Peptide carrier-mediated non-covalent delivery of unmodified cisplatin, methotrexate and other agents via intravenous route to the brain.
BACKGROUND
Rapid pre-clinical evaluation of chemotherapeutic agents against brain cancers and other neurological disorders remains largely unattained due to the presence of the blood-brain barrier (BBB), which limits transport of most therapeutic compounds to the brain. A synthetic peptide carrier, K16ApoE, was previously developed that enabled transport of target proteins to the brain by mimicking a ligand-receptor system. The peptide carrier was found to generate transient BBB permeability, which was utilized for non-covalent delivery of cisplatin, methotrexate and other compounds to the brain.


METHODS
Brain delivery of the chemotherapeutics and other agents was achieved either by injecting the carrier peptide and the drugs separately or as a mixture, to the femoral vein. A modification of the method comprised injection of K16ApoE pre-mixed with cetuximab, followed by injection of a 'small-molecule' drug.


RESULTS
Seven-of-seven different small molecules were successfully delivered to the brain via K16ApoE. Depending on the method, brain uptake with K16ApoE was 0.72-1.1% for cisplatin and 0.58-0.92% for methotrexate (34-50-fold and 54-92 fold greater for cisplatin and methotrexate, respectively, with K16ApoE than without). Visually intense brain-uptake of Evans Blue, Light Green SF and Crocein scarlet was also achieved. Direct intracranial injection of EB show locally restricted distribution of the dye in the brain, whereas K16ApoE-mediated intravenous injection of EB resulted in the distribution of the dye throughout the brain. Experiments with insulin suggest that ligand-receptor signaling intrinsic to the BBB provides a natural means for passive transport of some molecules across the BBB.


CONCLUSIONS
The results suggest that the carrier peptide can non-covalently transport various chemotherapeutic agents to the brain. Thus, the method offers an avenue for pre-clinical evaluation of various small and large therapeutic molecules against brain tumors and other neurological disorders.
Department of Experimental Pathology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America.
Gobinda
G
Sarkar
Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America.
Geoffry L
GL
Curran
Department of Radiation Oncology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America.
Jann N
JN
Sarkaria
Department of Nuclear Medicine, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America.
Val J
VJ
Lowe
Department of Experimental Pathology, Mayo Clinic and Foundation, Rochester, Minnesota, United States of America.
Robert B
RB
Jenkins
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002945:Cisplatin / Q000008:administration & dosage* / Q000378:metabolism*; D004396:Coloring Agents / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D007275:Injections, Intravenous; D007328:Insulin / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*
D004396:Coloring Agents; D004337:Drug Carriers; D007328:Insulin; D007457:Iodine Radioisotopes; D010455:Peptides; D002945:Cisplatin; D008727:Methotrexate