The use of scintigraphic imaging as a tool in the development of liposome formulations

doi:10.1016/S0163-7827(00)00014-X

Progress in Lipid Research

Volume 40, Issues 1–2, March 2001, Pages 95-123

https://doi.org/10.1016/S0163-7827(00)00014-X Get rights and content

Abstract

Scintigraphic imaging is a valuable tool that can be used during the development of liposome-based therapeutic agents. It provides the ability to non-invasively track and quantitate the distribution of liposomes in the body. This review article provides a general overview of the methods involved in producing scintigraphic images as well as methods of radiolabeling liposomes. Liposomes labeled with technetium-99m (^99mTc) are particularly useful for scintigraphic imaging due to the physical characteristics of ^99mTc, which provides a high quality image. Examples of how scintigraphic imaging studies have contributed to the development of a variety of liposome-based formulations are covered in this article. These liposome formulations include long-circulating liposome-based oxygen carriers, liposome-based anti-cancer drugs, liposomes encapsulating antibiotics and anti-fungals, and liposomes targeted to lymph nodes. Studies using scintigraphic imaging for the investigation of immune responses to liposomes are also discussed. These examples demonstrate the usefulness of scintigraphic imaging for the development of novel liposome formulations.

Introduction

Scintigraphic imaging is proving to be a valuable tool for the development of liposome-based therapeutic agents. In particular, this imaging modality can be used in the following areas: (1) tracking the distribution of liposomes in the body; (2) monitoring of therapeutic responses following the administration of liposome-encapsulated pharmaceuticals; and (3) investigating the physiological responses associated with liposome administration.

Scintigraphic imaging provides the ability to non-invasively track and quantitate the distribution of liposomes in the body using a gamma-emitting radionuclide label. A particular advantage of this imaging modality is that scintigraphy requires only a small amount of actual matter (usually in the nanogram range), which does not interfere with either the biodistribution of the labeled liposome or the physiological processes involved in its distribution. Other imaging modalities, such as magnetic resonance imaging (MRI) and computer tomographic imaging (CT), provide higher resolution images than scintigraphy, but require the administration of a significantly higher amount of matter to achieve image contrast (milligrams for MRI and grams for CT) [1]. The greater amount of contrast material required with these other imaging modalities can alter the normal biodistribution of the agent being tracked as well as increase the risk for an adverse reaction induced by the contrast agent. To date, clinicians have generally utilized MRI and CT contrast agents to demonstrate changes in vascular permeability and blood flow. On the other hand, scintigraphic imaging has been used to depict a wide variety of physiological processes, ranging from changes in glucose, protein and fatty acid metabolism to the demonstration of gene expression and detection of changes in the concentration of cell signaling receptors [2], [3], [4], [5], [6].

In particular, scintigraphic imaging has the following advantages for liposome research compared to other imaging modalities: (1) the total organism can be imaged in a single whole body scan; (2) a time course of the movement of a radionuclide agent can be easily obtained by acquiring images at varying time points after administration of the radiolabeled agent; (3) scintigraphic imaging methods are inherently quantitative since each scintillation is recorded and scanned into an image matrix for assembly of the visual image; and (4) multiple agents can be tracked simultaneously in the same organism. The radionuclides typically used in scintigraphic imaging have energies ranging from 70 keV to 511 keV. Thus, with careful selection of the radionuclides so that there is an adequate separation of photon energies, several radiolabeled agents can be tracked simultaneously in the same organism. For example, the liposome vehicle labeled with one radionuclide can be tracked simultaneously with the encapsulated drug labeled with a different radionuclide.

Section snippets

Radioisotopes and procedures used for scintigraphic imaging

There are two classes of radioisotopes available for scintigraphic imaging: single photon radioisotopes and positron-emitting radioisotopes. Methods to label liposomes with both classes of radioisotopes are under investigation. The procedures used to perform an imaging study with each class of radioisotope are also outlined in this section.

