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In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer

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Abstract

Gemcitabine (GEM) is presently the standard option for the treatment of advanced pancreatic cancer (PC). We investigated the in vitro and in vivo antitumor potential of GEM-loaded PEGylated liposomes (L-GEM) as a novel agent for the treatment of PC. In vitro analysis of antitumor activity against human PC cell lines, BXPC-3 and PSN-1, showed a significant time- and dose-dependent reduction of cell viability following exposure to L-GEM as compared to free GEM [at 72 h, IC50: 0.009 vs. 0.027 μM (P = 0.003) for BXPC-3 and 0.003 vs. 0.009 μM (P < 0.001) for PSN1, respectively]. Confocal laser scanning microscopy demonstrated an effective liposome/cell interaction and internalization process following 3-h cell exposure to L-GEM. The in vivo antitumor activity of L-GEM was investigated in a cohort of SCID mice bearing BxPC-3 or PSN-1 xenografts. Animals were i.p. treated with L-GEM (5 mg/kg), or a threefold increased dose of free GEM (15 mg/kg), or empty liposomes or vehicle, twice a week for 35 days. A significant higher inhibition of tumor growth in mice treated with L-GEM versus free GEM (P = 0.006 and P = 0.004 for BXPC-3 and PSN-1, respectively) or control groups (P = 0.0001), translated in a survival advantage of L-GEM treated animals versus other groups. Pharmacokinetic studies showed enhancement of systemic bioavailability of L-GEM (t 1/2 = 8 h) versus to GEM (t 1/2 = 1.5 h). Our findings demonstrate that L-GEM is an effective agent against PC and exerts higher antitumor activity as compared to free GEM with no appreciable increase in toxicity. These results provide the pre-clinical rational for L-GEM clinical development for the treatment of PC patients.

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Abbreviations

AUC:

Area under the curve

Chol:

Cholesterol

CLSM:

Confocal laser scanning microscopy

C max :

Maximum plasmatic concentration

DPPC:

1, 2-Dipalmitoyl-sn-glycero-3-phospocholine monohydrate

DSPE-MPEG 2000:

N-(Carbonyl-methoxypolyethylene glycol-2000)-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine

EPR:

Enhanced permeation and retention

Fluorescein-DHPE:

N-(Fluorescein-5-tiocarbamoyl)-1, 2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine triethylammonium salt

GEM:

Gemcitabine—2I, 2I-difluorodeoxycytidine

HPLC:

High performance liquid chromatography

L-GEM:

Gemcitabine-loaded pegylated small unilamellar liposomes

PBS:

Phosphate buffer saline solution

PC:

Human pancreatic adenocarcinoma cancer

PEG:

Poly-ethylene glycol

t 1/2 :

Plasma half-life

V d :

Volume of distribution

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Acknowledgments

This investigation was supported by a grant from the Italian Ministry of University and Research (PRIN 2006, P.I.:M.F., from the Italian Ministry of Health—Regione Calabria Dipartimento Tutela della Salute Politiche Sanitarie e Sociali), from the Italian Ministry of University and Research (PRIN 2007, P.I.:P.T.), and from Associazione Italiana Ricerca sul Cancro (AIRC, P.I.:P.T.).

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Authors and Affiliations

  1. Department of Pharmacobiological Sciences, University “Magna Græcia”, Campus Salvatore Venuta, Catanzaro, Italy

    Donato Cosco, Christian Celia, Nicola Costa & Massimo Fresta

  2. Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer Center, University “Magna Græcia”, Campus Salvatore Venuta, Viale Europa, 88100, Catanzaro, Italy

    Alessandra Bulotta, Monica Ventura, Teresa Calimeri, Gino Perri, Paola Neri, Pierosandro Tagliaferri & Pierfrancesco Tassone

  3. Department of Experimental and Clinical Medicine G. Salvatore, University “Magna Græcia”, Campus Salvatore Venuta, Catanzaro, Italy

    Donatella Paolino, Paola Neri, Pierosandro Tagliaferri & Pierfrancesco Tassone

Authors
  1. Donato Cosco
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  2. Alessandra Bulotta
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  3. Monica Ventura
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  4. Christian Celia
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  5. Teresa Calimeri
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  7. Donatella Paolino
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  8. Nicola Costa
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  9. Paola Neri
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  10. Pierosandro Tagliaferri
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  11. Pierfrancesco Tassone
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  12. Massimo Fresta
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Corresponding author

Correspondence to Pierfrancesco Tassone.

Additional information

In memory of Prof. Salvatore Venuta, MD, a victim of pancreatic cancer, an oncologist and a scientist who lived future frontiers of cancer therapeutics by strongly trusting in biomedical nanotechnologies.

D. Cosco and A. Bulotta contributed equally to this work.

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Cosco, D., Bulotta, A., Ventura, M. et al. In vivo activity of gemcitabine-loaded PEGylated small unilamellar liposomes against pancreatic cancer. Cancer Chemother Pharmacol 64, 1009–1020 (2009). https://doi.org/10.1007/s00280-009-0957-1

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  • DOI: https://doi.org/10.1007/s00280-009-0957-1

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