Background Paclitaxel (PTX) is a potent anti-cancer chemotherapeutic agent and is widely used in the treatments of solid tumors, particularly of the breast and ovaries. An effective and safe micellar formulation of PTX was used to administer higher doses of PTX than Taxol？ (the current commercialized drug). We hypothesize that PTX-loaded micelles (M-PTX) may enhance tumor radiosensitivity by increasing the tumor oxygenation (pO2). Our goals were (i) to evaluate the contribution of the “oxygen effect” to the radiosensitizing effect of PTX; (ii) to demonstrate the therapeutic relevance of the combination of M-PTX and irradiation and (iii) to investigate the underlying mechanisms of the observed oxygen effect. Methodology and Principal Findings We used (PEG-p-(CL-co-TMC)) polymeric micelles to solubilize PTX. pO2 was measured on TLT tumor-bearing mice treated with M-PTX (80 mg/kg) using electron paramagnetic resonance (EPR) oximetry. The regrowth delay following 10 Gy irradiation 24 h after M-PTX treatment was measured. The tumor perfusion was assessed by the patent blue staining. The oxygen consumption rate and the apoptosis were evaluated by EPR oximetry and the TUNEL assay, respectively. EPR oximetry experiments showed that M-PTX dramatically increases the pO2 24 h post treatment. Regrowth delay assays demonstrated a synergy between M-PTX and irradiation. M-PTX increased the tumor blood flow while cells treated with M-PTX consumed less oxygen and presented more apoptosis. Conclusions M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO2 can be explained both by an increased blood flow and an inhibition of O2 consumption.
References
[1]
Singla AK, Garg A, Aggarwal D (2002) Paclitaxel and its formulations, Int. J. Pharm(235): 179–92.
[2]
Adams JD, Flora KP, Goldspiel BR, Wilson JW, Arbuck SG, et al. (1993) Taxol: a history of pharmaceutical development and current pharmaceutical concerns, J. Natl. Cancer Inst. Monogr. pp. 141–47.
[3]
Milas L, Hunter N, Mason KA, Milross C, Peters LJ (1995) Tumor reoxygenation as a mechanism of taxol-induced enhancement of tumor radioresponse, Acta Oncol. 34: 409–412.
[4]
Tishler RB, Geard CR, Hall EJ, Schiff PB (1992) Taxol sensitizes human astrocytoma cells to radiation, Cancer Res. 52: 3495–97.
[5]
Milas L, Hunter NR, Mason KA, Milross CG, Saito Y, et al. (1995) Role of reoxygenation in induction of enhancement of tumor radioresponse by paclitaxel, Cancer Res. 55: 3564–68.
[6]
Overgaard J (2007) Hypoxic radiosensitization: adored and ignored. J. Clin. Oncol. 25: 4066–74.
[7]
Gallez B, Baudelet C, Jordan BF (2004) Assessment of tumor oxygenation by electron paramagnetic resonance: principles and applications, NMR Biomed. 17: 240–62.
[8]
Vaupel P, Kelleher DK, Thews O (1998) Modulation of tumor oxygenation, Int. J. Radiat. Oncol. Biol. Phys. 42: 843–48.
[9]
Danhier F, Magotteaux N, Ucakar B, Lecouturier N, Brewster M, et al. (2009) Novel self-assembling PEG-p-(CL-co-TMC) polymeric micelles as safe and effective delivery system for Paclitaxel, Eur. J. Pharm. Biopharm. 73: 230–38.
[10]
Maeda H (2001) The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting, Adv. Enzyme Regul(41): 189–207.
[11]
Danhier F, Feron O, Préat V (2010) To exploit the tumor microenvironment: passive and active tumor targeting of nanocarriers for anti-cancer drug delivery. J. Control. Rel. 148: 135–146.
[12]
Ould-Ouali L, Arien A, Rosenblatt J, Natan A, Twaddle T, et al. (2004) Biodegradable self-assembling PEG-copolymer as vehicle for poorly water-soluble drugs, Pharm. Res. 21: 1581–90.
[13]
Taper HS, Woolley GW, Teller MN, Lardis MP (1966) A new transplantable mouse liver tumor of spontaneous origin, Cancer Res. 26: 143–48.
[14]
14. Gallez B, Jordan BF, Baudelet C, Misson PD (1999) Pharmacological modifications of the partial pressure of oxygen in murine tumors: evaluation using in vivo EPR oximetry, Magn Reson. Med. 42: 627–30.
[15]
Jordan BF, Misson P, Demeure R, Baudelet C, Beghein N, et al. (2000) Changes in tumor oxygenation/perfusion induced by the no donor, isosorbide dinitrate, in comparison with carbogen: monitoring by EPR and MRI, Int. J. Radiat. Oncol. Biol. Phys. 48: 565–70.
[16]
Ansiaux R, Baudelet C, Jordan BF, Beghein N, Sonveaux P, et al. (2005) Thalidomide radiosensitizes tumors through early changes in the tumor microenvironment. Clin. Cancer Res. 11: 743–50.
[17]
Crokart N, Jordan BF, Baudelet C, Beghein N, Sonveaux P, et al. (2005) Early reoxygenation in tumors after irradiation: determining factors and consequences for radiotherapy regimens using daily multiple fractions, Int. J. Radiat. Oncol. Biol. Phys. 63: 901–10.
[18]
James PE, Jackson SK, Grinberg OY, Swartz HM (1995) The effects of endotoxin on oxygen consumption of various cell types in vitro: an EPR oximetry study, Free Radic. Biol. Med. 18: 641–47.
[19]
Jordan BF, Sonveaux P, Feron O, Gregoire V, Beghein N, et al. (2003) Nitric oxide-mediated increase in tumor blood flow and oxygenation of tumors implanted in muscles stimulated by electric pulses, Int. J. Radiat. Oncol. Biol. Phys. 55: 1066–73.
[20]
20. Milross CG, Mason KA, Hunter NR, Terry NH, Patel N, et al (1997) Enhanced radioresponse of paclitaxel-sensitive and -resistant tumours in vivo, Eur. J. Cancer 33: 1299–308.
[21]
Ansiaux R, Baudelet C, Cron G, Segers J, Dessy C, et al. (2006) Botulinium toxin potentiates cancer radiotherapy and chemotherapy. Clin. Cancer Res. 12: 1276–83.
[22]
Diepart C, Karroum O, Magat J, Feron O, Verrax J, et al. (2012) Arsenic trioxide treatment decreases the oxygen consumption rate of tumor cells and radiosensitizes solid tumors. Cancer Res. 72: 482–90.
[23]
Negishi T, Koizumi F, Uchino H (2006) NK105, a paclitaxel-incorporating micellar nanoparticle, is a more potent radiosensitising agent compared to free paclitaxel. Brit. J. Cancer 95: 601–6.