Liposome labeling methods for use with scintigraphic imaging

Many methods have been developed for labeling liposomes with gamma-emitting radionuclides for use in scintigraphic imaging [11], [12]. Although radioisotopes can simply be encapsulated within liposomes, this type of labeling protocol is generally not practical due to the requirement of rapid liposome manufacture and imaging within a short time period. This is particularly true with radioisotopes with decay half-lives under 24 h, which includes ^99mTc and ¹⁸F. A better approach is the labeling of

Some examples of the application of scintigraphic imaging during liposome drug development

As described in Section 1, scintigraphic imaging can be a very beneficial tool during liposome drug development. This section describes some specific examples where scintigraphic imaging was helpful in: (1) determining the optimal lipid formulation for a particular liposome drug application; (2) determining potential clinical indications for a particular liposome drug; and (3) deciding the optimal time for the delivery of a liposomal anti-cancer drug when used in combination with other therapy

Use of scintigraphic imaging in the study of the immune response to liposomes

Scintigraphic imaging studies have lead to unexpected insights regarding the interaction of liposomes with the immune system. For example, during clinical trials of ^99mTc-PEG-liposomes as an infection/inflammation imaging agent by Dams et al. as previously described in Section 4.3, patients were administered a low diagnostic dose of liposomes which was only 1/20th of the lipid dose of a standard therapeutic liposome-based pharmaceutical. Unexpectedly, despite the low lipid dose used in this

Human scintigraphic imaging for studies of drug delivery

Human scintigraphic studies of new therapeutic liposome formulations labeled with radionuclides will be useful for determining what percentage of the drug formulation actually reaches the therapeutic site. The therapeutic success, or lack thereof, of a particular liposome formulation can then be predicted in each individual patient. If there is no significant uptake of liposomes in the disease process, the likelihood of therapeutic success will be diminished. Altered biodistribution in

Summary

Scintigraphic imaging is an ideal modality for use in the development of liposome-encapsulated pharmaceuticals. These imaging studies are useful for formulation development in the pre clinical stages and for the non-invasive monitoring of patients in clinical trials.

Scintigraphic imaging has the potential to provide new medical insights that will further the development of liposome-encapsulated pharmaceuticals.

Acknowledgements

The authors thank Robert Klipper for the skilled assistance with the animal experiments and for providing the schematic diagram shown in Fig. 1; and Sandy Solano for preparation of this manuscript. The authors would also like to thank Dr. Don Thrall, North Carolina State University, for providing the images depicted in Fig. 5 and Dr. Peter Laverman, University Hospital, Nijmegen, The Netherlands, for providing the images depicted in Fig. 6, Fig. 7.

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ReviewThe use of scintigraphic imaging as a tool in the development of liposome formulations

Abstract

Introduction

Section snippets

Radioisotopes and procedures used for scintigraphic imaging

Liposome labeling methods for use with scintigraphic imaging

Some examples of the application of scintigraphic imaging during liposome drug development

Use of scintigraphic imaging in the study of the immune response to liposomes

Human scintigraphic imaging for studies of drug delivery

Summary

Acknowledgements

Int J Rad Appl Instrum B

Adv Drug Deliv Rev.

Adv Drug Delivery Rev.

Nucl Med Biol.

Advanced Drug Delivery Reviews

Biochim Biophys Acta

Nucl Med Biol.

Methods Enzymol.

FEBS Letters

Biochim Biophys Acta

Biochim Biophys Acta

Lancet

Adv Drug Delivery Rev.

FEBS Letters

Prog Biophys Mol Biol.

Biochim Biophys Acta

Biochim Biophys Acta

Vaccine

Cell Immunol.

Semin Nucl Med.

Surgery

Life Sci.

Biochim Biophys Acta

J Controlled Release

Semin Nucl Med.

Biochim Biophys Acta

Arch Biochem Biophys

Oncologist

Adv Neurol.

J Neurosci Res.

Med Phys

J Nucl Med.

J. Nucl. Med.

J Liposome Res.

J Nucl Med.

Med Res Rev.

Proc Natl Acad Sci USA

J Drug Target

Br J Cancer

Artif Cells Blood Substit Immobil Biotechnol

J Nucl Med.

J Pharmacol Exp Ther.

Lab Invest.

Cancer Res.

Br J Cancer

Review
The use of scintigraphic imaging as a tool in the development of liposome formulations