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Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster

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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 mm3 vs 150.5 mm3, p = 0.045), and the treatment effect amplified to final mean volumes of 220.4 mm3 vs 806.1 mm3 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.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Tamimi AF, Juweid M (2017) Epidemiology and outcome of glioblastoma. In: Glioblastoma; Exon Publication, Brisbane. p 143

  2. Johnson DR, O’Neill BP (2012) Glioblastoma survival in the United States before and during the temozolomide era. J Neurooncol 107:359

    CAS  PubMed  Google Scholar 

  3. Wallner KE, Galicich JH, Krol G et al (1989) Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. Int J Radiat Oncol Biol Phys 16:1405

    CAS  PubMed  Google Scholar 

  4. Sanai N, Polley M-Y, McDermott MW et al (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–8

    PubMed  Google Scholar 

  5. Lacroix M, Abi-Said D, Fourney DR et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198

    CAS  PubMed  Google Scholar 

  6. Brown TJ, Brennan MC, Li M et al (2016) Association of the extent of resection with survival in glioblastoma. JAMA Oncol 2:1460

    PubMed  PubMed Central  Google Scholar 

  7. Orringer D, Lau D, Khatri S et al (2012) Extent of resection in patients with glioblastoma: limiting factors, perception of resectability, and effect on survival. J Neurosurg 117:851

    PubMed  Google Scholar 

  8. Stummer W, Pichlmeier U, Meinel T et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma : a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401

    CAS  PubMed  Google Scholar 

  9. Hong G, Antaris AL, Dai H (2017) Near-infrared fluorophores for biomedical imaging. Nat.Biomed. Eng 1:1–22

    Google Scholar 

  10. Schols RM, Connell NJ, Stassen LPS (2015) Near-infrared fluorescence imaging for real-time intraoperative anatomical guidance in minimally invasive surgery: a systematic review of the literature. World J Surg 39:1069–1079

    PubMed  Google Scholar 

  11. Lee JYK, Thawani JP, Pierce J et al (2016) Intraoperative near-infrared optical imaging can localize gadolinium-enhancing gliomas during surgery. Neurosurgery 79:856–871

    PubMed  PubMed Central  Google Scholar 

  12. Lee JYK, Pierce JT, Zeh R et al (2017) Intraoperative near-infrared optical contrast can localize brain metastases. World Neurosurg 106:120–130

    PubMed  Google Scholar 

  13. Lee JYK, Pierce JT, Thawani JP et al (2017) Near-infrared fluorescent image-guided surgery for intracranial meningioma. Neurosurgery 128:380–390

    Google Scholar 

  14. Carr JA, Franke D, Caram JR et al (2018) Shortwave infrared fluorescence imaging with the clinically approved near-infrared dye indocyanine green. Proc Natl Acad Sci USA 115:4465

    CAS  PubMed  Google Scholar 

  15. Maruyama T, Muragaki Y, Nitta M et al (2016) Photodynamic therapy for malignant brain tumors. Japanese J Neurosurg 25:895

    Google Scholar 

  16. Eljamel S (2010) Photodynamic applications in brain tumors: a comprehensive review of the literature. Photodiagnosis Photodyn Ther 7:76

    CAS  PubMed  Google Scholar 

  17. Eljamel MS, Goodman C, Moseley H (2008) ALA and Photofrin® Fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial. Lasers Med Sci 23:361

    PubMed  Google Scholar 

  18. Li Y, Yu Y, Kang L, Lu Y (2014) Effects of chlorin e6-mediated photodynamic therapy on human colon cancer SW480 cells. Int J Clin Exp Med 7:4867

    PubMed  PubMed Central  Google Scholar 

  19. Nann T (2011) Nanoparticles in photodynamic therapy. Nano Biomed Eng 3:137

    CAS  Google Scholar 

  20. Paul S, Heng PWS, Chan LW (2013) Optimization in solvent selection for chlorin e6 in photodynamic therapy. J Fluoresc 23:283

    CAS  PubMed  Google Scholar 

  21. Kelkar SS, Reineke TM (2011) Theranostics: combining imaging and therapy. Bioconjug Chem 22:1879–1903

    CAS  PubMed  Google Scholar 

  22. Lee JH, Lee K, Moon SH et al (2009) All-in-One target-cell-specific magnetic nanoparticles for simultaneous molecular imaging and siRNA delivery. Angew Chem Int Ed Engl 48:4174–4179

