Tumor-specific delivery of gemcitabine with activatable liposomes

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

Research output: Contribution to journalArticle

Abstract

Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper (II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole%) then reached 12 wt% loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine‑copper mixture. The optimized gemcitabine liposomes released 60% and 80% of the gemcitabine within 1 and 5 min, respectively, at 42 °C. Liposomal encapsulation resulted in a circulation half-life of ~2 h in vivo (compared to reported circulation of 16 min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model of murine breast cancer with limited toxicity, enhancing survival when compared to treatment with gemcitabine alone. With 5% of the free gemcitabine dose (5 rather than 100 mg/kg), tumor growth was suppressed to the same degree as gemcitabine. Additionally, in a more aggressive tumor model of murine pancreatic cancer, liposomal gemcitabine combined with local hyperthermia induced cell death and regions of apoptosis and necrosis.

Original languageEnglish (US)
Pages (from-to)277-288
Number of pages12
JournalJournal of Controlled Release
Volume309
DOIs
StatePublished - Sep 10 2019

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gemcitabine
Liposomes
Neoplasms
Pancreatic Neoplasms
Gluconates
Breast Neoplasms

Keywords

  • Breast cancer
  • Gemcitabine
  • Pancreatic ductal adenocarcinoma
  • Temperature-sensitive liposome
  • Ultrasound

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Tucci, S. T., Kheirolomoom, A., Ingham, E. S., Mahakian, L. M., Tam, S. M., Foiret, J., ... Ferrara, K. W. (2019). Tumor-specific delivery of gemcitabine with activatable liposomes. Journal of Controlled Release, 309, 277-288. https://doi.org/10.1016/j.jconrel.2019.07.014

Tumor-specific delivery of gemcitabine with activatable liposomes. / Tucci, Samantha T.; Kheirolomoom, Azadeh; Ingham, Elizabeth S.; Mahakian, Lisa M.; Tam, Sarah M.; Foiret, Josquin; Hubbard, Neil; Borowsky, Alexander D; Baikoghli, Mo; Cheng, R. Holland; Ferrara, Katherine W.

In: Journal of Controlled Release, Vol. 309, 10.09.2019, p. 277-288.

Research output: Contribution to journalArticle

Tucci, ST, Kheirolomoom, A, Ingham, ES, Mahakian, LM, Tam, SM, Foiret, J, Hubbard, N, Borowsky, AD, Baikoghli, M, Cheng, RH & Ferrara, KW 2019, 'Tumor-specific delivery of gemcitabine with activatable liposomes', Journal of Controlled Release, vol. 309, pp. 277-288. https://doi.org/10.1016/j.jconrel.2019.07.014
Tucci ST, Kheirolomoom A, Ingham ES, Mahakian LM, Tam SM, Foiret J et al. Tumor-specific delivery of gemcitabine with activatable liposomes. Journal of Controlled Release. 2019 Sep 10;309:277-288. https://doi.org/10.1016/j.jconrel.2019.07.014
Tucci, Samantha T. ; Kheirolomoom, Azadeh ; Ingham, Elizabeth S. ; Mahakian, Lisa M. ; Tam, Sarah M. ; Foiret, Josquin ; Hubbard, Neil ; Borowsky, Alexander D ; Baikoghli, Mo ; Cheng, R. Holland ; Ferrara, Katherine W. / Tumor-specific delivery of gemcitabine with activatable liposomes. In: Journal of Controlled Release. 2019 ; Vol. 309. pp. 277-288.
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abstract = "Gemcitabine delivery to pancreatic ductal adenocarcinoma is limited by poor pharmacokinetics, dense fibrosis and hypo-vascularization. Activatable liposomes, with drug release resulting from local heating, enhance serum stability and circulation, and the released drug retains the ability to diffuse within the tumor. A limitation of liposomal gemcitabine has been the low loading efficiency. To address this limitation, we used the superior solubilizing potential of copper (II) gluconate to form a complex with gemcitabine at copper:gemcitabine (1:4). Thermosensitive liposomes composed of DPPC:DSPC:DSPE-PEG2k (80:15:5, mole{\%}) then reached 12 wt{\%} loading, 4-fold greater than previously reported values. Cryo transmission electron microscopy confirmed the presence of a liquid crystalline gemcitabine‑copper mixture. The optimized gemcitabine liposomes released 60{\%} and 80{\%} of the gemcitabine within 1 and 5 min, respectively, at 42 °C. Liposomal encapsulation resulted in a circulation half-life of ~2 h in vivo (compared to reported circulation of 16 min for free gemcitabine in mice), and free drug was not detected within the plasma. The resulting gemcitabine liposomes were efficacious against both murine breast cancer and pancreatic cancer in vitro. Three repeated treatments of activatable gemcitabine liposomes plus ultrasound hyperthermia regressed or eliminated tumors in the neu deletion model of murine breast cancer with limited toxicity, enhancing survival when compared to treatment with gemcitabine alone. With 5{\%} of the free gemcitabine dose (5 rather than 100 mg/kg), tumor growth was suppressed to the same degree as gemcitabine. Additionally, in a more aggressive tumor model of murine pancreatic cancer, liposomal gemcitabine combined with local hyperthermia induced cell death and regions of apoptosis and necrosis.",
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AU - Kheirolomoom, Azadeh

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AU - Tam, Sarah M.

AU - Foiret, Josquin

AU - Hubbard, Neil

AU - Borowsky, Alexander D

AU - Baikoghli, Mo

AU - Cheng, R. Holland

AU - Ferrara, Katherine W.

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