Cancer Chemotherapy and Pharmacology

, Volume 64, Issue 5, pp 1009–1020

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

  • Donato Cosco
  • Alessandra Bulotta
  • Monica Ventura
  • Christian Celia
  • Teresa Calimeri
  • Gino Perri
  • Donatella Paolino
  • Nicola Costa
  • Paola Neri
  • Pierosandro Tagliaferri
  • Pierfrancesco Tassone
  • Massimo Fresta
Original Article

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 cancer Liposomes Gemcitabine Mouse models BXPC-3 PSN-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

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Donato Cosco
    • 1
  • Alessandra Bulotta
    • 2
  • Monica Ventura
    • 2
  • Christian Celia
    • 1
  • Teresa Calimeri
    • 2
  • Gino Perri
    • 2
  • Donatella Paolino
    • 3
  • Nicola Costa
    • 1
  • Paola Neri
    • 2
    • 3
  • Pierosandro Tagliaferri
    • 2
    • 3
  • Pierfrancesco Tassone
    • 2
    • 3
  • Massimo Fresta
    • 1
  1. 1.Department of Pharmacobiological SciencesUniversity “Magna Græcia”, Campus Salvatore VenutaCatanzaroItaly
  2. 2.Medical Oncology Unit and Referal Unit for Genetic Counselling and Innovative Treatments, Tommaso Campanella Cancer CenterUniversity “Magna Græcia”, Campus Salvatore VenutaCatanzaroItaly
  3. 3.Department of Experimental and Clinical Medicine G. SalvatoreUniversity “Magna Græcia”, Campus Salvatore VenutaCatanzaroItaly

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