    CAS  PubMed  Google Scholar 

  23. Thawani JP, Amirshaghaghi A, Yan L et al (2017) Photoacoustic-guided surgery with indocyanine green-coated superparamagnetic iron oxide nanoparticle clusters. Small 13:1–9

    Google Scholar 

  24. Kircher MF, De La Zerda A, Jokerst JV et al (2012) A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nat Med 18:829–834

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Li J, Zhao J, Tan T et al (2020) Nanoparticle drug delivery system for glioma and its efficacy improvement strategies: a comprehensive review. Int J Nanomed 15:2563–2582

    CAS  Google Scholar 

  26. Guo J, Gao X, Su L et al (2011) Aptamer-functionalized PEG-PLGA nanoparticles for enhanced anti-glioma drug delivery. Biomaterials 32:8010–8020

    CAS  PubMed  Google Scholar 

  27. Jordan A, Scholz R, Maier-Hauff K et al (2006) The effect of thermotherapy using magnetic nanoparticles on rat malignant glioma. J Neurooncol 78:7–14

    CAS  PubMed  Google Scholar 

  28. Michael JS, Lee B-S, Zhang M, Yu JS (2018) Nanotechnology for treatment of glioblastoma multiforme. J Transl Intern Med 6:128–133

    Google Scholar 

  29. Pardridge WM (2005) The blood-brain barrier and neurotherapeutics. NeuroRx 2:1–2

    PubMed  PubMed Central  Google Scholar 

  30. Chen H, Zhen Z, Todd T et al (2013) Nanoparticles for improving cancer diagnosis. Mater Sci Eng R Reports 74:35–69

    Google Scholar 

  31. Chenthamara D, Subramaniam S, Ramakrishnan SG et al (2019) Therapeutic efficacy of nanoparticles and routes of administration. Biomater Res 23:20

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Huynh E, Zheng G (2013) Engineering multifunctional nanoparticles: all-in-one versus one-for-all. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:250–265

    CAS  PubMed  Google Scholar 

  33. Higbee-Dempsey E, Amirshaghaghi A, Case MJ et al (2019) Indocyanine green–coated gold nanoclusters for photoacoustic imaging and photothermal therapy. Adv Ther 2:1900088

    CAS  Google Scholar 

  34. Amirshaghaghi A, Yan L, Miller J et al (2019) Chlorin e6-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters as a theranostic agent for dual-mode imaging and photodynamic therapy. Sci Rep 9:1–9

    CAS  Google Scholar 

  35. Yan L, Amirshaghaghi A, Huang D et al (2018) Protoporphyrin IX (PpIX)-coated superparamagnetic iron oxide nanoparticle (SPION) nanoclusters for magnetic resonance imaging and photodynamic therapy. Adv Funct Mater 28:1707030

    PubMed  PubMed Central  Google Scholar 

  36. Munnier E, Cohen-Jonathan S, Linassier C et al (2008) Novel method of doxorubicin–SPION reversible association for magnetic drug targeting. Int J Pharm 363:170–176

    CAS  PubMed  Google Scholar 

  37. Husain SR, Behari N, Kreitman RJ et al (1998) Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy. Cancer Res 58:3649–3653

    CAS  PubMed  Google Scholar 

  38. Zeh R, Sheikh S, Xia L et al (2017) The second window ICG technique demonstrates a broad plateau period for near infrared fluorescence tumor contrast in glioblastoma. PLoS ONE 12:e0182034

    PubMed  PubMed Central  Google Scholar 

  39. Baumann BC, Dorsey JF, Benci JL et al (2012) Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme. J Vis Exp 67:e4089

    Google Scholar 

  40. Yuan A, Tang X, Qiu X et al (2015) Activatable photodynamic destruction of cancer cells by NIR dye/photosensitizer loaded liposomes. Chem Commun 51:3340–3342

    CAS  Google Scholar 

  41. Herve P, Nome F, Fendler JH (1984) Magnetic effects on chemical reactions in the absence of magnets. Effects of surfactant vesicle entrapped magnetite particles on benzophenone photochemistry. J Am Chem Soc 106:8291.

