Research Article

Magnetic polymeric nanobubbles with optimized core size for MRI/ultrasound bimodal molecular imaging of prostate cancer

Department of Ultrasound in Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China

‡Authors contributed equally

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Ying Sun‡

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China

‡Authors contributed equally

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Weiyong Liu

Department of Ultrasound in Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China

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Wenbin Guan

Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China

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Huanhuan Liu

Department of Radiology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China

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Yourong Duan

*Author for correspondence:

E-mail Address: yrduan@shsci.org

https://orcid.org/0000-0002-3781-7845

State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, PR China

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Yaqing Chen

**Author for correspondence:

E-mail Address: chenyaqing@xinhuamed.com.cn

https://orcid.org/0000-0001-5132-0096

Department of Ultrasound in Medicine, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, 1665 Kongjiang Road, Shanghai 200092, PR China

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Published Online:10 Dec 2020https://doi.org/10.2217/nnm-2020-0188

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Abstract

Aim: To design MRI/ultrasound (US) dual modality imaging probes with optimized size for prostate cancer imaging by targeting prostate-specific membrane antigen (PSMA). Materials & methods: The PSMA-targeting polypeptide-nanobubbles (PP-NBs) with core size of 400 and 700 nm were fabricated and evaluated. Results: With excellent physical property and specificity, PP-NBs of both core size could image PSMA expression in prostate cancer xenografts. Particularly, 400 nm PP-NBs generated higher PSMA-specific MRI/US dual modality contrast enhancement than 700 nm PP-NBs in correlation with histopathologic findings. Conclusion: Benefit from the smaller core size, 400 nm PP-NBs had higher permeability and specificity than 700 nm PP-NBs, hence producing better PSMA-specific MRI/US dual modality imaging.

