Thermally targeted delivery of a c-Myc inhibitory polypeptide inhibits tumor progression and extends survival in a rat glioma model.
Treatment of glioblastoma is complicated by the tumors' high resistance to chemotherapy, poor penetration of drugs across the blood brain barrier, and damaging effects of chemotherapy and radiation to normal neural tissue. To overcome these limitations, a thermally responsive polypeptide was developed for targeted delivery of therapeutic peptides to brain tumors using focused hyperthermia. The peptide carrier is based on elastin-like polypeptide (ELP), which is a thermally responsive biopolymer that forms aggregates above a characteristic transition temperature. ELP was modified with cell penetrating peptides (CPPs) to enhance delivery to brain tumors and mediate uptake across the tumor cells' plasma membranes and with a peptide inhibitor of c-Myc (H1). In rats with intracerebral gliomas, brain tumor targeting of ELP following systemic administration was enhanced up to 5-fold by the use of CPPs. When the lead CPP-ELP-fused c-Myc inhibitor was combined with focused hyperthermia of the tumors, an additional 3 fold increase in tumor polypeptide levels was observed, and 80% reduction in tumor volume, delayed onset of tumor-associated neurological deficits, and at least doubled median survival time including complete regression in 80% of animals was achieved. This work demonstrates that a c-Myc inhibitory peptide can be effectively delivered to brain tumors.
Department of Neurology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Gene L
GL
Bidwell
Eddie
E
Perkins
Joshua
J
Hughes
Majid
M
Khan
Judy R
JR
James
Drazen
D
Raucher
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D018450:Disease Progression; D004337:Drug Carriers; D005910:Glioma / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D007259:Infrared Rays / Q000627:therapeutic use; D008297:Male; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors*; D051381:Rats; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D004337:Drug Carriers; D016271:Proto-Oncogene Proteins c-myc