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International Journal of Nanomedicine Volume 13, 2018 - Issue
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Original Research

Intravenously-injected gold nanoparticles (AuNPs) access intracerebral F98 rat gliomas better than AuNPs infused directly into the tumor site by convection enhanced delivery

Henry M Smilowitz1 Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, [email protected]Correspondence[email protected]
,
Alexandria Meyers1 Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, [email protected]
,
Khalil Rahman1 Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, [email protected]
,
Nathaniel A Dyment2 Department of Orthopedic Surgery, University of Pennsylvania, Philadelphia, PA
,
Dan Sasso1 Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, [email protected]
,
Crystal Xue3 George Washington University School of Medicine, Washington, DC
,
Douglas L Oliver4 Department of Neuroscience, University of Connecticut Health Center, Farmington, CT
,
Alexander Lichtler5 Department of Reconstructive Sciences, University of Connecticut Health Center, Farmington, CT
,
Xiaomeng Deng6 David Geffen School of Medicine at UCLA, Student Affairs Office, Los Angeles, CA
,
Sharif M Ridwan1 Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, [email protected]
,
Lauren J Tarmu7 Department of Human Behavior, College of Southern Nevada;8 Department of Anthropology, University of Nevada, Las Vegas, NV
,
Qian Wu9 Department of Anatomic Pathology, University of Connecticut Health Center, Farmington
,
Andrew L Salner10 The Gray Cancer Center, Hartford Hospital, Hartford
,
Ketan R Bulsara11 Division of Neurosurgery, UConn Health, Farmington, CT
,
Daniel N Slatkin12 Nanoprobes, Inc, Yaphank, NY, USA
&
James F Hainfeld12 Nanoprobes, Inc, Yaphank, NY, USA
 show all
Pages 3937-3948 | Published online: 04 Jul 2018

Figures & data

Figure 1 Tumor cells and edema in the brains of rats with advanced F98 gliomas.

Notes: (A and B) Left hemisphere (two separate rats) and (C) right hemisphere. (A–C) mCherry red (tumor, red), anti-albumin (edema, green), and DAPI (nuclei, blue).

Figure 1 Tumor cells and edema in the brains of rats with advanced F98 gliomas.Notes: (A and B) Left hemisphere (two separate rats) and (C) right hemisphere. (A–C) mCherry red (tumor, red), anti-albumin (edema, green), and DAPI (nuclei, blue).

Figure 2 IV-injected AuNPs colocalize with F98 tumors. (A) Rat 1, left hemisphere, fluorescence; (B) Rat 1, left hemisphere, gold enhance; (C) Rat 1, right hemisphere, fluorescence; (D) Rat 1, right hemisphere, gold enhance; (E) Rat 2, left hemisphere, fluorescence; (F) Rat 2, left hemisphere, gold enhance; (G) Rat 2, right hemisphere, fluorescence; and (H) Rat 2, right hemisphere, gold enhance. (A–G) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B–F) gold enhanced (gold stained, black).

Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 2 IV-injected AuNPs colocalize with F98 tumors. (A) Rat 1, left hemisphere, fluorescence; (B) Rat 1, left hemisphere, gold enhance; (C) Rat 1, right hemisphere, fluorescence; (D) Rat 1, right hemisphere, gold enhance; (E) Rat 2, left hemisphere, fluorescence; (F) Rat 2, left hemisphere, gold enhance; (G) Rat 2, right hemisphere, fluorescence; and (H) Rat 2, right hemisphere, gold enhance. (A–G) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B–F) gold enhanced (gold stained, black).Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 3 Complete lack of gold enhancement in saline-injected rats.

Notes: (A) Left hemisphere, fluorescence; (B) left hemisphere, gold enhance; (C) right hemisphere, fluorescence; and (D) right hemisphere, gold enhance. (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).

Abbreviation: CD31, cluster of differentiation 31.

Figure 3 Complete lack of gold enhancement in saline-injected rats.Notes: (A) Left hemisphere, fluorescence; (B) left hemisphere, gold enhance; (C) right hemisphere, fluorescence; and (D) right hemisphere, gold enhance. (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).Abbreviation: CD31, cluster of differentiation 31.

Figure 4 IV-injected AuNPs are associated with tumor cells lining blood vessels far from the main tumor mass.

Notes: Region far from the central tumor: (A) fluorescence and (B) gold enhanced. Saline control far from the central tumor: (C) fluorescence and (D) gold enhanced. (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).

Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 4 IV-injected AuNPs are associated with tumor cells lining blood vessels far from the main tumor mass.Notes: Region far from the central tumor: (A) fluorescence and (B) gold enhanced. Saline control far from the central tumor: (C) fluorescence and (D) gold enhanced. (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 5 IV-injected AuNPs are found around tumor cells lining blood vessels and edema in peritumor region.

Notes: Peritumor region: (A) fluorescence, mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B) gold enhanced (gold stained, black). Scale bar, 50 μm.

Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 5 IV-injected AuNPs are found around tumor cells lining blood vessels and edema in peritumor region.Notes: Peritumor region: (A) fluorescence, mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B) gold enhanced (gold stained, black). Scale bar, 50 μm.Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31; IV, intravenous.

Figure 6 Directly injected AuNPs are found in the white matter track and peritumor region but not in the main tumor region.

Notes: (A) Left hemisphere, fluorescence; (B) left hemisphere containing a brain tumor, gold enhanced; (B, inset) left hemisphere with no brain tumor, gold enhanced; (C) right hemisphere, fluorescence; (D) right hemisphere, gold enhanced; (D, inset) right hemisphere with no brain tumor; and (E) another animal, left hemisphere, stained for neurons (anti-Tuj 1, red fluorescence). (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B, D, and F) gold enhanced (gold stained, black).

Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31.

Figure 6 Directly injected AuNPs are found in the white matter track and peritumor region but not in the main tumor region.Notes: (A) Left hemisphere, fluorescence; (B) left hemisphere containing a brain tumor, gold enhanced; (B, inset) left hemisphere with no brain tumor, gold enhanced; (C) right hemisphere, fluorescence; (D) right hemisphere, gold enhanced; (D, inset) right hemisphere with no brain tumor; and (E) another animal, left hemisphere, stained for neurons (anti-Tuj 1, red fluorescence). (A and C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B, D, and F) gold enhanced (gold stained, black).Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31.

Figure 7 Directly injected AuNPs are largely found in the edema surrounding the tumor cells in peritumor region but not in and around the tumor cells themselves.

Notes: (A and C) Left hemisphere and (B and D) left hemisphere, gold enhanced. (A–C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).

Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31.

Figure 7 Directly injected AuNPs are largely found in the edema surrounding the tumor cells in peritumor region but not in and around the tumor cells themselves.Notes: (A and C) Left hemisphere and (B and D) left hemisphere, gold enhanced. (A–C) mCherry red (tumor, red), anti-albumin (edema, green), DAPI (nuclei, blue), and anti-CD31 (blood vessels, white) and (B and D) gold enhanced (gold stained, black).Abbreviations: AuNPs, gold nanoparticles; CD31, cluster of differentiation 31.

Figure 8 Quantification of the percentage of F98 containing BVs (F98 [+] BV) that also contained either a relatively large amount of AuNPs (AuNP++) or a relatively smaller amount of AuNPs (AuNP+) in the main tumor mass or in the peritumor region after either the direct infusion of AuNPs into the tumors or IV injection of AuNPs.

Abbreviations: AuNPs, gold nanoparticles; BV, blood vessel; IV, intravenous.

Figure 8 Quantification of the percentage of F98 containing BVs (F98 [+] BV) that also contained either a relatively large amount of AuNPs (AuNP++) or a relatively smaller amount of AuNPs (AuNP+) in the main tumor mass or in the peritumor region after either the direct infusion of AuNPs into the tumors or IV injection of AuNPs.Abbreviations: AuNPs, gold nanoparticles; BV, blood vessel; IV, intravenous.

Figure 9 Uptake of AuNPs into brain microglia and astrocytes after injection of AuNPs directly into control brains (non-tumor).

Notes: (A and C) Gold enhanced (gold stained, black); (B) fluorescence, anti-Iba-1 (microglia, green); and (D) fluorescence, anti-GFAP (astrocytes, green).

Abbreviations: AuNPs, gold nanoparticles; GFAP, glial fibrillary acidic protein.

Figure 9 Uptake of AuNPs into brain microglia and astrocytes after injection of AuNPs directly into control brains (non-tumor).Notes: (A and C) Gold enhanced (gold stained, black); (B) fluorescence, anti-Iba-1 (microglia, green); and (D) fluorescence, anti-GFAP (astrocytes, green).Abbreviations: AuNPs, gold nanoparticles; GFAP, glial fibrillary acidic protein.

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