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Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
MedlineGoogle Scholar
2. Swanson GP, Epstein JI, Ha CS, Kryvenko ON. Pathological characteristics of low risk prostate cancer based on totally embedded prostatectomy specimens. Prostate 75(4), 424–429 (2015).
Medline CASGoogle Scholar
3. Kitzing YX, Prando A, Varol C, Karczmar GS, Maclean F, Oto A. Benign conditions that mimic prostate carcinoma: MR imaging features with histopathologic correlation. Radiographics 36(1), 162–175 (2016).
MedlineGoogle Scholar
4. Grey A, Ahmed HU. Multiparametric ultrasound in the diagnosis of prostate cancer. Curr. Opin. Urol. 26(1), 114–119 (2016).
MedlineGoogle Scholar
5. Turkbey B, Pinto PA, Mani H et al. Prostate cancer: value of multiparametric MR imaging at 3 T for detection--histopathologic correlation. Radiology 255(1), 89–99 (2010).
MedlineGoogle Scholar
6. Chatterjee A, Thomas S, Oto A. Prostate MR: pitfalls and benign lesions. Abdom. Radiol. (NY) doi:10.1007/s00261-019-02302-x (.2019) (Epub ahead of print).
MedlineGoogle Scholar
7. Rastinehad AR, Turkbey B, Salami SS et al. Improving detection of clinically significant prostate cancer: magnetic resonance imaging/transrectal ultrasound fusion guided prostate biopsy. J. Urol. 191(6), 1749–1754 (2014).
MedlineGoogle Scholar
8. Guttilla A, Zazzara M, Zattoni F et al. Histopathological characteristics of microfocal prostate cancer detected during systematic prostate biopsy. BJU Int. 116(2), 202–206 (2015).
Medline CASGoogle Scholar
9. Mai Z, Xiao Y, Yan W et al. Comparison of lesions detected and undetected by template-guided transperineal saturation prostate biopsy. BJU Int. 121(3), 415–420 (2018).
MedlineGoogle Scholar
10. Priester A, Natarajan S, Khoshnoodi P et al. Magnetic resonance imaging underestimation of prostate cancer geometry: use of patient specific molds to correlate images with whole mount pathology. J. Urol. 197(2), 320–326 (2017).
MedlineGoogle Scholar
11. Qi TY, Chen YQ, Jiang J, Zhu YK, Yao XH, Qi J. Contrast-enhanced transrectal ultrasonography: measurement of prostate cancer tumor size and correlation with radical prostatectomy specimens. Int. J. Urol. 20(11), 1085–1091 (2013).
MedlineGoogle Scholar
12. Muller BG, Van Den Bos W, Brausi M et al. Role of multiparametric magnetic resonance imaging (MRI) in focal therapy for prostate cancer: a Delphi consensus project. BJU Int. 114(5), 698–707 (2014).
MedlineGoogle Scholar
13. Saji H. In Vivo Molecular imaging. Biol. Pharm. Bull. 40(10), 1605–1615 (2017).
Medline CASGoogle Scholar
14. Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J. Cell. Biochem. 91(3), 528–539 (2004).
Medline CASGoogle Scholar
15. Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin. Cancer Res. 3(1), 81–85 (1997).
Medline CASGoogle Scholar
16. Kasperzyk JL, Finn SP, Flavin R et al. Prostate-specific membrane antigen protein expression in tumor tissue and risk of lethal prostate cancer. Cancer Epidemiol. Biomarkers Prev. 22(12), 2354–2363 (2013).
Medline CASGoogle Scholar
17. Bravaccini S, Puccetti M, Bocchini M et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Sci. Rep. 8(1), 4254 (2018).
MedlineGoogle Scholar
18. Schwarzenboeck SM, Rauscher I, Bluemel C et al. PSMA ligands for PET imaging of prostate cancer. J. Nucl. Med. 58(10), 1545–1552 (2017).
Medline CASGoogle Scholar
19. Werner RA, Derlin T, Lapa C et al. (18)F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging. Theranostics 10(1), 1–16 (2020).
Medline CASGoogle Scholar
20. Junker D, Schafer G, Kobel C et al. Comparison of real-time elastography and multiparametric MRI for prostate cancer detection: a whole-mount step-section analysis. AJR Am. J. Roentgenol. 202(3), W263–269 (2014).
MedlineGoogle Scholar
21. Yang F, Li Y, Chen Z, Zhang Y, Wu J, Gu N. Superparamagnetic iron oxide nanoparticle-embedded encapsulated microbubbles as dual contrast agents of magnetic resonance and ultrasound imaging. Biomaterials 30(23–24), 3882–3890 (2009). • Fabrication of magnetic microbubbles for MRI/ultrasound dual modality imaging.
Medline CASGoogle Scholar
22. Yoon YI, Ha SW, Lee HJ. An ultrasound-responsive dual-modal US/T1-MRI contrast agent for potential diagnosis of prostate cancer. J. Magn. Reson. Imaging 48(6), 1610–1616 (2018). •• Fabrication of prostate specific membrane antigen (PSMA) targeting MRI contrast agents loaded microbubbles for PSMA imaging.
MedlineGoogle Scholar
23. Wu H, Abenojar EC, Perera R, De Leon AC, An T, Exner AA. Time-intensity-curve analysis and tumor extravasation of nanobubble ultrasound contrast agents. Ultrasound Med. Biol. 45(9), 2502–2514 (2019).
MedlineGoogle Scholar
24. Kaneko OF, Willmann JK. Ultrasound for molecular imaging and therapy in cancer. Quant. Imaging Med. Surg. 2(2), 87–97 (2012).
MedlineGoogle Scholar
25. Hobbs SK, Monsky WL, Yuan F et al. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc. Natl Acad. Sci. USA 95(8), 4607–4612 (1998).
Medline CASGoogle Scholar
26. Ding Y, Cao Q, Qian S et al. Optimized anti-prostate-specific membrane antigen single-chain variable fragment-loaded nanobubbles as a novel targeted ultrasound contrast agent for the diagnosis of prostate cancer. J. Ultrasound Med. 39(4), 761–773 (2020).
MedlineGoogle Scholar
27. Fan X, Wang L, Guo Y et al. Ultrasonic nanobubbles carrying anti-PSMA nanobody: construction and application in prostate cancer-targeted imaging. PLoS ONE 10(6), e0127419 (2015).
MedlineGoogle Scholar
