Magnetic targeting of magnetoliposomes to solid tumors with MR imaging monitoring in mice: feasibility.

PURPOSE To establish the feasibility of magnetoliposome tumor targeting with an extracorporeal magnet. MATERIALS AND METHODS Animal experiments were performed in compliance with Institut National de la Santé Et de la Recherche Médicale animal protection guidelines and were approved by local government authorities. Magnetophoresis was used to measure the velocity of magnetoliposomes constituted of polyethylene glycol-lipids and anionic maghemite nanocrystals in a calibrated magnetic field in vitro. For in vivo studies, 38 male Swiss nude mice bearing a PC3 human prostate carcinoma tumor in each flank received an intravenous injection of magnetoliposomes (n = 27), saline (n = 9), or nonencapsulated superparamagnetic particles (n = 2) after a small magnet with a magnetic field of 0.3 T and a field gradient of 11 T/m was fixed to the skin above one tumor. The animals were examined at magnetic resonance (MR) imaging with eight different sequences, iron doses (13 mice), and magnet-application durations (12 mice). Their excised tumors were then stained with Perls Prussian blue and hematoxylin-eosin and were examined histologically. With use of the paired Student t test, signal intensity, tumor surface enhancement, and number of stained cells were compared between the control and magnet-exposed tumors to determine significant differences (P </= .01). RESULTS The mean magnetoliposome velocity ranged from 10 to 40 mum/sec when the magnetic field equaled 0.13 T and the field gradient equaled 25 T/m. At T1-weighted three-dimensional spoiled gradient-echo MR imaging in vivo, the tumor exposed to the magnet showed strong negative enhancement, -52%, compared with the -7% enhancement of the other tumor. Maximal enhancement occurred after 3 hours of magnet application. After 24 hours of magnet application, intracapillary iron particle accumulation was observed in the targeted tumors only. CONCLUSION Magnetic targeting of sterically stabilized magnetoliposomes after they are intravenously injected is feasible in vivo.

[1]  D. Müller-Schulte,et al.  Biotinylated Stealth magnetoliposomes. , 2002, Chemistry and physics of lipids.

[2]  Mark Wilson,et al.  Hepatocellular carcinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/ conventional angiography suite--initial experience with four patients. , 2004, Radiology.

[3]  U. Häfeli,et al.  Magnetizable needles and wires--modeling an efficient way to target magnetic microspheres in vivo. , 2004, Biorheology.

[4]  Maruyama,et al.  Possibility of active targeting to tumor tissues with liposomes. , 1999, Advanced drug delivery reviews.

[5]  R. Weissleder,et al.  Trapping of dextran-coated colloids in liposomes by transient binding to aminophospholipid: preparation of ferrosomes. , 1994, Biochimica et biophysica acta.

[6]  J. Bacri,et al.  Biomedical applications of maghemite ferrofluid. , 1998, Biochimie.

[7]  R. Jain,et al.  Microvascular permeability and interstitial penetration of sterically stabilized (stealth) liposomes in a human tumor xenograft. , 1994, Cancer research.

[8]  Florence Gazeau,et al.  Magnetophoresis and ferromagnetic resonance of magnetically labeled cells , 2002, European Biophysics Journal.

[9]  Richard O. Claus,et al.  Synthesis, characterization and targeting of biodegradable magnetic nanocomposite particles by external magnetic fields , 2005 .

[10]  V. Cabuil,et al.  Monodisperse magnetic nanoparticles: Preparation and dispersion in water and oils , 1998 .

[11]  F. Hirayama,et al.  X-ray crystallographic characterization of nilvadipine monohydrate and its phase transition behavior. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[12]  H. Honda,et al.  Anticancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes , 2003, Melanoma research.

[13]  M. Woodle,et al.  Sterically stabilized liposome therapeutics , 1995 .

[14]  F. Marcucci,et al.  Active targeting with particulate drug carriers in tumor therapy: fundamentals and recent progress. , 2004, Drug discovery today.

[15]  Scott Goodwin,et al.  Intravesical administration of doxorubicin to swine bladder using magnetically targeted carriers , 2003, Cancer Chemotherapy and Pharmacology.

[16]  C Alexiou,et al.  Clinical applications of magnetic drug targeting. , 2001, The Journal of surgical research.

[17]  R. Felix,et al.  MRI after magnetic drug targeting in patients with advanced solid malignant tumors , 2004, European Radiology.

