Original Article
Targeting prostate cancer with Clostridium perfringens enterotoxin functionalized nanoparticles co-encapsulating imaging cargo enhances magnetic resonance imaging specificity

https://doi.org/10.1016/j.nano.2021.102477Get rights and content

Abstract

Magnetic resonance is a key imaging tool for the detection of prostate cancer; however, better tools focusing on cancer specificity are required to distinguish benign from cancerous regions. We found higher expression of claudin-3 (CLDN-3) and -4 (CLDN-4) in higher grade than lower-grade human prostate cancer biopsies (n = 174), leading to the design of functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand Clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to Cldn-3 and Cldn-4 receptors. We developed a first-of-its-type, C-CPE-NP-based MRI detection tool in a prostate tumor-bearing mouse model. NPs with an average diameter of 152.9 ± 15.7 nm (RS1) had a 2-fold enhancement of tumor specificity compared to larger (421.2 ± 33.8 nm) NPs (RS4). There was a 1.8-fold (P < 0.01) and 1.6-fold (P < 0.01) upregulation of the tumor-to-liver signal intensities of C-RS1 and C-RS4 (functionalized NPs) compared to controls, respectively. Also, tumor specificity was 3.1-fold higher (P < 0.001) when comparing C-RS1 to C-RS4. This detection tool improved tumor localization of contrast-enhanced MRI, supporting potential clinical applicability.

Graphical Abstract

We developed functionalized nanoparticles (NPs) with a non-toxic truncated version of the natural ligand clostridium perfringens enterotoxin (C-CPE) that has a strong binding affinity to the Cldn-3 and Cldn-4 receptors. The C-CPE NP-based MRI detection tool provided 70% tumor coverage using a prostate tumor-bearing mouse model.

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Section snippets

Patient tissue specimens

All men were participants in the IRB approved Yale Urology Biospecimen and Data repository for prostate cancer. From August 2015 to December 2018 and within three months of receiving an mpMRI, an MRI-ultrasound fusion targeted biopsy of regions of interest (ROIs) and concurrent 12-core systematic biopsies under local anesthesia using the Artemis® biopsy device (Eigen, Grass Valley, CA) were performed. Biopsy cores were collected and immediately fixed. All biopsy cores were reviewed in a

Claudin expression and Decipher signature in human prostate cancer specimens

CLDN-3 mRNA expression in Gleason Grade Group 3+ (GG3+) (M = 1.313, SD = 0.385, n = 27) was higher than levels of expression in Gleason Grade Group 1 (GG1) (M = 1.014, SD = 0.278, n = 147), t(172) = 4.84, P < 0.0001, Cohen's d = 1.008 (Figure 1, A). CLDN-4 mRNA expression in Gleason GG3+ (M = 0.647, SD = 0.208) was higher than levels of expression in Gleason GG1 (M = 0.566, SD = 0.144), t(172) = 2.48, p = 0.014, Cohen's d = 0.520 (Figure 1, B). The Decipher signature in GG3+ (M = 0.624,

Discussion

MRI-US fusion technology has improved the detection of clinically significant prostate cancer. MRI-ultrasound has become the standard of clinical care to identify suspicious lesions within the prostate gland.5 We have biopsied over 1000 patients based on PI-RADS version 1 (v1) and version 2 (v2), with a cancer detection rate of 87%, which is comparable with other institutions including the University of California-Los Angeles (UCLA) at 80%30 and the University of Maryland at 92%.1 Even with the

Acknowledgements

The authors thank Drs. Emiliano Cocco, Richard Fan, and Alessandro D. Santin for initial project discussions. The authors also thank Dr. Hongliang Shen, Stellar Levy, and Mmaserame Gaefele for technical assistance, and Dr. Ashley M. Schnakenberg Martin for statistical assistance. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program under Award No. W81XWH-14-1-0487 (DTM). The opinions, interpretations,

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    Competing interests: There are no competing interests to report.

    1

    Contributed equally to this work.

    2

    Present address: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, China.

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