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Ultralong tumor retention of theranostic nanoparticles with short peptide-enabled active tumor homing.

ABSTRACT: Computer tomography (CT) and magnetic resonance imaging (MRI) are noninvasive cancer imaging methods in clinics. Hence, a material that enables MRI/CT dual-modal imaging-guided therapy is in high demand. Currently, the available materials lack active tumor targeting, deep tumor penetration, and ultralong tumor retention and may lose their imaging elements. To overcome these drawbacks, herein, nanoparticles (NPs) were deveopled by integrating an MRI contrast-enhancing chelated gadolinium (Gd) complex within a doxorubicin (DOX)-loaded protective silica shell as well as a CT imaging/photothermal biocompatible bismuth (Bi) nano-core, which surface-displayed an MCF-7 breast tumor-homing peptide (AREYGTRFSLIGGYR, termed AR); we found that the resultant NPs AR-Bi@SiO2-Gd/DOXNPs could home to and penetrate deep into the tumors with the unexpected ultralong retention of at least 14 days (as determined by CT/MRI imaging) and the tumor retention half-life of 104.5 h (as determined by ICP-MS analysis) under the guidance of the AR peptide. These NPs can be further used to image tumors with significantly increased sharp contrasts via both CT and MRI, which are much better than the commercial standard contrast agents; moreover, they significantly inhibit tumor growth via the synergistic action of both Bi-enabled photothermal therapy and DOX-induced chemotherapy. The NPs are cleared by the spleen, liver and kidney and then excreted from the body along with faeces and urine. The precise tumor targeting and ultralong tumor retention of these unique NPs would enable both precise tumor detection for early diagnosis and signal-persistent tumor tracking for monitoring the treatment with only a single injection of these NPs.

SUBMITTER: Li L

PROVIDER: S-EPMC7677965 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Ultralong tumor retention of theranostic nanoparticles with short peptide-enabled active tumor homing.

Li Lihua L Lu Yao Y Lin Zefeng Z Mao Angelina S AS Jiao Ju J Zhu Ye Y Jiang Chunyan C Yang Zhongmin Z Peng Mingying M Mao Chuanbin C

Materials horizons 20190617 9

Computer tomography (CT) and magnetic resonance imaging (MRI) are noninvasive cancer imaging methods in clinics. Hence, a material that enables MRI/CT dual-modal imaging-guided therapy is in high demand. Currently, the available materials lack active tumor targeting, deep tumor penetration, and ultralong tumor retention and may lose their imaging elements. To overcome these drawbacks, herein, nanoparticles (NPs) were deveopled by integrating an MRI contrast-enhancing chelated gadolinium (Gd) com ...[more]

PMID: 33224505

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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.

Project description: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.

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Ultralong tumor retention of theranostic nanoparticles with short peptide-enabled active tumor homing.

Publications

Ultralong tumor retention of theranostic nanoparticles with short peptide-enabled active tumor homing.

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