Targeting orthotopic gliomas with renal-clearable luminescent gold nanoparticles
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A major clinical translational challenge in nanomedicine is the potential of toxicity associated with the uptake and long-term retention of non-degradable nanoparticles (NPs) in major organs. The development of inorganic NPs that undergo renal clearance could potentially resolve this significant biosafety concern. However, it remains unclear whether inorganic NPs that can be excreted by the kidneys remain capable of targeting tumors with poor permeability. Glioblastoma multiforme, the most malignant orthotopic brain tumor, presents a unique challenge for NP delivery because of the blood-brain barrier and robust blood-tumor barrier of reactive microglia and macroglia in the tumor microenvironment. Herein, we used an orthotopic murine glioma model to investigate the passive targeting of glutathione-coated gold nanoparticles (AuNPs) of 3 nm in diameter that undergo renal clearance and 18-nm AuNPs that fail to undergo renal clearance. Remarkably, we report that 3-nm AuNPs were able to target intracranial tumor tissues with higher efficiency (2.3× relative to surrounding non-tumor normal brain tissues) and greater specificity (3.0×) than did the larger AuNPs. Pharmacokinetics studies suggested that the higher glioma targeting ability of the 3-nm AuNPs may be attributed to the longer retention time in circulation. The total accumulation of the 3-nm AuNPs in major organs was significantly less (8.4×) than that of the 18-nm AuNPs. Microscopic imaging of blood vessels and renal-clearable AuNPs showed extravasation of NPs from the leaky blood-tumor barrier into the tumor interstitium. Taken together, our results suggest that the 3-nm AuNPs, characterized by enhanced permeability and retention, are able to target brain tumors and undergo renal clearance.
Keywordsenhanced permeability and retention brain tumor passive targeting gold nanoparticles renal clearance
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This study was partially supported by CPRIT (Nos. RP140544 and RP160866), NIH (No. 1R01DK103363) and a start-up fund from the University of Texas at Dallas to J. Z., UTSW CRI start-up funds, UTSW High Impact/High Risk Grant and NINDS K99/R00 (No. R00NS073735) to W. P. G.
- Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res. 1986, 46, 6387–6392.Google Scholar
- Prabhakar, U.; Maeda, H.; Jain, R. K.; Sevick-Muraca, E. M.; Zamboni, W.; Farokhzad, O. C.; Barry, S. T.; Gabizon, A.; Grodzinski, P.; Blakey, D. C. Challenges and key considerations of the enhanced permeability and retention effect for nanomedicine drug delivery in oncology. Cancer Res. 2013, 73, 2412–2417.CrossRefGoogle Scholar
- Dvorak, H. F.; Brown, L. F.; Detmar, M.; Dvorak, A. M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am. J. Pathol. 1995, 146, 1029–1039.Google Scholar
- Groothuis, D. R. The blood-brain and blood-tumor barriers: A review of strategies for increasing drug delivery. Neuro Oncol. 2000, 2, 45–59.Google Scholar
- Yang, X. Q.; Hong, H.; Grailer, J. J.; Rowland, I. J.; Javadi, A.; Hurley, S. A.; Xiao, Y. L.; Yang, Y.; Zhang, Y.; Nickles, R. J. cRGD-functionalized, DOX-conjugated, and 64Cu-labeled superparamagnetic iron oxide nanoparticles for targeted anticancer drug delivery and PET/MR imaging. Biomaterials 2011, 32, 4151–4160.CrossRefGoogle Scholar
- Goel, S.; Chen, F.; Hong, H.; Valdovinos, H. F.; Hernandez, R.; Shi, S. X.; Barnhart, T. E.; Cai, W. B. VEGF121-conjugated mesoporous silica nanoparticle: A tumor targeted drug delivery system. ACS Appl. Mater. Interfaces 2014, 6, 21677–21685.Google Scholar
- Gao, J.; Chen, K.; Luong, R.; Bouley, D. M.; Mao, H.; Qiao, T.; Gambhir, S. S.; Cheng, Z. A novel clinically translatable fluorescent nanoparticle for targeted molecular imaging of tumors in living subjects. Nano Lett. 2011, 12, 281–286.Google Scholar
- Black, K. L.; Ningaraj, N. S. Modulation of brain tumor capillaries for enhanced drug delivery selectively to brain tumor. Cancer Control 2004, 11, 165–173.Google Scholar