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Multiscale Framework for Imaging Radiolabeled Therapeutics.

ABSTRACT: The resistance of a tumor to a drug is the result of bulk properties of the tumor tissue as well as phenotypic variations displayed by single cells. Here, we show that radioisotopic detection methods, commonly used for tracking the tissue distribution of drug compounds, can be extended to the single-cell level to image the same molecule over a range of physical scales. The anticancer drug rituximab was labeled with short-lived radionuclides ((89)Zr/(64)Cu) and its accumulation at the organ level was imaged using PET in a humanized transgenic mouse model of non-Hodgkin's lymphoma. To capture the distribution of the drug at a finer scale, tissue sections and single living cells were imaged using radioluminescence microscopy (RLM), a novel method that can detect radionuclides with single-cell resolution. In vivo PET images (24 h postinjection) showed that [(89)Zr]rituximab targeted the intended site of human CD20 expression, the spleen. Within this organ, RLM was used to resolve radiotracer accumulation in the splenic red pulp. In a separate study, RLM highlighted marked differences between single cells, with binding of the radiolabeled antibody ranging from background levels to 1200 radionuclides per cell. Overall, RLM images demonstrated significantly higher spatial resolution and sensitivity than conventional storage-phosphor autoradiography. In conclusion, this combination of PET and RLM provides a unique opportunity for exploring the molecular mechanism of drugs by tracking the same molecule over multiple physical scales, ranging from single living cells to organs substructures and entire living subjects.

SUBMITTER: Natarajan A

PROVIDER: S-EPMC4674817 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Multiscale Framework for Imaging Radiolabeled Therapeutics.

Natarajan Arutselvan A Türkcan Silvan S Gambhir Sanjiv S SS Pratx Guillem G

Molecular pharmaceutics 20151105 12

The resistance of a tumor to a drug is the result of bulk properties of the tumor tissue as well as phenotypic variations displayed by single cells. Here, we show that radioisotopic detection methods, commonly used for tracking the tissue distribution of drug compounds, can be extended to the single-cell level to image the same molecule over a range of physical scales. The anticancer drug rituximab was labeled with short-lived radionuclides ((89)Zr/(64)Cu) and its accumulation at the organ level ...[more]

PMID: 26460685

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Project description:Rationale: Fibroblast activation protein (FAP) targeted molecular imaging radiotracers have shown promising preclinical and clinical results in tumor diagnosis. However, rapid clearance and inadequate tumor retention of these molecules have hindered them for further clinical translation in cancer therapy. In this study, we aimed to develop a series of albumin binder-truncated Evans blue (EB) modified FAP targeted radiotracers, and optimize the pharmacokinetic (PK) characteristics to overcome the existing limitations in order to apply in the radionuclide therapy of cancer. Methods: A series of compounds with the general structure of EB-FAPI-Bn were synthesized based on a FAP inhibitor (FAPI) variant (FAPI-02) and radiolabeled with 177LuCl3. To verify the binding affinity and FAP targeting specificity of these tracers in vitro, U87MG cell uptake and competition assays were performed. Preclinical PK was evaluated in U87MG tumor-bearing mice using SPECT imaging and biodistribution studies. The lead compound EB-FAPI-B1 was selected and cancer therapeutic efficacy of 177Lu-EB-FAPI-B1 was assessed in U87MG tumor-bearing mice. Results: 177Lu-EB-FAPI-B1, B2, B3, B4 were stable in PBS (pH 7.4) and saline for at least 24 h. EB-FAPI-B1 showed high binding affinity (IC50 = 16.5 nM) to FAP in vitro, which was comparable with that of FAPI-02 (IC50 = 10.9 nM). SPECT imaging and biodistribution studies of 177Lu-EB-FAPI-B1, B2, B3, B4 have proved their prominently improved tumor accumulation and retention at 96 h post-injection, especially for 177Lu-EB-FAPI-B1, high tumor uptake and low background signal make it the optimal compound. Compared to the saline group, noteworthy tumor growth inhibitions of 177Lu-EB-FAPI-B1 have been observed after administration of different dosages. Conclusion: In this study, several EB modified FAPI-02 related radiopharmaceuticals have been synthesized successfully and evaluated. High binding affinity and FAP targeting specificity were identified in vitro and in vivo. Remarkably enhanced tumor uptake and retention of EB-FAPI-B1 were found over the unmodified FAPI-02. 177Lu-EB-FAPI-B1 showed remarkable tumor growth suppression in U87MG tumor model with negligible side effects, indicating that 177Lu-EB-FAPI-B1 is promising for clinical application and transformation.

Project description:Molecular probes targeting bacteria provide opportunities to target bacterial infections in vivo for both imaging and therapy. In the current study, we report the development of positron emission tomography (PET) probes for imaging of live bacterial infection based on the small molecules HLys-DOTA, a polycationic peptide synthesized as the D-isomer (RYWVAWRNRG) conjugated to 1, 4, 7, 10-tetraazacyclododecane-N',N″,N‴,N-tetraacetic acid (DOTA) and AB1-HLys-DOTA, which includes an unnatural amino acid AB1 that preferentially binds to bacteria membrane lipids with amine groups via formation of iminoboronates. HLys-DOTA and AB1-HLys-DOTA peptides were radiolabeled with 64Cu and investigated as PET imaging agents to track bacterial infection in vitro and in intramuscularly infected (IM) mice models. Cell uptake studies at 37°C in Staphylococcus aureus (SA) show higher uptake of 64Cu-AB1-HLys-DOTA; 98.47 ± 3.54% vs 64Cu-HLys-DOTA; 39.12 ± 3.27% at 24 h. Standard uptake values (SUV) analysis of the PET images resulted in mean SUV of 0.70 ± 0.08, 0.49 ± 0.04, and 0.31 ± 0.01 for 64Cu-AB1-HLys-DOTA and 0.17 ± 0.06, 0.16 ± 0.02, and 0.13 ± 0.01 for 64Cu-HLys-DOTA at 1, 4, and 24 h post injection, respectively, in the infected muscles. Similarly, in the biodistribution studies, dose uptake in the infected muscles was 4 times higher in the targeted 64Cu-AB1-HLys-DOTA group than in the 64Cu-HLys-DOTA group and 2-3 times higher than in the PBS control group at 1, 4, and 24 h post injection. 64Cu-AB1-HLys-DOTA was able to distinguish between SA-infected muscle and Pseudomonas aeruginosa (PA) infected muscle with lower mean SUV of 0.28 ± 0.10 at 1 h post injection. This illustrates the utility of the AB1 covalently targeting group in synergy with the HLys peptide, which noncovalently binds to bacterial membranes. These results suggest that 64Cu-labeled AB1-HLys-DOTA peptide could be used as an imaging probe for detection of bacterial infection in vivo with specificity for Gram-positive bacteria.

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Multiscale Framework for Imaging Radiolabeled Therapeutics.

Publications

Multiscale Framework for Imaging Radiolabeled Therapeutics.

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