28. Fan X, Guo Y, Wang L, Xiong X, Zhu L, Fang K. Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles. Int. J. Nanomedicine 11, 3939–3950 (2016).
Medline CASGoogle Scholar
29. Wu M, Zhao H, Guo L et al. Ultrasound-mediated nanobubble destruction (UMND) facilitates the delivery of A10-3.2 aptamer targeted and siRNA-loaded cationic nanobubbles for therapy of prostate cancer. Drug Deliv. 25(1), 226–240 (2018).
Medline CASGoogle Scholar
30. Sirsi S, Borden M. Microbubble compositions, properties and biomedical applications. Bubble Sci. Eng. Technol. 1(1–2), 3–17 (2009).
Medline CASGoogle Scholar
31. Yang H, Cai W, Xu L et al. Nanobubble-affibody: novel ultrasound contrast agents for targeted molecular ultrasound imaging of tumor. Biomaterials 37, 279–288 (2015).
Medline CASGoogle Scholar
32. Chen Y, Liang Y, Jiang P, Li F, Yu B, Yan F. Lipid/PLGA hybrid microbubbles as a versatile platform for noninvasive image-guided targeted drug delivery. ACS Appl. Mater. Interfaces 11(45), 41842–41852 (2019).
Medline CASGoogle Scholar
33. Sun Y, Zhu Y, Huang C, Li R, Chen Y, Duan Y. Magnetite loaded polypeptide-PLGA multifunctional microbubbles for dual-mode US/MR imaging. Contrast Media Mol. Imaging 11(2), 146–153 (2016).
Medline CASGoogle Scholar
34. Niu C, Wang Z, Lu G et al. Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes. Biomaterials 34(9), 2307–2317 (2013).
Medline CASGoogle Scholar
35. Lupold SE, Rodriguez R. Disulfide-constrained peptides that bind to the extracellular portion of the prostate-specific membrane antigen. Mol. Cancer Ther. 3(5), 597–603 (2004). • PSMA targeting polypeptide.
Medline CASGoogle Scholar
36. Liu X, Kaminski MD, Chen H, Torno M, Taylor L, Rosengart AJ. Synthesis and characterization of highly-magnetic biodegradable poly(d,l-lactide-co-glycolide) nanospheres. J. Control. Release 119(1), 52–58 (2007).
Medline CASGoogle Scholar
37. Yu MK, Kim D, Lee IH, So JS, Jeong YY, Jon S. Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles. Small 7(15), 2241–2249 (2011).
Medline CASGoogle Scholar
38. Zhu Y, Sun Y, Chen Y et al. In vivo molecular MRI imaging of prostate cancer by targeting PSMA with polypeptide-labeled superparamagnetic iron oxide nanoparticles. Int. J. Mol. Sci. 16(5), 9573–9587 (2015).
Medline CASGoogle Scholar
39. Zhang J, Li B, Yang W, Li J. Synthesis of magnetic Fe3O4@hierarchical hollow silica nanospheres for efficient removal of methylene blue from aqueous solutions. Ind. Eng. Chem. Res. 53(16), 10629–10636 (2014).
CASGoogle Scholar
40. Poselt E, Kloust H, Tromsdorf U et al. Relaxivity optimization of a PEGylated iron-oxide-based negative magnetic resonance contrast agent for T(2)-weighted spin-echo imaging. ACS Nano 6(2), 1619–1624 (2012). • Correlation between nanoparticle core size and transverse relaxation rate.
Medline CASGoogle Scholar
41. Jung AJ, Westphalen AC. Imaging prostate cancer. Radiol. Clin. North Am. 50(6), 1043–1059 (2012).
MedlineGoogle Scholar
42. Monsky WL, Fukumura D, Gohongi T et al. Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor. Cancer Res. 59(16), 4129–4135 (1999). •• Correlation between nanoparticle core size and permeability.
Medline CASGoogle Scholar
43. Jiang Z, Guan J, Qian J, Zhan C. Peptide ligand-mediated targeted drug delivery of nanomedicines. Biomater. Sci. 7(2), 461–471 (2019).
Medline CASGoogle Scholar
44. Wu H, Rognin NG, Krupka TM et al. Acoustic characterization and pharmacokinetic analyses of new nanobubble ultrasound contrast agents. Ultrasound Med. Biol. 39(11), 2137–2146 (2013).
MedlineGoogle Scholar
45. Yin T, Wang P, Zheng R et al. Nanobubbles for enhanced ultrasound imaging of tumors. Int. J. Nanomedicine 7, 895–904 (2012).
Medline CASGoogle Scholar
46. Ho YJ, Li JP, Fan CH, Liu HL, Yeh CK. Ultrasound in tumor immunotherapy: current status and future developments. J. Control. Release 323, 12–23 (2020).
Medline CASGoogle Scholar

Vol. 15, No. 30

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History

Received 1 May 2020

Accepted 21 October 2020

Published online 10 December 2020

Published in print December 2020

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Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2020-0188

Author contributions

Y Zhu contributed to the cellular experiments, animal experiments and manuscript writing. Y Sun contributed to imaging probe fabrication, and revision of the manuscript. W Liu contributed to culture cell maintaining, cell viability and uptake experiments. W Guan contributed to the pathological evaluations. H Liu contributed to MRI experiments. Y Duan contributed to imaging probe design and fabrication. Y Chen contributed to ultrasound experiments, design and planning of experiments, and revision of the manuscript.

Financial & competing interests disclosure

This project has been supported by the grant from the National Natural Science Foundation of China (No. 81671708, 81271595, 81572999, 81771839 and 81773272), Shanghai Shen Kang Hospital Development Center Research Project (No. 16CR3092B) and the Fund of Shanghai Jiaotong University (No. YG2014ZD04). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval and the animal experiments were approved by Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine Animal Care and Use Committee (approval no: XHEC-F-2019-022).

Data sharing statement

Data are available for bona fide researchers who request it from the corresponding author.

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