Naslov
Anti-Tumor Activity of a Thermally Responsive Polypeptide-Doxorubicin Conjugate in a Syngeneic Mouse Breast Cancer Model

Autori
Kratz, Felix ; Perkins, Eddie ; Moktan, Shama ; Raucher, Dražen

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research / - , 2010

Skup
102nd Annual Meeting of the American Association for Cancer Research

Mjesto i datum
Orlando (FL), Sjedinjene Američke Države, 02.04.2011. - 06.04.2011

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Doxorubicin; Targeted drug delivery; Breast cancer

Sažetak
A thermally responsive macromolecular carrier based on elastin-like polypeptide (ELP) was conjugated to (6-maleimidocaproyl) hydrazone derivatives of doxorubicin (Dox) via three terminal cysteine residues on ELP. ELPs undergo phase transition at a critical temperature known as the inverse transition temperature (Tt). At temperatures below Tt, ELPs remain soluble in aqueous solutions ; however, at temperatures above Tt, they aggregate and separate from solution. By changing the molecular composition of ELP, which influences its transition temperature, we have genetically engineered an ELP molecule that is soluble at physiological temperature and aggregates in response to mild hyperthermia at 42°C. The ELP-drug conjugate can therefore be actively targeted to the tumor region by the application of localized heat, and passively targeted through the enhanced retention and permeability effect, making it less likely to be toxic to normal tissues. In this study, ELP was modified at the N-terminus by the addition of the SynB1 cell penetrating peptide to enhance intratumor and intracellular delivery. The doxorubicin prodrug contains a pH-sensitive hydrazone linker that is cleaved in the acidic environment of endosomes/lysosomes allowing a controlled intracellular release of the drug. The antitumor activity of the thermally responsive polypeptide-doxorubicin conjugate, SynB1-ELP1-Dox3 was evaluated in a mouse breast cancer syngeneic model. Tumor bearing animals were intravenously treated with either free Dox or SynB1-ELP1-Dox3 at 5 mg Dox equivalent/kg body weight for 3 alternate days. In the heat treatment group, hyperthermia was applied immediately after injection using an infrared light emitting diode device. Tumor growth was monitored up to 14 days after the initial treatment. Hyperthermia enhanced the antitumor activity of SynB1-ELP1-Dox3 by almost 2-fold, which was comparable to free Dox. Relative to the pre-treatment weight, mice treated with SynB1-ELP1-Dox3 showed no weight loss compared to 5% weight loss seen in mice treated with free Dox. The drug-free carrier SynB1-ELP1 as well as the thermally insensitive control, SynB1-ELP2-Dox3 did not exhibit any anti-tumor effect either in the presence or absence of hyperthermia indicating that hyperthermia enhanced potency of SynB1-ELP1-Dox3 is specific to the phase transition of ELP1. HPLC was used to evaluate the plasma clearance and biodistribution of SynB1-ELP1-Dox3 with and without heat and was compared to free drug. Additional in vivo studies at higher doses of SynB1-ELP1-Dox3 to examine the optimal antitumor efficacy as well as the reduction in cardiac toxicity are underway to validate the therapeutic potential of this thermally responsive doxorubicin conjugate.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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