F8-SIP mediated targeted photodynamic therapy leads to microvascular dysfunction and reduced glioma growth
- 252 Downloads
The extra domain A (ED A) of fibronectin has been identified as a tumor vessel specific neovascular marker in glioma. Antibody based vascular targeting against ED A of fibronectin allows precise accumulation of photosensitizer in glioma microvasculature and thereby promises to overcome drawbacks of current photodynamic therapy (PDT) for glioma treatment. Our aim was to characterize microcirculatory consequences of F8-small immunoprotein (SIP) mediated PDT by intravital microscopy (IVM) and to analyze the effects on glioma growth. For IVM SF126 glioma cells were implanted into dorsal skinfold-chamber of nude mice. PDT was performed after intravenous injection of photosensitizer (PS)-coupled F8-SIP or PBS (n = 4). IVM was performed before and after PDT for 4 days. Analysis included total and functional (TVD, FVD) vessel densities, perfusion index (PI), microvascular permeability and blood flow rate (Q). To assess tumor growth SF126 glioma cells were implanted subcutaneously. PDT was performed as a single and repetitive treatment after PS-F8-SIP injection (n = 5). Subcutaneous tumors were treated after uncoupled F8-SIP injection as control group (n = 5). PDT induced microvascular stasis and thrombosis with reduced FVD (24 h: 115.98 ± 0.7 vs. 200.8 ± 61.9 cm/cm2) and PI (39 ± 11 vs. 70 ± 10 %), whereas TVD was not altered (298 ± 39.2 vs. 278.2 ± 51 cm/cm2). Microvascular dysfunction recovered 4 days after treatment. Microvascular dysfunction led to a temporary reduction of glioma growth in the first 48 h after treatment with complete recovery 5 days after treatment. Repetitive PDT resulted in sustained reduction of tumor growth. F8-SIP mediated PDT leads to microvascular dysfunction and reduced glioma growth in a preclinical glioma model with recovery of microcirculation 4 days after treatment. Repetitive application of PDT overcomes microvascular recovery and leads to prolonged antiglioma effects.
KeywordsVascular targeting PDT F8-SIP Intravital microscopy
This study was funded by the Immuno-PDT consortium and the Berliner Krebsgesellschaft e.V.
Compliance with ethical standards
Conflict of interest
H.D.M. was a senior director at Bayer Schering Pharma and owns few regular stocks from an employee stock purchase plan since February 2008. Dario Neri is a co-founder and shareholder of Philogen, the biotech company which has inlicensed the F8 antibody from ETH Zurich. The remaining authors declare no competing conflicts of interest.
- 7.Villa A, Trachsel E, Kaspar M, Schliemann C, Sommavilla R, Rybak J-N, Rösli C, Borsi L, Neri D (2008) A high-affinity human monoclonal antibody specific to the alternatively spliced EDA domain of fibronectin efficiently targets tumor neo-vasculature in vivo. Inte J cancer 122(11):2405–2413CrossRefGoogle Scholar
- 9.Palumbo A, Hauler F, Dziunycz P, Schwager K, Soltermann A, Pretto F, Alonso C, Hofbauer GF, Boyle RW, Neri D (2011) A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels. Br J Cancer 104(7):1106–1115CrossRefPubMedPubMedCentralGoogle Scholar
- 12.Beck TJ, Kreth FW, Beyer W, Mehrkens JH, Obermeier A, Stepp H, Stummer W, Baumgartner R (2007) Interstitial photodynamic therapy of nonresectable malignant glioma recurrences using 5-aminolevulinic acid induced protoporphyrin IX. Lasers Surg Med 39(5):386–393. doi: 10.1002/lsm.20507 CrossRefPubMedGoogle Scholar
- 13.Muragaki Y, Akimoto J, Maruyama T, Iseki H, Ikuta S, Nitta M, Maebayashi K, Saito T, Okada Y, Kaneko S, Matsumura A, Kuroiwa T, Karasawa K, Nakazato Y, Kayama T (2013) Phase II clinical study on intraoperative photodynamic therapy with talaporfin sodium and semiconductor laser in patients with malignant brain tumors. J Neurosurg 119(4):845–852. doi: 10.3171/2013.7.JNS13415 CrossRefPubMedGoogle Scholar
- 17.Lawrence JE, Steele CJ, Rovin RA, Belton RJ Jr, Winn RJ (2015) Dexamethasone alone and in combination with desipramine, phenytoin, valproic acid or levetiracetam interferes with 5-ALA-mediated PpIX production and cellular retention in glioblastoma cells. J Neurooncol. doi: 10.1007/s11060-015-2012-x Google Scholar
- 19.Yi W, Xu HT, Tian DF, Wu LQ, Zhang SQ, Wang L, Ji BW, Zhu XN, Okechi H, Liu G, Chen QX (2015) Photodynamic therapy mediated by 5-aminolevulinic acid suppresses gliomas growth by decreasing the microvessels. J Huazhong Univ Sci Technol Med Sci 35(2):259–264. doi: 10.1007/s11596-015-1421-6 CrossRefPubMedGoogle Scholar