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111In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues.

ABSTRACT: Targeted delivery of drug-encapsulated nanoparticles is a promising new approach to safe and effective therapeutics for cancer. Here we investigate the pharmacokinetics and biodistribution of a prostate-specific membrane antigen (PSMA)-targeted nanoparticle based on a poly(lactic acid)-polyethylene glycol copolymer by utilizing single photon emission computed tomography (SPECT) and fluorescence imaging of a low-molecular-weight, PSMA-targeting moiety attached to the surface and oriented toward the outside environment. Tissue biodistribution of the radioactive, PSMA-targeted nanoparticles in mice containing PSMA(+) PC3 PIP and PSMA(-) PC3 flu (control) tumors demonstrated similar accumulation compared to the untargeted particles within all tissues except for the tumor and liver by 96 h postinjection. For PSMA(+) PC3 PIP tumor, the targeted nanoparticle demonstrated retention of 6.58% injected dose (ID)/g at 48 h and remained nearly at that level out to 96 h, whereas the untargeted nanoparticle showed a 48 h retention of 8.17% ID/g followed by a significant clearance to 2.37% ID/g at 96 h (P < 0.02). On the other hand, for control tumor, both targeted and untargeted particles displayed similar 48 h retentions and rates of clearance over 96 h. Ex vivo microscopic analysis with near-infrared versions of the nanoparticles indicated retention within PSMA(+) tumor epithelial cells as well as tumor-associated macrophages for targeted particles and primarily macrophage-associated uptake for the untargeted particles. Retention in control tumor was primarily associated with tumor vasculature and macrophages. The data demonstrate the utility of radioimaging to assess nanoparticle biodistribution and suggest that active targeting has a modest positive effect on tumor localization of PSMA-targeted PLA-PEG nanoparticles that have been derivatized for imaging.

SUBMITTER: Banerjee SR

PROVIDER: S-EPMC5516902 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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<sup>111</sup>In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues.

Banerjee Sangeeta R SR Foss Catherine A CA Horhota Allen A Pullambhatla Mrudula M McDonnell Kevin K Zale Stephen S Pomper Martin G MG

Biomacromolecules 20161221 1

Targeted delivery of drug-encapsulated nanoparticles is a promising new approach to safe and effective therapeutics for cancer. Here we investigate the pharmacokinetics and biodistribution of a prostate-specific membrane antigen (PSMA)-targeted nanoparticle based on a poly(lactic acid)-polyethylene glycol copolymer by utilizing single photon emission computed tomography (SPECT) and fluorescence imaging of a low-molecular-weight, PSMA-targeting moiety attached to the surface and oriented toward t ...[more]

PMID: 28001364

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Project description:BackgroundCombining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor resection. Trastuzumab is a monoclonal antibody against the human epidermal growth factor-2 (HER2) receptor and dual-labeled trastuzumab with both a fluorophore (IRDye800CW) and a radioactive label (111In) can be used for multimodal imaging of HER2-positive breast cancer. The aim of this study was to demonstrate the feasibility of HER2-targeted multimodal imaging using [111In]In-DTPA-trastuzumab-IRDye800CW in an orthotopic breast cancer model.MethodsTrastuzumab was conjugated with p-isothiocyanatobenzyl (ITC)-diethylenetriaminepentaacetic acid (DTPA) and IRDye800CW-NHS ester and subsequently labeled with 111In. In a dose escalation study, the biodistribution of 10, 30, and 100 μg [111In]In-DTPA-trastuzumab-IRDye800CW was determined 48 h after injection in BALB/c nude mice with orthotopic high HER2-expressing tumors. Also, a biodistribution study was performed in a low HER2-expressing breast cancer model. In addition, multimodal image-guided surgery was performed in each group. Autoradiography, fluorescence microscopy, and immunohistochemically stained slices of the tumors were compared for co-localization of tumor tissue, HER2 expression, fluorescence, and radiosignal.ResultsBased on the biodistribution data, a 30 μg dose of dual-labeled trastuzumab (tumor-to-blood ratio 13 ± 2) was chosen for all subsequent studies. [111In]In-DTPA-trastuzumab-IRDye800CW specifically accumulated in orthotopic HER2-positive BT474 tumors (101 ± 7 %IA/g), whereas uptake in orthotopic low HER2-expressing MCF7 tumor was significantly lower (1.2 ± 0.2 %IA/g, p = 0.007). BT474 tumors could clearly be visualized with both micro-SPECT/CT, fluorescence imaging and subsequently, image-guided resection was performed. Immunohistochemical analyses of BT474 tumors demonstrated correspondence in fluorescence, radiosignal, and high HER2 expression.ConclusionsDual-labeled trastuzumab showed specific accumulation in orthotopic HER2-positive BT474 breast tumors with micro-SPECT/CT and fluorescence imaging and enabled image-guided tumor resection. In the clinical setting, [111In]In-DTPA-trastuzumab-IRDye800CW could be valuable for preoperative detection of (metastatic) tumors by SPECT/CT imaging, and intraoperative localization by using a gamma probe and fluorescence image-guided surgery to improve radical resection of tumor tissue in patients with HER2-positive tumors.

Project description:PurposeTargeted delivery in vivo remains an immense roadblock for the translation of nanomaterials into the clinic. The greatest obstacle is the mononuclear phagocyte system (MPS), which sequesters foreign substances from general circulation and causes accumulation in organs such as the liver and spleen. The purpose of this study was to determine whether attaching an active targeting antibody, 5B1, to the surface of gold nanoparticles and using clodronate liposomes to deplete liver and splenic macrophages could help to minimize uptake by MPS organs, increase targeted delivery to CA19.9-positive pancreatic tumors, and enhance pancreatic tumor delineation.ProceduresTo produce the antibody-gold nanoparticle conjugate (Ab-AuNP), the Ab was conjugated to p-isothiocyanatobenzyl-desferrioxamine (p-SCN-DFO) and subsequently conjugated to NHS-activated gold nanoparticles. The Ab-AuNP was characterized by transmission electron microscopy (TEM) and atomic force microscopy (AFM). Modified Lindmo assay was performed to assess binding affinity and internalization potential in vitro. The Ab-AuNP was radiolabeled with 89Zr and injected into CA19.9-positive BxPc-3 pancreatic orthotopic tumor-bearing mice pretreated with or without clodronate liposomes for PET imaging and biodistribution studies. Inductively coupled plasma-optical emission spectrometry (ICP-OES) analysis was used to confirm delivery of gold nanoparticles to BxPc-3 pancreatic subcutaneous xenografts.ResultsMice pretreated with clodronate liposomes in an orthotopic setting demonstrated decreased liver uptake at early time points (12.2 ± 2.3 % ID/g vs. 22.8 ± 3.8 % ID/g at 24 h) and increased tumor uptake at 120 h (13.8 ± 8.0 % ID/g vs. 6.0 ± 1.2 % ID/g). This allowed for delineation of orthotopic pancreatic xenografts in significantly more mice treated with clodronate (6/6) than in mice not treated with clodronate (2/6) or mice injected with gold nanoparticles labeled with a nonspecific antibody (0/5).ConclusionsThe combination of clodronate liposomes and an active targeting antibody on the surface of gold nanoparticles allowed for PET/CT imaging of subcutaneous and orthotopic pancreatic xenografts in mice.

Dataset Information

111In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues.

Publications

<sup>111</sup>In- and IRDye800CW-Labeled PLA-PEG Nanoparticle for Imaging Prostate-Specific Membrane Antigen-Expressing Tissues.

Similar Datasets

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