Noninvasive Visualization of Pharmacokinetics,Biodistribution and Tumor Targeting of Poly[<Emphasis Type="BoldItalic">N</Emphasis>-(2-hydroxypropyl)methacrylamide] in Mice Using Contrast Enhanced MRI |
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Authors: | Yanli Wang Furong Ye Eun-Kee Jeong Yongen Sun Dennis L Parker Zheng-Rong Lu |
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Institution: | (1) Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 421 Wakara Way, Suite 318, Salt Lake City, Utah 84108, USA;(2) Department of Radiology, University of Utah, Salt Lake City, Utah 84108, USA |
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Abstract: | Purpose To study a non-invasive method of using contrast enhanced magnetic resonance imaging (MRI) to visualize the real-time pharmacokinetics,
biodistribution and tumor accumulation of paramagnetically labeled polyN-(2-hydroxypropyl)methacrylamide] (PHPMA) copolymer conjugates with different molecular weights and spacers in tumor-bearing
mice.
Materials and Methods Paramagnetically labeled HPMA copolymer conjugates were synthesized by free radical copolymerization of HPMA with monomers
containing a chelating ligand, followed by complexation with Gd(OAc)3. A stable paramagnetic chelate, Gd-DO3A, was conjugated to the copolymers via a degradable spacer GlyPheLeuGly and a non-degradable
spacer GlyGly, respectively. The conjugates with molecular weights of 28, 60 and 121 kDa and narrow molecular weight distributions
were prepared by fractionation with size exclusion chromatography. The conjugates were injected into athymic nude mice bearing
MDA-MB-231 human breast carcinoma xenografts via a tail vein. MR images were acquired before and at various time points after
the injection with a 3D FLASH sequence and a 2D spin-echo sequence at 3T. Pharmacokinetics, biodistribution and tumor accumulation
of the conjugates were visualized based on the contrast enhancement in the blood, major organs and tumor tissue at various
time points. The size effect of the conjugates was analyzed among the conjugates.
Results Contrast enhanced MRI resulted in a real-time, three-dimensional visualization of blood circulation, pharmacokinetics, biodistribution
and tumor accumulation of the conjugates, and the size effect on these pharmaceutical properties. HPMA copolymer conjugates
with high molecular weight had a prolonged blood circulation time and high passive tumor targeting efficiency. Non-biodegradable
HPMA copolymers with molecular weights higher than the threshold of renal filtration demonstrated higher efficiency for tumor
drug delivery than biodegradable poly(L-glutamic acid).
Conclusions Contrast enhanced MRI is an effective method for non-invasive visualization of in vivo properties of the paramagnetically labeled polymer conjugates in preclinical studies. |
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Keywords: | conjugates drug delivery magnetic resonance imaging (MRI) non-invasive visualization poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) |
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