of glioblastoma.
Task 1
In silico screening of potential drug candidates penetrating the blood-brain-barrier and in vitro efficacy to select potential antitumor activity.
Steps / Workflow
- in silico pre-selection of promising drug candidates against brain tumors
- in vitro efficacy screening
Task 2
Plasma and tissue drug quantification in mouse models using simultaneous drug administrations
Steps / Workflow
- FDA/EMA-compliant development of validated assays for simultaneous quantification of drugs in relevant biological matrices
- Quantification of drug exposure at the site of action
- DMPK analysis of drug candidates
Task 3
Suitability confirmation of the most promising drug candidates and drug delivery candidates using microdialysis
Steps / Workflow
- in vivo assessment of drug disposition using brain and intratumor microdialysis, plasma, and tissue samples (blood-brain permeability)
- definition of concentrationeffect relationship (tumor response, efficacy, potency, and tolerability)
Task 4
Development of methods to increase the accumulation of non-brain-susceptible drugs by lipid-nanoparticles (LNP)
Steps / Workflow
- Preparation of lipidconjugates to target LAT1
- Preparation of LNP formulations that are surface modified
- in vitro evaluation of brain capillary endothelial cell binding and uptake
- Pharmacological evaluation according to task 2 and 3
Task 5
Translational preparation of selected drug candidates
Steps / Workflow
- identification of target indication and efficacy testing
- allometric scaling
- development of study design and dosing schedule
- preparation of scientific advice
Previous funding period
PRINCIPLE INVESTIGATORS
PFISTER, STEFAN, PROF. DR. MED.
Director Preclinical Research
Hopp Children ́s Cancer Center Heidelberg, German Cancer Research Center (DKFZ), Division of Pediatric Neurooncology & Heidelberg University Hospital, Dep. of Pediatric Hematology and Oncology,
Im Neuenheimer Feld 580, 69120 Heidelberg, Germany
BAJRAKTARI-SYLEJMANI, GZONA, DR. RER. NAT.
Group Leader
Heidelberg University Hospital, Department of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany