Thermally Targeted Delivery of a c-Myc Inhibitory Polypeptide Inhibits Tumor Progression and Extends Survival in a Rat Glioma Model

Abstract

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.

Ubiquitin-specific protease 28 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity by regulating MYC expression

“…Enhanced levels of MYC are thought to contribute to genesis of many human tumors, including glioma. [11][12][13] These results suggested that USP28 plays a role in the oncogenesis of some malignancies. However, whether USP28 expression contributes to glioma development and progression is unknown.…”

The deubiquitinase USP28 controls intestinal homeostasis and promotes colorectal cancer

“…Due to its key role in tumorigenesis, much recent research has been directed to finding ways to target c-MYC function (24)(25)(26)(27)(28)(29). Dominant-negative approaches targeting c-MYC function impair intestinal tumor formation, and c-Myc heterozygous mice show reduced tumor development in the Apc min/+ model (16,17).…”

Nanotechnological Approaches to Therapeutic Delivery Using Elastin-Like Recombinamers

“…The results showed an 80% reduction in tumour volume after hyperthermia-induced aggregation, therefore this approach was suggested to be an alternative for drug delivery to brain tumours. 49 However, experiments regarding the cellular uptake efficiency and retention of ELRs in solid tumours after hyperthermia were only performed recently. These studies showed that larger ELRs are better when these properties are taken into account.…”