[18]  Carl K. Hoh,et al.  Targeting and retention of magnetic targeted carriers (MTCs) enhancing intra-arterial chemotherapy , 1999 .

[19]  M. Dewhirst,et al.  In vivo monitoring of tissue pharmacokinetics of liposome/drug using MRI: Illustration of targeted delivery , 2004, Magnetic resonance in medicine.

[20]  Sanyog Jain,et al.  RGD-anchored magnetic liposomes for monocytes/neutrophils-mediated brain targeting. , 2003, International journal of pharmaceutics.

[21]  G. Barratt,et al.  Colloidal drug carriers: achievements and perspectives , 2003, Cellular and Molecular Life Sciences CMLS.

[22]  H. Buhr,et al.  Liposome-encapsulated superparamagnetic iron oxide particles as markers in an MRI-guided search for tumor-specific drug carriers. , 1997, Anti-cancer drug design.

[23]  Hiroyuki Honda,et al.  Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma , 2003, Cancer science.

[24]  P Reichardt,et al.  Clinical experiences with magnetic drug targeting: a phase I study with 4'-epidoxorubicin in 14 patients with advanced solid tumors. , 1996, Cancer research.

[25]  J. Bulte,et al.  Magnetoliposomes as contrast agents. , 2003, Methods in enzymology.

[26]  S. Lesieur,et al.  Evidence of surfactant-induced formation of transient pores in lipid bilayers by using magnetic-fluid-loaded liposomes. , 2003, Journal of the American Chemical Society.

[27]  I Horikoshi,et al.  Magnetic targeting of thermosensitive magnetoliposomes to mouse livers in an in situ on-line perfusion system. , 1995, Life sciences.

[28]  K. Widder,et al.  Tumor remission in Yoshida sarcoma-bearing rts by selective targeting of magnetic albumin microspheres containing doxorubicin. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Takashi Sugita,et al.  Evaluation of systemic chemotherapy with magnetic liposomal doxorubicin and a dipole external electromagnet , 2004, International journal of cancer.

[30]  R. Massart,et al.  Preparation of aqueous magnetic liquids in alkaline and acidic media , 1981 .

[31]  Okuhata,et al.  Delivery of diagnostic agents for magnetic resonance imaging. , 1999, Advanced drug delivery reviews.

[32]  J. Bulte,et al.  Preparation, relaxometry, and biokinetics of PEGylated magnetoliposomes as MR contrast agent , 1999 .

[33]  U. Häfeli,et al.  Magnetically modulated therapeutic systems. , 2004, International journal of pharmaceutics.

[34]  Hitoshi Sato,et al.  Release of 5-fluorouracil from thermosensitive magnetoliposomes induced by an electromagnetic field , 1997 .

[35]  Valérie Cabuil,et al.  Generation of superparamagnetic liposomes revealed as highly efficient MRI contrast agents for in vivo imaging. , 2005, Journal of the American Chemical Society.

[36]  Jessie L.-S. Au,et al.  Drug Delivery and Transport to Solid Tumors , 2003, Pharmaceutical Research.

[37]  Tilcock.  Delivery of contrast agents for magnetic resonance imaging, computed tomography, nuclear medicine and ultrasound. , 1999, Advanced drug delivery reviews.

[38]  G. Storm,et al.  ACTIVE TARGETING WITH PARTICULATE CARRIER SYSTEMS IN THE BLOOD COMPARTMENT , 1995 .

[39]  C. Driscoll,et al.  Magnetic targeting of microspheres in blood flow. , 1984, Microvascular research.

[40]  A. Gabizon,et al.  Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[41]  K. Amighi,et al.  Surfactant induced drug delivery based on the use of thermosensitive polymers. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[42]  W Siegenthaler,et al.  Red blood cell velocity in nailfold capillaries of man measured by a television microscopy technique. , 1974, Microvascular research.

[43]  Hiroyuki Honda,et al.  Heat-inducible TNF-α gene therapy combined with hyperthermia using magnetic nanoparticles as a novel tumor-targeted therapy , 2001, Cancer Gene Therapy.

[44]  Oku.  Anticancer therapy using glucuronate modified long-circulating liposomes. , 1999, Advanced drug delivery reviews.

[45]  O. Kuznetsov,et al.  Application of magnetic liposomes for magnetically guided transport of muscle relaxants and anti-cancer photodynamic drugs , 2001 .

[46]  M. Tsujimoto,et al.  Potential usage of thermosensitive liposomes for site-specific delivery of cytokines. , 2000, Cancer letters.