Pharmacokinetics and biodistribution of human serum albumin-TIMP-2 fusion protein using near-infrared optical imaging.

Abstract

PURPOSE:

TIMP-2 has been studied as an attractive cancer therapeutic candidate, and a TIMP-2 fusion protein (HSA/TIMP-2) displayed effective anticancer activity, despite a lack of information about its pharmacokinetics (PK) and biodistribution. The purpose of this work was to assess the PK and biodistribution of HSA/TIMP-2 as well as to quantify accumulated HSA/TIMP-2 in tumors.

METHODS:

Cy5.5 near-infrared (NIR) fluorescence was conjugated to the HSA/TIMP-2 protein (Cy5.5-HSA/TIMP-2) for monitoring spatio-temporal changes in vivo. For PK and biodistribution analysis, 0.2 μg/g body weight of Cy5.5-HSA/TIMP-2 was injected into MAT-LyLu prostate tumor xenografts, which were then imaged using an IVIS-200 optical imaging system. To quantify the accumulated HSA/TIMP-2 in tumors, we introduced a standard curve with depth-corrected fluorescence measurement.

RESULTS:

In the vascular tube formation assay with human umbilical vein endothelial cells (HUVECs), Cy5.5-HSA/TIMP-2 showed an antiangiogenic effect. In prostate cancer xenografts, Cy5.5-HSA/TIMP-2 exhibited a prolongation of blood half-life to 19.6 h and relatively preferential distribution to the tumor. The amount of tumor-accumulated Cy5.5-HSA/TIMP-2 was calculated to be 4.5 ± 0.5 ng/g body weight at 2 days, representing 2.25 ± 0.25% of the initial dose.

CONCLUSIONS:

We evaluated the pharmacokinetic profile and biodistribution of HSA/TIMP-2 with favorable results, providing new information for more effective approaches to cancer therapeutics using HSA/TIMP-2. Additionally, real-time in vivo fluorescence imaging analysis using a depth-corrected standard curve may serve as a platform to quantify biodistributed drug in anticancer therapeutic studies.

• Authors: Mi-Sook Lee, Young Han Kim, Yeon Joo Kim, Seung-Hae Kwon, Jeong-Kyu Bang, Sang-Mok Lee, Yun Seon Song, Dae-Hyun Hahm, Insop Shim, Daeseok Han, Song Her
• Journal: Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques (J Pharm Pharm Sci) Vol. 14 Issue 3 Pg. 368-77 ( 2011) ISSN: 1482-1826 [Electronic] Switzerland
• PMID: 21962154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ALB protein, human
• Angiogenesis Inhibitors
• CY5.5 cyanine dye
• Carbocyanines
• Recombinant Fusion Proteins
• Serum Albumin
• Tissue Inhibitor of Metalloproteinase-2
• Serum Albumin, Human

Topics

• Angiogenesis Inhibitors (blood, pharmacokinetics)
• Animals
• Carbocyanines (chemistry, pharmacokinetics)
• Half-Life
• Human Umbilical Vein Endothelial Cells (cytology, drug effects)
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Transplantation (methods)
• Prostatic Neoplasms (blood, metabolism)
• Rats
• Recombinant Fusion Proteins (blood, pharmacokinetics)
• Serum Albumin (pharmacokinetics)
• Serum Albumin, Human
• Spectroscopy, Near-Infrared (methods)
• Tissue Distribution
• Tissue Inhibitor of Metalloproteinase-2 (pharmacokinetics)
• Transplantation, Heterologous
• Tumor Cells, Cultured