Gd-Labeled Glycol Chitosan as a pH-Responsive Magnetic Resonance Imaging Agent for Detecting Acidic Tumor Microenvironments

Neoplastic lesions can create a hostile tumor microenvironment with low extracellular pH. It is commonly believed that these conditions can contribute to tumor progression as well as resistance to therapy. We report the development and characterization of a pH-responsive magnetic resonance imaging contrast agent for imaging the acidic tumor microenvironment. The preparation included the conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid 1-(2,5-dioxo-1-pyrrolidinyl) ester (DOTA-NHS) to the surface of a water-soluble glycol chitosan (GC) polymer, which contains pH-titrable primary amines, followed by gadolinium complexation (GC-NH₂-GdDOTA). GC-NH₂-GdDOTA had a chelate-to-polymer ratio of approximately1:24 and a molar relaxivity of 9.1 mM^–1 s^–1. GC-NH₂-GdDOTA demonstrated pH-dependent cellular association in vitro compared to the control. It also generated a 2.4-fold enhancement in signal in tumor-bearing mice 2 h postinjection. These findings suggest that glycol chitosan coupled with contrast agents can provide important diagnostic information about the tumor microenvironment

Biodegradable Polydisulfide Dendrimer Nanoclusters as MRI Contrast Agents

Gadolinium-conjugated dendrimer nanoclusters (DNCs) are a promising platform for the early detection of disease; however, their clinical utility is potentially limited due to safety concerns related to nephrogenic systemic fibrosis (NSF). In this paper, biodegradable DNCs were prepared with polydisulfide linkages between the individual dendrimers to facilitate excretion. Further, DNCs were labeled with premetalated Gd chelates to eliminate the risk of free Gd becoming entrapped in dendrimer cavities. The biodegradable polydisulfide DNCs possessed a circulation half-life of >1.6 h in mice and produced significant contrast enhancement in the abdominal aorta and kidneys for as long as 4 h. The DNCs were reduced in circulation as a result of thiol–disulfide exchange, and the degradation products were rapidly excreted <i>via</i> renal filtration. These agents demonstrated effective and prolonged <i>in vivo</i> contrast enhancement and yet minimized Gd tissue retention. Biodegradable polydisulfide DNCs represent a promising biodegradable macromolecular MRI contrast agent for magnetic resonance angiography and can potentially be further developed into target-specific MRI contrast agents

The relationship between serum iron and interleukin-6 levels in all subjects.

<p>(Dependent variable: serum iron concentration).</p><p>*<i>P</i><0.05 and **<i>P</i><0.001, general linear model. AMI, acute myocardial infarction; IL-6, interleukin 6; SE, standardized error. The intercept is the predicted value of serum iron concentration in AMI group. The predicted value is 71.872 µg/dl. The serum iron concentration in the control group was, on average, 35.494 µg/dl higher than that in the AMI group. For every one unit increase in IL-6 concentration, there was a decrease of 0.625 units in serum iron concentration.</p

The relationship between serum iron concentration and IL-6 levels in all enrolled subjects.

<p>The result indicated that the serum iron concentration was negatively correlated with circulating IL-6 concentration in all study subjects. The linear relationship was well described by Serum iron = 95.994−1.246 (IL-6), R² = 0.133 and <i>P</i><0.001.</p

Univariate correlation between serum iron concentration and patient characteristics after acute myocardial infarction.

<p>*<i>P</i><0.05, Spearman’s rho correlation.6 M, six months; TIMI, thrombolysis in myocardial infarction; EF 6 M, left ventricular ejection fraction at 6–month follow-up.</p

The relationships between serum iron concentration and TIMI risk scores after primary angioplasty for AMI.

<p>The AMI patients were divided into four subgroups according to TIMI risk score for STEMI: Group 1 (TIMI risk score 1, n = 8); Group 2 (TIMI risk score 2, n = 15); Group 3 (TIMI risk score 3, n = 19); and Group 4 (TIMI risk score ≥4, n = 13). Trend analysis with Jonckheere-Terpstra test found that serum iron concentration significantly decreased as TIMI risk score rose (<i>P</i> = 0.002).</p

Characteristics of patients grouped by change in left ventricular ejection fraction 6 months after percutaneous coronary interventions for acute myocardial infarction.

<p>*<i>P</i><0.05, Mann–Whitney U test.</p><p>6 M, six months; BMI, body mass index; CPK, creatine- phosphor-kinase; CKMB, creatine phosphokinase-MB; HbA1C, glycohemoglobin; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; hsCRP, high sensitivity C reactive protein; IL-6, interleukin 6; WMSI, wall motion score index; TIMI, thrombolysis in myocardial infarction; LVMI, left ventricular mass index; LVEF, left ventricular ejection fraction; E/A ratio, the ratio of the peak velocities of early (E wave) and late (A wave) diastolic filling; DT, the deceleration time of the E wave; EDV, left ventricular end diastolic volume; ESV, left ventricular end systolic volume; Hb, hemoglobin; RDW, red blood cell distribution width; LAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery; D2B, door to balloon; PCI, percutaneous coronary interventions; TIMI, thrombolysis in myocardial infarction.</p

Lower serum iron concentration is associated with higher inflammatory markers and TIMI risk score after acute myocardial infarction.

<p>*<i>P</i><0.05, Mann–Whitney U test. TIMI, thrombolysis in myocardial infarction; IL-6, interleukin 6.</p

Trend analysis showed serum iron concentration was inversely proportional to IL-6 concentration in STEMI patients.

<p>AMI patients were divided into three subgroups according to circulating IL-6 concentration tertile: group 1, IL-6 concentration ≤10.48 pg/ml (n = 19); group 2, IL-6 concentration between 10.49–19.67 pg/ml (n = 20); group 3, IL-6 concentration ≥19.68 pg/ml (n = 16). Trend analysis showed serum iron concentration was inversely proportional to IL-6 concentration. (Jonckheere-Terpstra test, <i>P</i> = 0.043).</p

Multiple linear regression analysis of variables associated with ejection fraction 6 months after primary angioplasty for acute myocardial infarction.

<p>(Dependent variable: ejection fraction at 6 months).</p><p><i>R²</i> = 0.620.</p><p>*<i>P</i><0.05 and **<i>P</i><0.001.</p><p>CPK MB, creatine phosphokinase-MB; IL-6, interleukin 6; WMSI, wall motion score index; IRA, infarct related artery; LAD, left anterior descending artery; RCA, right coronary artery; LCX, left circumflex artery.</p