A dual CT‐MR dendrimer contrast agent as a surrogate marker for convection‐enhanced delivery of intracerebral macromolecular therapeutic agents

Regino, Celeste A.S.; Walbridge, Stuart; Bernardo, Marcelino; Wong, Karen; Johnson, Dennis W.; Lonser, Russell R.; Oldfield, Edward H.; Choyke, Peter L.; Brechbiel, Martin W.

doi:10.1002/cmmi.223

Cited by 57 publications

(53 citation statements)

References 22 publications

(24 reference statements)

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“…This study used MRI to follow the distribution of the MR contrast agent, Gd-DTPA. The range of tracers used in CED studies is wide, including small-molecular-weight compounds such as Gd-DTPA, 18,19,32 dendrimers, 21 iron oxides, 20,36 nanoparticles, 33 and viruses 5,32,33 with attached Gd moieties. The Gd-DTPA tracer is a small-molecularweight contrast agent with the widest FDA approval for use in CNS, body, and head and neck applications in both adults and children.…”

Section: Discussionmentioning

confidence: 99%

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Fan

Nelson

Ai³

et al. 2015

JNS

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OBJECT Assessing the safety and feasibility of chronic delivery of compounds to the brain using convection-enhanced delivery (CED) is important for the further development of this important therapeutic technology. The objective of this study was to follow and model the distribution of a compound delivered by CED into the putamen of rhesus monkeys. METHODS The authors sequentially implanted catheters into 4 sites spanning the left and right putamen in each of 6 rhesus monkeys. The catheters were connected to implanted pumps, which were programmed to deliver a 5-mM solution of the MRI contrast agent Gd-DTPA at 0.1 μl/minute for 7 days and 0.3 μl/minute for an additional 7 days. The animals were followed for 28 days per implant cycle during which they were periodically examined with MRI. RESULTS All animals survived the 4 surgeries with no deficits in behavior. Compared with acute infusion, the volume of distribution (Vd) increased 2-fold with 7 days of chronic infusion. Increasing the flow rate 3-fold over the next week increased the Vd an additional 3-fold. Following withdrawal of the compound, the half-life of Gd-DTPA in the brain was estimated as 3.1 days based on first-order pharmacokinetics. Histological assessment of the brain showed minimal tissue damage limited to the insertion site. CONCLUSIONS These results demonstrate several important features in the development of a chronically implanted pump and catheter system: 1) the ability to place catheters accurately in a predetermined target; 2) the ability to deliver compounds in a chronic fashion to the putamen; and 3) the use of MRI and MR visible tracers to follow the evolution of the infusion volume over time.

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Section: Discussionmentioning

confidence: 99%

Continuous intraputamenal convection-enhanced delivery in adult rhesus macaques

Fan

Nelson

Ai³

et al. 2015

JNS

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“…12,13 However, very few contrast agents have been developed that provide multiple imaging contrast effects (ie, effective for both MR and CT imaging). These multimodal imaging probes, such as iohexol-gadoteridol, 14 Gd-G8 dendrimer, 15 Gd-chelated AuNPs, 16,17 and FePt NPs, 18 have offered somewhat limited sensitivity, stability, or blood circulation time. Therefore, the preparation of a dual-modality contrast agent that is stable while permitting sensitive imaging with both MR and CT still remains a great challenge.…”

Section: Introductionmentioning

confidence: 99%

Multifunctional dendrimer-based nanoparticles for in vivo MR/CT dual-modal molecular imaging of breast cancer

Li¹,

Wen²,

Larson³

et al. 2013

IJN

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Development of dual-mode or multi-mode imaging contrast agents is important for accurate and self-confirmatory diagnosis of cancer. We report a new multifunctional, dendrimer-based gold nanoparticle (AuNP) as a dual-modality contrast agent for magnetic resonance (MR)/computed tomography (CT) imaging of breast cancer cells in vitro and in vivo. In this study, amine-terminated generation 5 poly(amidoamine) dendrimers modified with gadolinium chelate (DOTA-NHS) and polyethylene glycol monomethyl ether were used as templates to synthesize AuNPs, followed by Gd(III) chelation and acetylation of the remaining dendrimer terminal amine groups; multifunctional dendrimer-entrapped AuNPs (Gd-Au DENPs) were formed. The formed Gd-Au DENPs were used for both in vitro and in vivo MR/CT imaging of human MCF-7 cancer cells. Both MR and CT images demonstrate that MCF-7 cells and the xenograft tumor model can be effectively imaged. The Gd-Au DENPs uptake, mainly in the cell cytoplasm, was confirmed by transmission electron microscopy. The cell cytotoxicity assay, cell morphology observation, and flow cytometry show that the developed Gd-Au DENPs have good biocompatibility in the given concentration range. Our results clearly suggest that the synthetic Gd-Au DENPs are amenable for dual-modality MR/CT imaging of breast cancer cells.

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“…Recent efforts aimed at achieving higher tumor contrast enhancement and imaging sensitivity have motivated the development of nanoparticle-based imaging contrast agents. Nanoparticle-based CT contrast agents include atoms of high atomic number with superior X-ray attenuation capabilities, such as gold [96], Gd [97], iodine [98], bismuth [99], and ytterbium [100]. Encapsulation, coating or functionalization of these atoms can be leveraged to increase biocompatibility, prolong circulation half-life, and enable conjugation with targeting moieties for tumor-specific delivery and uptake.…”

Section: Ct Imagingmentioning

confidence: 99%