TY - JOUR
T1 - Water-Soluble Nanoconjugate for Enhanced Cellular Delivery of Receptor-Targeted Magnetic Resonance Contrast Agents
AU - Moore, Laura K.
AU - Caldwell, Michael A.
AU - Townsend, Taryn R.
AU - Macrenaris, Keith W.
AU - Moyle-Heyrman, Georgette
AU - Rammohan, Nikhil
AU - Schonher, Erika K.
AU - Burdette, Joanna E.
AU - Ho, Dean
AU - Meade, Thomas J.
N1 - Funding Information:
This work was supported by the NIH National Institute of Biomedical Imaging and Bioengineering award no. R01EB005866 and by NIH grant R01EB014806, V Foundation for Cancer Research Scholars Award, Wallace H. Coulter Foundation Translational Research Award, National Cancer Institute Grant 1F30CA174156-01, and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM105538 and R01AT008824-1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Funding Information:
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Laura Moore and Taryn Townsend planned and conducted the experimental work. Michael Caldwell analyzed the data and wrote the manuscript with the assistance of Laura Moore and Taryn Townsend. Georgette Heyrman-Moyle conducted binding assays. Keith MacRenaris conducted all ICP analyses. Nikhil Rammohan and Erika Schonher synthesized compounds used in this work. L.K.M. and M.A.C. contributed equally. This work was supported by the NIH National Institute of Biomedical Imaging and Bioengineering award no. R01EB005866 and by NIH grant R01EB014806, V Foundation for Cancer Research Scholars Award, Wallace H. Coulter Foundation Translational Research Award, National Cancer Institute Grant 1F30CA174156-01, and by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM105538 and R01AT008824-1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing financial interest.
Funding Information:
The authors would like to thank Daniel Lantivit for help with animal experiments and The Center for Advanced Molecular Imaging (CAMI) staff, Drs. Chad Haney and Alex Waters for helpful discussions. Confocal microscopy was performed at the Northwestern University Quantitative Bioelement Imaging Center generously supported by the National Science Foundation CHE-9810378/005. Metal analysis was performed at the Northwestern University Quantitative Bioelement Imaging Center generously supported by NASA Ames Research Center NNA06CB93G.
PY - 2019/11/20
Y1 - 2019/11/20
N2 - ProGlo is an efficient steroid receptor-targeted magnetic resonance (MR) imaging contrast agent (CA). It has been shown to bind to the progesterone receptor (PR) and produce enhanced image contrast in PR-positive cells and tissues in vitro and in vivo. However, the hydrophobicity of the steroid targeting domain of ProGlo (logP = 1.4) limits its formulation and delivery at clinically relevant doses. In this work, a hydrophobic moiety was utilized to drive efficient adsorption onto nanodiamond (ND) clusters to form a water-soluble nanoconstruct (logP = -2.4) with 80% release in 8 h under biological conditions. In cell culture, the ND-ProGlo construct delivered increased concentrations of ProGlo to target cells compared to ProGlo alone. Importantly, these results were accomplished without the use of solvents such as DMSO, providing a significant advance toward formulating ProGlo for translational applications. Biodistribution studies confirm the delivery of ProGlo to PR(+) tissues with enhanced efficacy over untargeted controls. These results demonstrate the potential for a noncovalent ND-CA construct as a general strategy for solubilizing and delivering hydrophobic targeted MR CAs.
AB - ProGlo is an efficient steroid receptor-targeted magnetic resonance (MR) imaging contrast agent (CA). It has been shown to bind to the progesterone receptor (PR) and produce enhanced image contrast in PR-positive cells and tissues in vitro and in vivo. However, the hydrophobicity of the steroid targeting domain of ProGlo (logP = 1.4) limits its formulation and delivery at clinically relevant doses. In this work, a hydrophobic moiety was utilized to drive efficient adsorption onto nanodiamond (ND) clusters to form a water-soluble nanoconstruct (logP = -2.4) with 80% release in 8 h under biological conditions. In cell culture, the ND-ProGlo construct delivered increased concentrations of ProGlo to target cells compared to ProGlo alone. Importantly, these results were accomplished without the use of solvents such as DMSO, providing a significant advance toward formulating ProGlo for translational applications. Biodistribution studies confirm the delivery of ProGlo to PR(+) tissues with enhanced efficacy over untargeted controls. These results demonstrate the potential for a noncovalent ND-CA construct as a general strategy for solubilizing and delivering hydrophobic targeted MR CAs.
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U2 - 10.1021/acs.bioconjchem.9b00640
DO - 10.1021/acs.bioconjchem.9b00640
M3 - Article
C2 - 31589412
AN - SCOPUS:85074280099
VL - 30
SP - 2947
EP - 2957
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
SN - 1043-1802
IS - 11
ER -