  42. Saravanakumar G, Kim J, Kim WJ (2016) Reactive-oxygen-species-responsive drug delivery systems: promises and challenges. Adv Sci 4:1600124

    Google Scholar 

  43. Enochs WS, Harsh G, Hochberg F, Weissleder R (1999) Improved delineation of human brain tumors on MR images using a long- circulating, superparamagnetic iron oxide agent. J Magn Reson Imaging 9:228

    CAS  PubMed  Google Scholar 

  44. Madajewski B, Judy BF, Mouchli A et al (2012) Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. Clin Cancer Res 18:5741–5752

    PubMed  PubMed Central  Google Scholar 

  45. Raucher D, Dragojevic S, Ryu J (2018) Macromolecular drug carriers for targeted glioblastoma therapy: preclinical studies, challenges, and future perspectives. Front Oncol 8:624

    PubMed  PubMed Central  Google Scholar 

  46. Béduneau A, Saulnier P, Benoit J-P (2007) Active targeting of brain tumors using nanocarriers. Biomaterials 28:4947–4967

    PubMed  Google Scholar 

  47. Xin H, Jiang X, Gu J et al (2011) Angiopep-conjugated poly(ethylene glycol)-co-poly(ε-caprolactone) nanoparticles as dual-targeting drug delivery system for brain glioma. Biomaterials 32:4293–4305

    CAS  PubMed  Google Scholar 

  48. Jackson H, Muhammad O, Daneshvar H, et al (2007) Quantum dots are phagocytized by macrophages and colocalize with experimental gliomas. Neurosurgery 60:524–530

    PubMed  Google Scholar 

  49. Rosenblum D, Joshi N, Tao W et al (2018) Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun 9:1–12

    Google Scholar 

  50. Amirshaghaghi A, Altun B, Nwe K et al (2018) Site-specific labeling of cyanine and porphyrin dye-stabilized nanoemulsions with affibodies for cellular targeting. J Am Chem Soc 140:13550–13553

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

National Institutes of Health (R01EB029238 to A.T., R21 EB023989 to A.T., R01NS100892 to Z.C., R01CA175480 to Z.C., P01CA087971 to T.M.B., P30CA016520 to Z.C., T.M.B., and A.T., R01CA236362 to T.M.B.); National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR000003 to JYKL, TL1TR001880 to SS Cho); The U. of Penn. University Research Foundation Award to A.T.; Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania to JYKL;

Author information

Author notes

  1. Clare W. Teng and Ahmad Amirshaghaghi contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Hospital of the University of Pennsylvania, 801 Spruce Street, 8th Floor, Philadelphia, PA, 19107, USA

    Clare W. Teng, Steve S. Cho, Emma De Ravin, Yash Singh & John Y. K. Lee

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Clare W. Teng, Steve S. Cho & Emma De Ravin

  3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Ahmad Amirshaghaghi, Shuting S. Cai, Zhiliang Cheng & Andrew Tsourkas

  4. Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Joann Miller, Saad Sheikh, Theresa M. Busch & Jay F. Dorsey

  5. Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA

    Edward Delikatny

  6. Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Sunil Singhal

Authors
  1. Clare W. Teng
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Contributions

CWT and AA contributed equally to this work. CWT, AA, AT and JYKL designed the research; CWT, AA, SS Cho, SS Cai, EDR, YS performed the research; JM, S. Sheikh, ED, ZC, TMB, JFD, S Singhal supplied critical research resource and space; CWT, AA and SS Cho analyzed data; CWT and AA wrote the manuscript. All authors edited and reviewed the final manuscript.

Corresponding author

Correspondence to John Y. K. Lee.

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The authors declare no conflict of interest.

Ethical approval

All animal procedus were conducted according to a protocol approved by the Institutional Animal Care and Use Committee at the University of Pennsylvania (#805979, #806516) and NIH and ARRIVE guidelines.

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Teng, C.W., Amirshaghaghi, A., Cho, S.S. et al. Combined fluorescence-guided surgery and photodynamic therapy for glioblastoma multiforme using cyanine and chlorin nanocluster. J Neurooncol 149, 243–252 (2020). https://doi.org/10.1007/s11060-020-03618-1

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