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Molecular imaging with theranostic nanoparticles.

ABSTRACT: Nanoparticles (NPs) offer diagnostic and therapeutic capabilities not available with small molecules or microscale tools. As the field of molecular imaging has emerged from the blending of molecular biology with medical imaging, NP imaging is increasingly common for both therapeutic and diagnostic applications. The term theranostic describes technology with concurrent and complementary diagnostic and therapeutic capabilities. Although NPs have been FDA-approved for clinical use as transport vehicles for nearly 15 years, full translation of their theranostic potential is incomplete. However, NPs have shown remarkable success in the areas of drug delivery and magnetic resonance imaging. Emerging applications include image-guided resection, optical/photoacoustic imaging in vivo, contrast-enhanced ultrasound, and thermoablative therapy. Diagnosis with NPs in molecular imaging involves the correlation of the signal with a phenotype. The location and intensity of NP signals emanating from a living subject indicate the disease area's size, stage, and biochemical signature. Therapy with NPs uses the image for resection or delivery of a small molecule or RNA therapeutic. Ablation of the affected area is also possible via heat or radioactivity. The ideal theranostic NP includes several features: (1) it selectively and rapidly accumulates in diseased tissue; (2) it reports biochemical and morphological characteristics of the area; (3) it delivers an effective therapeutic; and (4) it is safe and biodegrades with nontoxic byproducts. Such a system contains a central imaging core surrounded by small molecule therapeutics. The system targets via ligands such as IgG and is protected from immune scavengers by a cloak of protective polymer. Although no NP has achieved all of the above criteria, many NPs possess one or more of these features. While the most clinically translatable NPs have been used in the field of magnetic resonance imaging, other types in development are quickly becoming more biocompatible through methods that modify their toxicity and biodistribution profiles. In this Account, we describe diagnostic imaging and therapeutic uses of NPs. We propose and offer examples of five primary types of nanoparticles with concurrent diagnostic and therapeutic uses.

SUBMITTER: Jokerst JV

PROVIDER: S-EPMC3196845 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Molecular imaging with theranostic nanoparticles.

Jokerst Jesse V JV Gambhir Sanjiv S SS

Accounts of chemical research 20110915 10

Nanoparticles (NPs) offer diagnostic and therapeutic capabilities not available with small molecules or microscale tools. As the field of molecular imaging has emerged from the blending of molecular biology with medical imaging, NP imaging is increasingly common for both therapeutic and diagnostic applications. The term theranostic describes technology with concurrent and complementary diagnostic and therapeutic capabilities. Although NPs have been FDA-approved for clinical use as transport vehi ...[more]

PMID: 21919457

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Project description:PurposeTargeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapy-probe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI).Experimental designCRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T2-weighted segmentations quantified tumor growth.ResultsGenetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P < 0.001) and precipitated dose-dependent growth inhibition (P < 0.01 overall, P < 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P < 0.001).ConclusionsThese findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-by-cancer basis.

Project description:The synthesis of self-assembled peptide nanoparticles using a facile one-pot synthesis approach is gaining increasing attention, allowing therapy in combination with diagnosis. Their drawback is limited diagnostic potential, which can be improved after necessary modifications and efficacious functionalization. Herein, a cyclic heptapeptide having the Arg-Gly-Asp-Lys-Leu-Ala-Lys sequence was modified by conjugation of the ε-amino group of the terminal lysine residue with diethylenetriamine pentaacetic acid (DTPA) as a bifunctional chelating agent (BFC) for radiolabeling with a γ-emitting radionuclide (99mTc, half-life 6.01 h; energy 140 keV). Further, the free amino group of the middle lysine residue was successfully conjugated with near-infrared fluorescence (NIRF) dye Cyanine5.5 N-succinimidyl ester (Ex/Em = 670/701 nm) by a co-assembly method to form newly designed novel NIRF dye conjugated self-assembled peptide-DTPA (Cy5.5@SAPD) nanoparticles. The fluorescent nanoparticle formation was confirmed by using a fluorescence spectrophotometer (Ex/Em = 650/701 nm), and the transmission electron microscope (TEM) images showed a size of ∼ 40 nm with a lattice fringe distance of 0.294 nm. Cytotoxicity and confocal laser scanning microscopy (CLSM) studies showed that these nanoparticles possess a high affinity for the αvβ3-integrin receptor overexpressed on brain tumor glioblastoma with an EC50 = 20 μM. Moreover, these nanoparticles were observed to have potential to internalize into U87MG cells more prominently than HEK-293 cancer cells and induce apoptosis. The apoptosis assay showed 79.5% apoptotic cells after 24 h treatment of Cy5.5@SAPD nanoparticles. Additionally, these nanoparticles were also radiolabeled with 99mTc for the single photon emission computed tomography (SPECT) imaging study in tumor-bearing female Balb/c mice. The excellent imaging feature of Cy5.5@SAPD-99mTc nanoparticles as a multimodal (SPECT/NIRF) diagnostic probe, as well as noteworthy therapeutic potential was observed. The results suggested that our newly designed novel dual-targeting dual-imaging nanoparticles may serve as an admirable theranostic probe to treat brain tumor glioblastoma multiforme.

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Molecular imaging with theranostic nanoparticles.

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Molecular imaging with theranostic nanoparticles.

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