Abstract
Abstract Elastin-like Polypeptide (ELP) is a macromolecular carrier for various therapeutic peptides and has the ability to penetrate tumor vasculature. This penetration ability is mediated by a cell-penetrating peptide. The polymer is soluble at normal physiological temperature but aggregates above 40 °C. Peptides without carriers have very short half-lives, so ELP not only allows for longer circulation time, but its thermal properties allow the peptide to accumulate inside the tumor when heated. Bac-ELP-p21 is an ELP conjugate that uses the CPP Bac to penetrate the nucleus and the therapeutic peptide p21 to inhibit the cell cycle at G1/S. ELP-p21 lacks the CPP and therefore the cell penetrating capabilities. Both of these constructs can be actively targeted to the tumor site using local hyperthermia. In this study, tumor accumulation and biodistribution of fluorescently labeled Bac-ELP-p21 and ELP-p21 were monitored in a mouse xenograft model by whole animal imaging using the IVIS® system. Luciferase transfected S2013 pancreatic cells were used to establish the tumor, allowing monitored tumor growth by quantifying luciferase signal over a period of time. The animals were intravenously injected with Alexa750 labeled Bac-ELP-p21 or ELP-p21. Animals were imaged for fluorescent signal at specific times after treatment to observe the level of protein with respect to time. This allowed for the detection and quantification of the protein level throughout the body and compared with uptake inside the tumor. Heated tumors accumulated 3-fold more protein with both Bac-ELP-p21 and ELP-p21. For biodistribution and plasma clearance studies, blood draws were performed on separate groups at 5, 15, 30 min and continuing every 30 min for 4h. At the end of the 4h, organs and tumors were harvested for later dissection. This allowed for comparison of the protein in the organs and monitored the amount of protein in the plasma over time. At 5 minutes, 2 times the amount of ELP-p21 was detectable in blood plasma compared to Bac-ELP-p21. At 2 hours, this ratio increases to 2.5 fold. Protein was still detectable in the tumor at 48h after treatment, indicating that modification of macromolecular carrier with cell penetrating peptide results in its faster plasma clearance due to the rapid accumulation in tumor and/or tissues. In conclusion, fusing a therapeutic peptide to a macromolecular carrier results in its improved pharmacokinetics and accumulation of the peptide, preferentially in the tumor tissue due to passive targeting, which is improved due to externally induced hyperthermia while this active targeting is increased due to the addition of a CPP. This approach will allow us to use lower concentrations of drug systemically and therefore reduce side effects in normal tissues. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 355. doi:1538-7445.AM2012-355
Published Version
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