A thermally targeted c-Myc inhibitory polypeptide inhibits breast tumor growth

Abstract

Although surgical resection with adjuvant chemotherapy and/or radiotherapy are used to treat breast tumors, normal tissue tolerance, development of metastases, and inherent tumor resistance to radiation or chemotherapy can hinder a successful outcome. We have developed a thermally responsive polypeptide, based on the sequence of Elastin-like polypeptide (ELP), that inhibits breast cancer cell proliferation by blocking the activity of the oncogenic protein c-Myc. Following systemic administration, the ELP – delivered c-Myc inhibitory peptide was targeted to tumors using focused hyperthermia, and significantly reduced tumor growth in an orthotopic mouse model of breast cancer. This work provides a new modality for targeted delivery of a specific oncogene inhibitory peptide, and this strategy may be expanded for delivery of other therapeutic peptides or small molecule drugs.

Applications of elastin-like polypeptides in drug delivery

“…The delivery of the H1 peptide by Bac-ELP was shown to effectively reduce tumor burden in mammary pad breast tumors, following intraperitoneal administration [85], and also demonstrated increased tumor accumulation and prolonged survival in a model of rat glioma, following intravenous administration [86]. In both applications, four cycles of tumor heating and cooling enhanced local tumor accumulation of temperature-sensitive CPP-ELPs and improved therapeutic response, as compared to tumors that were not heated.…”

Cell-penetrating peptides: strategies for anticancer treatment

“…Furthermore, in an in vivo study that used both a CPP-ELP conjugate and applied local hyperthermia, intratumoral drug accumulation was doubled in comparison to the group without hyperthermia, leading to enhanced antitumor efficacy and possibly suggesting a discriminated toxic response between heated and nonheated tissues [66]. This research group then developed an ELP loaded with an anticancer molecule, the p21 Waf1/Cip1 inhibitory peptide (ELP-p21) [67].…”

Corneal Penetrating Elastin-Like Polypeptide Carriers

“…Elastin-like polypeptide (ELP) is a synthetic protein made of repeated units of a 5 amino acid motif, and it has been applied as a drug carrier in several preclinical disease models. [6][7][8][9][10][11] ELP is advantageous as a drug delivery vector because it is nonimmunogenic, is easily purified by taking advantage of its unique property of thermally triggered aggregation, [12][13][14] and is amenable to fusion with small molecule, peptide, or protein-based therapeutic agents (reviewed in Raucher et al 15 ). ELP is produced recombinantly, and its coding sequence is easily modified for fusion of targeting or cell-penetrating peptides (CPPs) and with therapeutic proteins, peptides, or drug conjugation sites using basic molecular biology protocols.…”