Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe

Abstract

A first-in-human clinical trial of ultrasmall inorganic hybrid nanoparticles, "C dots" (Cornell dots), in patients with metastatic melanoma is described for the imaging of cancer. These renally excreted silica particles were labeled with (124)I for positron emission tomography (PET) imaging and modified with cRGDY peptides for molecular targeting. (124)I-cRGDY-PEG-C dot particles are inherently fluorescent, containing the dye, Cy5, so they may be used as hybrid PET-optical imaging agents for lesion detection, cancer staging, and treatment management in humans. However, the clinical translation of nanoparticle probes, including quantum dots, has not kept pace with the accelerated growth in minimally invasive surgical tools that rely on optical imaging agents. The safety, pharmacokinetics, clearance properties, and radiation dosimetry of (124)I-cRGDY-PEG-C dots were assessed by serial PET and computerized tomography after intravenous administration in patients. Metabolic profiles and laboratory tests of blood and urine specimens, obtained before and after particle injection, were monitored over a 2-week interval. Findings are consistent with a well-tolerated inorganic particle tracer exhibiting in vivo stability and distinct, reproducible pharmacokinetic signatures defined by renal excretion. No toxic or adverse events attributable to the particles were observed. Coupled with preferential uptake and localization of the probe at sites of disease, these first-in-human results suggest safe use of these particles in human cancer diagnostics.

Trial registration: ClinicalTrials.gov NCT01266096.

Copyright © 2014, American Association for the Advancement of Science.

Figures

Fig. 1. Core-shell hybrid silica nanoparticles (124I-cRGDY–PEG–C dots) and overview of first-in-human study design

(A) Schematic of the hybrid (PET-optical) imaging nanoparticle (NP) probe showing the core-containing Cy5 dye and surface-attached poly(ethylene glycol) (PEG) chains that bear cRGDY peptide ligands at their ends and 124I radiolabels. cRGDY binds to human ανβ3 integrin–expressing tumors. (B) Absorption-matched spectra (left, open black arrow) and emission spectra (right, solid black arrow) for free and encapsulated dyes. a.u., arbitrary units. (C) Patient (n = 5) screening evaluation and clinical history. Stage was determined using the 2010 TNM American Joint Committee on Cancer Cutaneous Melanoma staging system. (D) Clinical trial events after single-dose particle injection. Timeline denotes acquisition of serial PET-CT imaging studies and collection of blood and urine specimens.

Fig. 2. Whole-body distribution and PK of 124I-cRGDY–PEG–C dots

(A) Maximum intensity projection PET images at 2, 24, and 72 hours after intravenous injection of 124I-cRGDY–PEG–C dots (patient #3) reveal probe activity in bladder (*), heart (yellow arrow), and bowel (white arrowhead), displayed as SUV values. (B) Decay-corrected percent injected dose per gram (%ID/g) of urine and plasma collected at about 30 min, 4 hours, 24 hours, and 72 hours after injection of the particles as determined by gamma counting. ROIs were drawn on major organs for each patient’s PET scans to derive standardized uptake values and %ID/g. Data for major organs and tissues are plotted individually for n = 5 patients. Plasma clearance half-times, t1/2,1 and t1/2,2, are attributed to renal and hepatobiliary clearance, respectively.

Fig. 3. Metabolic analyses of biological specimens

Data are shown for patient #3. (A) Time-dependent activity concentrations (%ID/g × 0.01) in plasma and urine, decay-corrected to the time of injection. (B and C) RadioTLC (4:1 acetic acid/methanol as mobile phase) of plasma (B) and urine (C) specimens [decay-corrected counts per minute (CPM)]. Data are shown for 0.5-, 3-, and 24-hour time points. (D) Chromatograms of standards: injectate, radio-iodinated (131I) peptide, and free 131I. Vertical lines discriminate peaks corresponding to the particle tracer (long dashes; Rf = 0.04), 131I-cRGDY (short dashes; Rf = 0.2), and 131I (dotted; Rf = 0.7). Data for remaining patients are shown in figs. S1 and S2.

Fig. 4. Dosimetry of 124I-cRGDY–PEG–C dots

Absorbed doses per unit administered activity (mGy/MBq) of major organs and tissues were derived for each patient (n = 5) from serial whole-body PET scans acquired over a 72-hour time interval after injection of the particle tracer and using ROI-based time-activity data. Data are also displayed as averages ± SD in the gray-colored bar graph for all patients.

Fig. 5. Whole-body PET-CT imaging of particle biodistribution and tumor uptake after systemic injection of 124I-cRGDY–PEG–C dots

(A) Reformatted coronal CT in patient #1 demonstrates a hypodense left hepatic lobe metastasis (arrowhead). (B) Coronal PET image at 4 hours after injection demonstrates particle activity along the peripheral aspect of the tumor (arrowhead), in addition to the bladder, gastrointestinal tract (stomach, intestines), gallbladder, and heart. (C and D) Co-registered PET-CT at 4 hours (C) and 24 hours (D) after injection localizes activity to the tumor margin. (E) Corresponding 18F-FDG PET-CT image showing the hepatic metastasis in (A) (arrowhead). Color and gray scales reflect SUV values.

Fig. 6. Multimodal imaging of particle uptake in a pituitary lesion

(A) Multiplanar contrast-enhanced MR axial and sagittal images of patient #2 at 72 hours after injection demonstrate a subcentimeter cystic focus (arrows) within the right aspect of the anterior pituitary gland. (B) Co-registered axial and sagittal MRI-PET images reveal increased focal activity (red, 124I-cRGDY–PEG–C dots) localized to the lesion site. (C) Axial and sagittal PET-CT images localize activity to the right aspect of the sella. (D) Axial PET images of 124I-cRGDY–PEG–C dots in the brain at 3, 24, and 72 hours after injection demonstrate progressive accumulation of activity within the sellar region. (E) Tumor-to-brain and tumor-to-liver activity ratios as a function of post-injection (p.i.) time. Data are averages ± SD (n = 1 ROI measurement per time point) calculated from images in (D).

Fig. 7. PET imaging of particle uptake in a patient with drug-induced nephrotoxicity

(A) Serial PET coronal images of patient #4 acquired at 3, 24, and 72 hours after injection demonstrate initial presence of 124I-cRGDY–PEG–C dots within the cardiac blood pool (yellow arrow), small bowel (black arrowhead), and renal excretion, with accumulated urinary bladder activity (asterisk) and retention of activity in both renal cortices (red arrows). (B) Corresponding multiplanar CT sagittal and axial images at 72 hours after injection. White arrows point to perinephric stranding.