89Zr-Labeled Paramagnetic Octreotide-Liposomes for PET-MR Imaging of Cancer

PurposeDual-modality PET/MR platforms add a new dimension to patient diagnosis with high resolution, functional, and anatomical imaging. The full potential of this emerging hybrid modality could be realized by using a corresponding dual-modality probe. Here, we report pegylated liposome (LP) formulations, housing a MR T1 contrast agent (Gd) and the positron-emitting 89Zr (half-life: 3.27 days), for simultaneous PET and MR tumor imaging capabilities.Methods89Zr oxophilicity was unexpectedly found advantageous for direct radiolabeling of preformed paramagnetic LPs. LPs were conjugated with octreotide to selectively target neuroendocrine tumors via human somatostatin receptor subtype 2 (SSTr2). 89Zr-Gd-LPs and octreotide-conjugated homolog were physically, chemically and biologically characterized.Results89Zr-LPs showed reasonable stability over serum proteins and chelator challenges for proof-of-concept in vitro and in vivo investigations. Nuclear and paramagnetic tracking quantified superior SSTr2-recognition of octreotide-LP compared to controls.ConclusionsThis study demonstrated SSTr2-targeting specificity along with direct chelator-free 89Zr-labeling of LPs and dual PET/MR imaging properties.

[1]  S. Cherry,et al.  Simultaneous in vivo positron emission tomography and magnetic resonance imaging , 2008, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Abou,et al.  In vivo biodistribution and accumulation of 89Zr in mice. , 2011, Nuclear medicine and biology.

[3]  D. Euhus,et al.  Tumor measurement in the nude mouse , 1986, Journal of surgical oncology.

[4]  Marie-France Bellin,et al.  MR contrast agents, the old and the new. , 2006, European journal of radiology.

[5]  K. Nicolay,et al.  Relaxivity of liposomal paramagnetic MRI contrast agents , 2005, Magnetic Resonance Materials in Physics, Biology and Medicine.

[6]  V. Torchilin,et al.  Tumor-Targeted Nanomedicines: Enhanced Antitumor Efficacy In vivo of Doxorubicin-Loaded, Long-Circulating Liposomes Modified with Cancer-Specific Monoclonal Antibody , 2009, Clinical Cancer Research.

[7]  R E Jacobs,et al.  A model for MRI contrast enhancement using T1 agents. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[8]  D. Talham,et al.  Stable supported lipid bilayers on zirconium phosphonate surfaces. , 2009, Langmuir : the ACS journal of surfaces and colloids.

[9]  J. Reubi.  Peptide receptors as molecular targets for cancer diagnosis and therapy. , 2003, Endocrine reviews.

[10]  J. Seelig,et al.  Peptide binding to lipid bilayers. Nonclassical hydrophobic effect and membrane-induced pK shifts. , 1992, Biochemistry.

[11]  L. Tei,et al.  Paramagnetic Liposomes as Innovative Contrast Agents for Magnetic Resonance (MR) Molecular Imaging Applications , 2008, Chemistry and Biodiversity.

[12]  J C Stewart,et al.  Colorimetric determination of phospholipids with ammonium ferrothiocyanate. , 1980, Analytical biochemistry.

[13]  Y. Maitani,et al.  Octreotide-targeted liposomes loaded with CPT-11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma. , 2011, Molecular pharmaceutics.

[14]  S. Larson,et al.  Imaging Expression of the Human Somatostatin Receptor Subtype-2 Reporter Gene with 68Ga-DOTATOC , 2011, The Journal of Nuclear Medicine.

[15]  Kang-Choon Lee,et al.  Preparation and stability of poly(ethylene glycol) (PEG)ylated octreotide for application to microsphere delivery , 2003, AAPS PharmSciTech.

[16]  Jason S. Lewis,et al.  Standardized methods for the production of high specific-activity zirconium-89. , 2009, Nuclear medicine and biology.

[17]  Simon R Cherry,et al.  Multimodality imaging: beyond PET/CT and SPECT/CT. , 2009, Seminars in nuclear medicine.

[18]  H. Maeda,et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[19]  Ande Bao,et al.  Radioactive liposomes. , 2009, Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology.

[20]  Q. Ping,et al.  Octreotide-modification enhances the delivery and targeting of doxorubicin-loaded liposomes to somatostatin receptors expressing tumor in vitro and in vivo , 2010, Nanotechnology.

[21]  P. L. Jager,et al.  Biodistribution of 89Zr‐trastuzumab and PET Imaging of HER2‐Positive Lesions in Patients With Metastatic Breast Cancer , 2010, Clinical pharmacology and therapeutics.

[22]  Ronald G Blasberg,et al.  Multimodality Registration without a Dedicated Multimodality Scanner , 2007, Molecular imaging.

[23]  Valerie A Longo,et al.  Optimizing tumor targeting of the lipophilic EGFR-binding radiotracer SKI 243 using a liposomal nanoparticle delivery system. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[24]  I. Buvat,et al.  Partial-Volume Effect in PET Tumor Imaging* , 2007, Journal of Nuclear Medicine.

[25]  Y. Maitani,et al.  Dual functional octreotide‐modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts , 2012, Cancer science.

[26]  O. Boerman,et al.  In vivo applications of PEG liposomes: unexpected observations. , 2001, Critical reviews in therapeutic drug carrier systems.

[27]  S. Larson,et al.  89Zr-DFO-J591 for ImmunoPET of Prostate-Specific Membrane Antigen Expression In Vivo , 2010, The Journal of Nuclear Medicine.

[28]  H. Enoch,et al.  Formation and properties of 1000-A-diameter, single-bilayer phospholipid vesicles. , 1979, Proceedings of the National Academy of Sciences of the United States of America.