In Vivo Imaging of⁶⁴Cu-Labeled Polymer Nanoparticles Targeted to the Lung Endothelium

Abstract

Nanoparticles (NPs) targeting the intercellular adhesion molecule 1 (ICAM-1) hold promise as a mean of delivering therapeutics to the pulmonary endothelium in patients with acute and chronic respiratory diseases. As these new materials become available, strategies are needed to understand their behavior in vivo. We have evaluated the use of 64 Cu and PET to noninvasively image the lung uptake and distribution of NPs coated with an anti-ICAM antibody. Methods: Model fluorescent NPs were coated with a mixture of an anti-ICAM antibody (or nonspecific IgG) and 64 Cu-DOTA-IgG (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Biodistribution and small-animal PET and CT studies were performed in healthy mice and in mice pretreated with lipopolysaccharides (LPSs). Metabolism studies were also performed to evaluate the stability of 64 Cu-labeled NPs in lungs in vivo. Results: The lungs of mice administered anti-ICAM NPs labeled with 64 Cu were clearly imaged by small-animal PET 1, 4, and 24 h after administration. Both biodistribution and small-animal imaging showed a 3-to 4-fold higher uptake in the lungs of mice injected with ICAM-targeted NPs relative to that of the control group. Lung uptake was further enhanced by pretreating the mice with LPS, presumably because of ICAM-1 upregulation. However, an approximately 2-fold decrease in lung signal was observed in each experimental group over 24 h. Metabolism studies in lung tissues harvested from mice injected with 64 Cu-labeled anti-ICAM NPs showed considerable release of a small 64 Cu-radiometabolite from the NPs beginning as early as 1 h after injection. A decrease in lung fluorescence was also observed, most likely reflecting partial release of NPs from the lungs in vivo. Conclusion: The use of small-animal PET to track 64 Cu-labeled nanostructures in vivo shows potential as a strategy for the preclinical screening of new NP drug delivery agents targeting the lung endothelium and other tissues. Future design optimization to prolong the stability of the radiolabel in vivo will further improve this promising approach.

Antibody-Conjugated Nanoparticles for Therapeutic Applications

“…Muzykantov and colleagues have shown that lung delivery can be significantly enhanced by immunotargeting the pulmonary endothelium with MAbs directed against intercellular adhesion molecule 1 (ICAM-1) [149,215]. Although this immunoglobulin-like transmembrane endothelial adhesion molecule is constitutively expressed in the tissues of every organ, favorable pharmacokinetics (a result of the high-flow, highcapacity, and low-resistance nature of the pulmonary vasculature) ensure relatively high lung extraction of materials coupled to anti-ICAM antibodies [216]. NP targeting ICAM-1 hold promise as a mean of delivering therapeutics to the pulmonary endothelium.…”

Specific PET Imaging Probes for Early Detection of Prostate Cancer Metastases

“…were determined by a competitive cell-binding assay using 125 I-echistatin (PerkinElmer) as the α υ β 3 -specific radioligand. The experiments were performed on U87MG human glioblastoma cells by a previously reported method (1,2). Briefly, U87MG cells were grown in Dulbecco's modified Eagle medium (DMEM, low glucose) supplemented with 10% (v/v) fetal bovine serum (FBS) at 37ºC with 5% CO 2 .…”

“…In the Amino Acids paper, we demonstrated the potential of using NHGR 11 to develop specific PET imaging probes for distant prostate cancer metastases by both in vitro and in vivo evaluations performed with FITC-NHGR11 and 64 Cu-DOTA-NHGR11. [2,3] It has been demonstrated that creation of multimers of a targeting molecule on one scaffold can efficiently improve cell-specific binding affinity by several orders of magnitude. [3] As such, various approaches have been reported to exploit multivalent scaffolds for the construction of molecular imaging probes.…”

Synthesis and evaluation of radiolabeled, folic acid-PEG conjugated, amino silane coated magnetic nanoparticles in tumor bearing Balb/C mice

“…FRs are also overexpressed on activated and nonresting macrophages, although functional FRs are not expressed on resting macrophages or normal epithelial cells, which helps in targeting genetically altered cells [7]. Magnetic nanoparticles have been used extensively to investigate a wide range of biological phenomena such as tumor detection [10][11][12][13][14][15][16]. Copper-64 (t 1/2 = 12.7 h) is a unique isotope for radioisotope therapy which decays by -(39%), +/EC (61%).…”