Dataset Information

Real time ultrasound molecular imaging of prostate cancer with PSMA-targeted nanobubbles.

ABSTRACT: Contrast-enhanced ultrasound with microbubbles has shown promise in detection of prostate cancer (PCa), but sensitivity and specificity remain challenging. Targeted nanoscale-contrast agents with improved capability to accumulate in tumors may result in prolonged signal enhancement and improved detection of PCa with ultrasound. Here we report nanobubbles (NB) that specifically targets prostate specific membrane antigen (PSMA) overexpressed in PCa. The PSMA-targeted-NB (PSMA-NB) were utilized to simultaneously image dual-flank PCa (PSMA-positive PC3pip and PSMA-negative PC3flu) to examine whether the biomarker can be successfully detected and imaged in a mouse model. Results demonstrate that active targeting rapidly and selectively enhances tumor accumulation and tumor retention. Importantly, these processes could be visualized and quantified, in real-time, with clinical ultrasound. Such demonstration of the immense yet underutilized potential of ultrasound in the molecular imaging area can open the door to future opportunities for improving sensitivity and specificity of cancer detection using parametric NB-enhanced ultrasound imaging.

SUBMITTER: Perera RH

PROVIDER: S-EPMC7605099 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Real time ultrasound molecular imaging of prostate cancer with PSMA-targeted nanobubbles.

Perera Reshani H RH de Leon Al A Wang Xinning X Wang Yu Y Ramamurthy Gopal G Peiris Pubudu P Abenojar Eric E Basilion James P JP Exner Agata A AA

Nanomedicine : nanotechnology, biology, and medicine 20200426

Contrast-enhanced ultrasound with microbubbles has shown promise in detection of prostate cancer (PCa), but sensitivity and specificity remain challenging. Targeted nanoscale-contrast agents with improved capability to accumulate in tumors may result in prolonged signal enhancement and improved detection of PCa with ultrasound. Here we report nanobubbles (NB) that specifically targets prostate specific membrane antigen (PSMA) overexpressed in PCa. The PSMA-targeted-NB (PSMA-NB) were utilized to ...[more]

PMID: 32348874

Similar Datasets

Project description:Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with 68Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from 68Ga- to 18F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite 68Ge/68Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, 18F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, 18F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging 18F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available 18F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.

Project description:In the current study, we synthesized prostate cancer-targeting poly(lactide-co-glycolic acid) (PLGA) nanobubbles (NBs) modified using A10-3.2 aptamers targeted to prostate-specific membrane antigen (PSMA) and encapsulated paclitaxel (PTX). We also investigated their impact on ultrasound (US) imaging and therapy of prostate cancer. PTX-A10-3.2-PLGA NBs were developed using water-in-oil-in-water (water/oil/water) double emulsion and carbodiimide chemistry approaches. Fluorescence imaging together with flow cytometry verified that the PTX-A10-3.2-PLGA NBs were successfully fabricated and could specifically bond to PSMA-positive LNCaP cells. We speculated that, in vivo, the PTX-A10-3.2-PLGA NBs would travel for a long time, efficiently aim at prostate cancer cells, and sustainably release the loaded PTX due to the improved permeability together with the retention impact and US-triggered drug delivery. The results demonstrated that the combination of PTX-A10-3.2-PLGA NBs with low-frequency US achieved high drug release, a low 50% inhibition concentration, and significant cell apoptosis in vitro. For mouse prostate tumor xenografts, the use of PTX-A10-3.2-PLGA NBs along with low-frequency US achieved the highest tumor inhibition rate, prolonging the survival of tumor-bearing nude mice without obvious systemic toxicity. Moreover, LNCaP xenografts in mice were utilized to observe modifications in the parameters of PTX-A10-3.2-PLGA and PTX-PLGA NBs in the contrast mode and the allocation of fluorescence-labeled PTX-A10-3.2-PLGA and PTX-PLGA NBs in live small animals and laser confocal scanning microscopy fluorescence imaging. These results demonstrated that PTX-A10-3.2-PLGA NBs showed high gray-scale intensity and aggregation ability and showed a notable signal intensity in contrast mode as well as aggregation ability in fluorescence imaging. In conclusion, we successfully developed an A10-3.2 aptamer and loaded PTX-PLGA multifunctional theranostic agent for the purpose of obtaining US images of prostate cancer and providing low-frequency US-triggered therapy of prostate cancer that was likely to constitute a strategy for both prostate cancer imaging and chemotherapy.

Project description:The prostate-specific membrane antigen (PSMA)-targeted radiotracers 68Ga/177Lu-PSMA-I&T and 99mTc-PSMA-I&S (for i maging and s urgery) are currently successfully used for clinical PET imaging, radionuclide therapy, and radioguided surgery of metastatic prostate cancer. To additionally exploit the high sensitivity and spatial resolution of fluorescence imaging for improved surgical guidance, a PSMA-I&T-based hybrid tracer, PSMA-I&F (DOTAGA-k(Sulfo-Cy5)-y-nal-k-Sub-KuE), has been developed and evaluated. Methods: The in vitro PSMA-targeting efficiency of PSMA-I&F, the reference PSMA-I&T, and their corresponding natGa-/68Ga- and natLu/177Lu counterparts was determined in LNCaP cells via competitive binding assays (IC50) and dual-tracer radioligand and fluorescence internalization studies. Biodistribution and small-animal PET imaging studies were performed in CB17 SCID and LNCaP xenograft-bearing SHO mice, respectively, and complemented by intraoperative far-red fluorescence imaging using a clinical laparoscope. Additionally, fully automated serial cryosectioning and fluorescence imaging of 1 tumor-bearing animal as well as PSMA immunohistochemistry and fluorescence microscopy of organ cryosections (tumor, kidney, spleen) were also performed. Results: Compared with the parent PSMA-I&T analogs, the PSMA affinities of PSMA-I&F and its natGa-/natLu-complexes remained high and unaffected by dye conjugation (7.9 < IC50 < 10.5 nM for all ligands). The same was observed for the internalization of 68Ga- and 177Lu-PSMA-I&F. In vivo, blood clearance of 68Ga- and 177Lu-PSMA-I&F was only slightly delayed by high plasma protein binding (94%-95%), and very low accumulation in nontarget organs was observed already at 1 h after injection. Dynamic PET imaging confirmed PSMA-specific (as demonstrated by coinjection of 2-PMPA) uptake into the LNCaP xenograft (4.5% ± 1.8 percentage injected dose per gram) and the kidneys (106% ± 23 percentage injected dose per gram). Tumor-to-background ratios of 2.1, 5.2, 9.6, and 9.6 for blood, liver, intestines, and muscle, respectively, at 1 h after injection led to excellent imaging contrast in 68Ga-PSMA-I&F PET and in intraoperative fluorescence imaging. Furthermore, fluorescence imaging of tissue cryosections allowed high-resolution visualization of intraorgan PSMA-I&F distribution in vivo and its correlation with PSMA expression as determined by immunohistochemistry. Conclusion: Thus, with its high PSMA-targeting efficiency and favorable pharmacokinetic profile, 68Ga/177Lu-PSMA-I&F serves as an excellent proof-of-concept compound for the general feasibility of PSMA-I&T-based hybrid imaging. The PSMA-I&T scaffold represents a versatile PSMA-targeted lead structure, allowing relatively straightforward adaptation to the different structural requirements of dedicated nuclear or hybrid imaging agents.

Dataset Information

Real time ultrasound molecular imaging of prostate cancer with PSMA-targeted nanobubbles.

Publications

Real time ultrasound molecular imaging of prostate cancer with PSMA-targeted nanobubbles.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure