Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 5, pp 1009–1020

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

Authors

  • Donato Cosco
    • Department of Pharmacobiological SciencesUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Alessandra Bulotta
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Monica Ventura
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Christian Celia
    • Department of Pharmacobiological SciencesUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Teresa Calimeri
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Gino Perri
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Donatella Paolino
    • Department of Experimental and Clinical Medicine G. SalvatoreUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Nicola Costa
    • Department of Pharmacobiological SciencesUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Paola Neri
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
    • Department of Experimental and Clinical Medicine G. SalvatoreUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Pierosandro Tagliaferri
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
    • Department of Experimental and Clinical Medicine G. SalvatoreUniversity “Magna Græcia”, Campus Salvatore Venuta
    • Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore Venuta
    • Department of Experimental and Clinical Medicine G. SalvatoreUniversity “Magna Græcia”, Campus Salvatore Venuta
  • Massimo Fresta
    • Department of Pharmacobiological SciencesUniversity “Magna Græcia”, Campus Salvatore Venuta
Original Article

DOI: 10.1007/s00280-009-0957-1

Cite this article as:
Cosco, D., Bulotta, A., Ventura, M. et al. Cancer Chemother Pharmacol (2009) 64: 1009. doi:10.1007/s00280-009-0957-1

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 (t1/2 = 8 h) versus to GEM (t1/2 = 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.

Keywords

Pancreatic cancerLiposomesGemcitabineMouse modelsBXPC-3PSN-1

List of abbreviations

AUC

Area under the curve

Chol

Cholesterol

CLSM

Confocal laser scanning microscopy

Cmax

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

t1/2

Plasma half-life

Vd

Volume of distribution

Copyright information

© Springer-Verlag 2009