Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nano
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LABORATORY INVESTIGATION
Combined fluorescence‑guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster Clare W. Teng1,2 · Ahmad Amirshaghaghi3 · Steve S. Cho1,2 · Shuting S. Cai3 · Emma De Ravin1,2 · Yash Singh1 · Joann Miller4 · Saad Sheikh4 · Edward Delikatny5 · Zhiliang Cheng3 · Theresa M. Busch4 · Jay F. Dorsey4 · Sunil Singhal6 · Andrew Tsourkas3 · John Y. K. Lee1 Received: 25 June 2020 / Accepted: 4 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Introduction Glioblastoma multiforme (GBM) is the most common primary intracranial malignancy; survival can be improved by maximizing the extent-of-resection. Methods A near-infrared fluorophore (Indocyanine-Green, ICG) was combined with a photosensitizer (Chlorin-e6, Ce6) on the surface of superparamagnetic-iron-oxide-nanoparticles (SPIONs), all FDA-approved for clinical use, yielding a nanocluster (ICS) using a microemulsion. The physical–chemical properties of the ICS were systematically evaluated. Efficacy of photodynamic therapy (PDT) was evaluated in vitro with GL261 cells and in vivo in a subtotal resection trial using a syngeneic flank tumor model. NIR imaging properties of ICS were evaluated in both a flank and an intracranial GBM model. Results ICS demonstrated high ICG and Ce6 encapsulation efficiency, high payload capacity, and chemical stability in physiologic conditions. In vitro cell studies demonstrated significant PDT-induced cytotoxicity using ICS. Preclinical animal studies demonstrated that the nanoclusters can be detected through NIR imaging in both flank and intracranial GBM tumors (ex: 745 nm, em: 800 nm; mean signal-to-background 8.5 ± 0.6). In the flank residual tumor PDT trial, subjects treated with PDT demonstrated significantly enhanced local control of recurrent neoplasm starting on postoperative day 8 (23.1 m m3 3 3 3 vs 150.5 m m , p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 m m vs 806.1 m m on day 23 (p = 0.0055). Conclusion A multimodal theragnostic agent comprised solely of FDA-approved components was developed to couple optical imaging and PDT. The findings demonstrated evidence for the potential theragnostic benefit of ICS in surgical oncology that is conducive to clinical integration. Keywords Glioblastoma multiforme · Indocyanine green (ICG) · Chlorin-e6 (Ce6) · Nanoparticle · Fluorescence-guided surgery · Photodynamic therapy · Theragnostics Clare W. Teng and Ahmad Amirshaghaghi contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11060-020-03618-1) contains supplementary material, which is available to authorized users. * John Y. K. Lee [email protected] 1
Department of Neurosurgery, Hospital of the University of Pennsylvania, 801 Spruce Street, 8th Floor, Philadelphia, PA 19107, USA
2
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3
Department of Bioe
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