Abstract
Accurate time-resolved temperature mapping is crucial for the safe use of hyperthermia-mediated drug delivery. We here propose a magnetic resonance imaging temperature mapping method in which drug delivery systems serve not only to improve tumor targeting, but also as an accurate and absolute nano-thermometer. This method is based on the temperature-dependent chemical shift difference between water protons and the protons in different groups of drug delivery systems. We show that the chemical shift of the protons in the ethylene oxide group in polyethylene glycol (PEG) is temperature-independent, whereas the proton resonance of water decreases with increasing temperature. The frequency difference between both resonances is linear and does not depend on pH and physiological salt conditions. In addition, we show that the proton resonance of the methyl group in N-(2-hydroxypropyl)-methacrylamide (HPMA) is temperature-independent. Therefore, PEGylated liposomes, polymeric mPEG-b-pHPMAm-Lac2 micelles and HPMA copolymers can provide a temperature-independent reference frequency for absolute magnetic resonance (MR) thermometry. Subsequently, we show that multigradient echo MR imaging with PEGylated liposomes in situ allows accurate, time-resolved temperature mapping. In conclusion, nanocarrier materials may serve as highly versatile tools for tumor-targeted drug delivery, acting not only as hyperthermia-responsive drug delivery systems, but also as accurate and precise nano-thermometers.
Highlights
Drug delivery systems, such as liposomes, are designed to improve the biodistribution of systemically administered therapeutic agents, and to thereby increase the efficacy and reduce the toxicity associated with the therapy [1]
The method we propose for the specific purpose of hyperthermiamediated local drug delivery from drug carrier systems is based on the notions that (a) ethylene glycol is routinely used for temperature calibration in MR spectroscopy (MRS) experiments, (b) this calibration is based on the known temperature-dependent difference between the chemical shift of the hydroxyl and the ethylene group in ethylene glycol, and (c) the majority of the clinically relevant liposome formulations contain polyethylene glycol (PEG) [19]
A 2-fold increase of the magnetic resonance (MR) signal and replacing PEG-2000 polymers by PEG-5000 polymers increased the MR-signal by a factor of 2.5
Summary
Drug delivery systems, such as liposomes, are designed to improve the biodistribution of systemically administered (chemo-) therapeutic agents, and to thereby increase the efficacy and reduce the toxicity associated with the therapy [1]. There is growing evidence that mild hyperthermia can be used to potentiate drug targeting to tumors, either by enhancing the EPR-mediated extravasation of liposomes, polymers and micelles from the tumor vasculature, or by triggering drug release from thermosensitive liposomes [4,5,6]. In both cases, there is a delicate balance between improving tumor-directed drug delivery and drug release on the one hand, and shutting down tumor blood flow and causing thermal damage to surrounding healthy tissues on the other. There is a need for accurate and time-resolved temperature mapping in order to control the heating of tissues by external heat sources like laser, radiofrequency fields and high-intensity focused ultrasound (HIFU)
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