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Synthesis, Cellular Delivery and In vivo Application of Dendrimer-based pH Sensors
Published on: September 10, 2013
Concentration-independent MRI of pH with a dendrimer-based pH-responsive nanoprobe
Mohammed P I Bhuiyan1, Madhava P Aryal1, Branislava Janic1
1Henry Ford Hospital, Detroit, MI, USA.
Abstract:
The measurement of extracellular pH (pHe ) has significant clinical value for pathological diagnoses and for monitoring the effects of pH-altering therapies. One of the major problems of measuring pHe with a relaxation-based MRI contrast agent is that the longitudinal relaxivity depends on both pH and the concentration of the agent, requiring the use of a second pH-unresponsive agent to measure the concentration. Here we tested the feasibility of measuring pH with a relaxation-based dendritic MRI contrast agent in a concentration-independent manner at clinically relevant field strengths. The transverse and longitudinal relaxation times in solutions of the contrast agent (GdDOTA-4AmP)44 -G5, a G5-PAMAM dendrimer-based MRI contrast agent in water, were measured at 3 T and 7 T magnetic field strengths as a function of pH. At 3 T, longitudinal relaxivity (r1 ) increased from 7.91 to 9.65 mM(-1) s(-1) (on a per Gd(3+) basis) on changing pH from 8.84 to 6.35. At 7 T, r1 relaxivity showed pH response, albeit at lower mean values; transverse relaxivity (r2 ) remained independent of pH and magnetic field strengths. The longitudinal relaxivity of (GdDOTA-4AmP)44 -G5 exhibited a strong and reversible pH dependence. The ratio of relaxation rates R2 /R1 also showed a linear relationship in a pH-responsive manner, and this pH response was independent of the absolute concentration of (GdDOTA-4AmP)44 -G5 agent. Importantly, the nanoprobe (GdDOTA-4AmP)44 -G5 shows pH response in the range commonly found in the microenvironment of solid tumors.
Insights
This study introduces a novel dendritic MRI contrast agent, (GdDOTA-4AmP)44-G5, for concentration-independent extracellular pH (pHe) measurement. The agent shows a robust pH response, crucial for tumor microenvironment monitoring.
Area of Science:
- Magnetic Resonance Imaging (MRI)
- Nanoparticle Contrast Agents
- Biomedical Engineering
Background:
- Extracellular pH (pHe) measurement is vital for diagnosing pathologies and monitoring therapies.
- Existing MRI contrast agents face challenges in accurate pHe measurement due to concentration dependency.
- Dendritic contrast agents offer potential for improved pH-responsive imaging.
Purpose of the Study:
- To evaluate a dendritic MRI contrast agent, (GdDOTA-4AmP)44-G5, for concentration-independent pHe measurement.
- To assess the agent's performance at clinically relevant magnetic field strengths (3 T and 7 T).
- To determine the agent's pH sensitivity in the context of tumor microenvironments.
Main Methods:
- Synthesized and characterized the G5-PAMAM dendrimer-based MRI contrast agent (GdDOTA-4AmP)44-G5.
- Measured longitudinal (r1) and transverse (r2) relaxation times in solutions at 3 T and 7 T across a range of pH values.
- Analyzed the ratio of relaxation rates (R2/R1) for pH-dependent changes.
Main Results:
- The longitudinal relaxivity (r1) of (GdDOTA-4AmP)44-G5 demonstrated a significant and reversible pH dependence at both 3 T and 7 T.
- Transverse relaxivity (r2) remained independent of pH and magnetic field strength.
- The R2/R1 ratio exhibited a linear, concentration-independent pH response.
- The agent showed pH sensitivity within the range relevant to solid tumor microenvironments.
Conclusions:
- The dendritic MRI contrast agent (GdDOTA-4AmP)44-G5 enables concentration-independent extracellular pH measurement.
- This agent holds promise for in vivo pH monitoring, particularly in pathological conditions like cancer.
- The R2/R1 ratio offers a reliable metric for pH assessment using this novel contrast agent.
