Abstract 2171: Activatable nanodelivery of high payload gemcitabine augments therapeutic efficacy in murine breast and pancreatic cancer models Conference Paper uri icon

abstract

  • Abstract Gemcitabine (Gem) is the standard of treatment for metastatic pancreatic ductal adenocarcinoma (PDAC) and an effective anticancer drug for various solid tumors. However, clinical application of Gem chemotherapy is hampered by suboptimal delivery of the drug, mainly due to short circulation time and poor penetration of drug into the hypo-vascularized and dense fibrous stroma of PDAC. Here, we present a novel method to improve both loading and stability of Gem in temperature-sensitive liposomes (TSL). TSL have the potential to be locally activated by exposing tumor to ultrasound-mediated hyperthermia (USH) triggering release of large amounts of free drug in the tumor vasculature, which can then rapidly penetrate into the heated tumor. Gem was passively loaded into TSL composed of DPPC:DSPC:DSPE-PEG2k (80:15:5) in the presence of copper(II) gluconate and triethanolamine at final 0.12 mg-drug/mg-lipid. Formation of a CuGem complex improved drug loading and stability and reduced systemic toxicity. Mice with bilateral invasive neu deletion (NDL) tumors (4-5 mm) were treated with an i.v. administration of CuGem-TSL at 10 mg Gem/kg body weight. USH was employed to trigger the release of drug; one tumor in the bilateral tumor model was insonified with a peak ultrasound pressure of 1.1 MPa at a frequency of 1.5 MHz at 43C for 5 min prior to and 30 min post drug injection with a variable duty cycle. We found that copper(II) gluconate possesses superior potential to solubilize Gem up to 150 mg/mL and augments passive drug loading. Upon loading Gem, formation of a complex with copper further improved drug loading and stability within TSL. By optimizing the lipid composition of the liposomal shell, we achieved high loading content of Gem at up to 12% by weight in TSL (CuGem-TSL), 4-fold greater than previously reported. Cryo electron microscopy confirmed the presence of liquid crystalline structures within CuGem-TSL, which was not observed in the absence of copper (Gem-TSL). The resulting high-content CuGem-TSL displayed a rapid release of Gem (80%) within 5 min at 42C with only 25% release over 30 min at 37C in the presence of serum. In vitro CuGem-TSL demonstrated equivalent toxicity to free Gem against both murine breast cancer and pancreatic cancer. One hour following intravenous administration, 75% of Gem was effectively retained in circulating TSL, whereas no drug was detected in mouse plasma with free drug administration. Three repeated administrations of CuGem-TSL combined with USH over a two-week treatment course suppressed tumor growth in NDL, model of murine breast cancer, with limited toxicity, enhancing survival when compared to treatment with free Gem alone. Additionally, in a more aggressive tumor model of murine pancreatic cancer (KrasLSL-G12D/+; Trp53LSL-R172H/+; Pdx-Cre, mT4 tumor source), CuGem-TSL with USH induced cell death and regions of apoptosis and necrosis. Citation Format: Samantha T. Tucci, Azadeh Kheirolomoom, Elizabeth S. Ingham, Lisa M. Mahakian, Sarah M. Tam, Josquin Foiret, Neil E. Hubbard, Alexander D. Borowsky, Mo Baikoghli, R. Holland Cheng, Katherine W. Ferrara. Activatable nanodelivery of high payload gemcitabine augments therapeutic efficacy in murine breast and pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2171.

published proceedings

  • Cancer Research

author list (cited authors)

  • Tucci, S. T., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S. M., Foiret, J., ... Ferrara, K. W.

citation count

  • 0

complete list of authors

  • Tucci, Samantha T||Kheirolomoom, Azadeh||Ingham, Elizabeth S||Mahakian, Lisa M||Tam, Sarah M||Foiret, Josquin||Hubbard, Neil E||Borowsky, Alexander D||Baikoghli, Mo||Cheng, R Holland||Ferrara, Katherine W

publication date

  • July 2019