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. 2017 Oct 27:12:7937-7946.
doi: 10.2147/IJN.S140977. eCollection 2017.

Biodistribution of gold nanoparticles in BBN-induced muscle-invasive bladder cancer in mice

Henry M Smilowitz  1 , Lauren J Tarmu  1   2   3 , Mary Melinda Sanders  4 , John A Taylor 3rd  5 , Dharamainder Choudhary  6 , Crystal Xue  7 , Nathaniel A Dyment  8 , Dan Sasso  1 , Xiaomeng Deng  9 , James F Hainfeld  10
Affiliations

Biodistribution of gold nanoparticles in BBN-induced muscle-invasive bladder cancer in mice

Henry M Smilowitz et al. Int J Nanomedicine. .

Abstract

Bladder-sparing options are being developed for muscle-invasive bladder cancer in place of radical cystectomy, including the combination of chemotherapy and radiation therapy. We reasoned that improving the radiotherapy component of chemoradiation could improve the control of locally advanced disease. Previously, we showed that gold nanoparticles (AuNPs) are potent enhancers of radiation therapy. We hypothesized that if AuNPs were to preferentially localize to bladder tumors, they may be used to enhance the radiation component of muscle-invasive bladder tumor therapy. Mice were treated with the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 17, 20, and 22 weeks - long enough to induce muscle-invasive tumors. Mice were then anesthetized and injected intravenously with 1.9 nm AuNPs of which most were rapidly cleared from the blood and excreted after a 30-50 minute residence time in the bladder. We found AuNPs distributed throughout the bladder wall, but most of the AuNPs were associated with the stroma surrounding the tumor cells or extracellular keratin produced by the tumor cells. There were relatively few AuNPs in the tumor cells themselves. The AuNPs therefore localized to tumor-associated stroma and this tumor specificity might be useful for specific X-ray dose enhancement therapy of muscle-invasive bladder carcinomas.

Keywords: BBN; N-butyl-N-(4-hydroxybutyl)nitrosamine; gold nanoparticles; mouse model; muscle-invasive bladder cancer.

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Conflict of interest statement

Disclosure James Hainfeld is part owner of Nanoprobes, Inc. The other authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Normal bladder without BBN treatment or AuNPs at 40×. (B) High-grade muscle-invasive bladder cancer induced by BBN presenting at 22 weeks at 40× and (C) at 200×. (D) Gold enhanced normal bladder without BBN treatment or AuNPs at 40× illustrates average level of background noise from gold enhancement. (E) AuNPs aggregating in the stroma surrounding tumor cells. (F) AuNPs deposit all the way out to the outer edge of the bladder enveloping tumor masses. Abbreviations: AuNPs, gold nanoparticles; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine.
Figure 2
Figure 2
High-grade muscle-invasive bladder cancer induced by BBN treatment at 20 weeks. (A) H&E, 40×; (B) gold enhanced, 40×; (C) H&E, 100×; (D) gold enhanced, 100×; (E) gold enhanced, 200×; (F) gold enhanced region of bladder wall devoid of tumor, 100×. Abbreviations: BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; H&E, hematoxylin and eosin; T, tumor; S, stroma.
Figure 3
Figure 3
High-grade muscle-invasive bladder cancer induced by BBN treatment at 17 weeks without gold injection. (A) H&E, 40×; (B) gold enhanced, 40×; (C) H&E, 100×; (D) gold enhanced, 100×; (E) H&E, 200×; (F) gold enhanced, 200×. Abbreviations: H&E, hematoxylin and eosin; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine.
Figure 4
Figure 4
Bladder from age matched mouse that was not treated with BBN but received AuNP injection. (A) H&E, 40×; (B) gold enhanced, 40×; (C) H&E, 100×; (D) gold enhanced, 100×; (E) H&E, 200×; (F) gold enhanced, 200×. Abbreviations: AuNP, gold nanoparticle; H&E, hematoxylin and eosin; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine.
Figure 5
Figure 5
Representative urothelial regions in bladders of mice that received AuNP injection. (A) BBN-treated, gold enhanced, 40×; (B) non-BBN-treated, gold enhanced, 40×. Abbreviations: AuNP, gold nanoparticle; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine.
Figure 6
Figure 6
Keratin in the lumen of bladder from a mouse treated with BBN and stained with H&E. (A) 40×; (B) 100×; (C) gold enhanced, 200×. Abbreviations: H&E, hematoxylin and eosin; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine.
Figure 7
Figure 7
Low background AuNP distribution in bladders from untreated control and BBN-treated mice. (A, B) BBN, 17 weeks; (C, D) BBN, 22 weeks; (E, F) control untreated, 22 weeks. Abbreviations: AuNP, gold nanoparticle; BBN, N-butyl-N-(4-hydroxybutyl)nitrosamine; T, tumor; S, stroma.
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