Conventional Liposome Performance and Evaluation: Lessons from the Development of Vescan

Abstract

In the early 1980s, Vestar Inc., a company founded on the basis of science developed by the California Institute of Technology and the City of Hope, brought into development an imaging agent based on liposome encapsulated (111)In(3+). This agent, named Vescan, together with the gamma ray perturbed angular correlation spectroscopy technique to examine liposome integrity, was envisioned as a broadly applicable in vivo tumor diagnostic agent. While not ultimately commercialized, the agent was used to successfully image a variety of tumors, and was evaluated in late-stage clinical trials. Lessons learned from the formulation and process development of this product, and the wealth of non-clinical and clinical results, revealed valuable information about the properties of stable, RES avoiding conventional liposomes. This technology ultimately would lead (at NeXstar Pharmaceuticals and, later, at Gilead Sciences) to the technology that created commercialized liposomal products such as AmBisome and DaunoXome as well as other development stage product candidates.

Correlation between Ferumoxytol Uptake in Tumor Lesions by MRI and Response to Nanoliposomal Irinotecan in Patients with Advanced Solid Tumors: A Pilot Study

“…These studies demonstrated that permeability rates depended on molecular or particle properties such as hydrodynamic diameter and shape (4). Liposomal imaging agents based on single-photon emission computed tomographic (SPECT) or positron emission tomographic (PET) imaging have been examined as well (20)(21)(22). A widely studied class of imaging agents is superparamagnetic iron oxide nanoparticles, which have excellent MRI contrast characteristics and demonstrate concentration-related negative contrast on T2-and T2 Ã -weighted sequences.…”

Radionuclide imaging of liposomal drug delivery

“…With their half-life of, respectively, 6 h and 2.8 days, 99m Tc and 111 In are well suited to monitor the fate of liposomes in vivo using SPECT imaging, since liposomes usually have a half-life of less than 24 h in rodents and 48 h in humans [64][65][66][67]. The only liposome-based radiotracer formulation that was used in late-stage clinical trials was a liposomal formulation radiolabeled with 111 In, which was enabled by incorporation of the ionophore A23187 in the lipid bilayer and encapsulation of NTA as chelator [68]. Clinical studies with this formulation showed that liposomes containing phospholipids and cholesterol were well tolerated and that a wide variety of tumors could be imaged.…”

“…The well-known positron emitters for PET imaging, 18 F and 68 Ga, have been used successfully to radiolabel liposomes and to image different types of cancers. 18 F and 68 Ga-labeled liposomes showed stable radiolabel retention in vivo and their accumulation in tumor lesions was sufficient to visualize tumor lesions with PET imaging [80][81][82].…”

“…Lipophilic chelators, such as 8-hydroxyquinoline (oxine), can be used for the remote loading of radionuclides, such as 67 Ga, 68 Ga, 111 In or, 99m Tc to obtain radiolabeled liposomes. Radionuclides can form complexes with lipophilic chelators, and these complexes can diffuse through the lipid bilayer.…”

“…These photons are registered by detectors that acquire multiple two-dimensional (2D) projections. These 2D images, obtained from different angles, can be reconstructed into 3D images [ Figure 2( PET imaging is based on the emission of positrons by radioisotopes, such as 18 F (t ½ = 110 min), 68 Ga (t ½ = 68 min), or 64 Cu (t ½ = 12.7 h). These positrons annihilate with an electron that results in a pair of γ-photons, each of 511 keV, directed in opposite direction.…”