Pharmaceutics and Drug Delivery, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
PLoS One. 2012;7(7):e40772. doi: 10.1371/journal.pone.0040772. Epub 2012 Jul 12.
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 (pO(2)). 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.
We used (PEG-p-(CL-co-TMC)) polymeric micelles to solubilize PTX. pO(2) 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 pO(2) 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.
M-PTX improved the tumor oxygenation which leads to synergy between this treatment and irradiation. This increased pO(2) can be explained both by an increased blood flow and an inhibition of O(2) consumption.
紫杉醇（PTX）是一种有效的抗癌化疗药物，广泛用于治疗实体瘤，特别是乳腺癌和卵巢癌。我们使用一种有效的、安全的紫杉醇胶束制剂，以比 Taxol®（目前的商业化药物）更高的剂量给予紫杉醇。我们假设紫杉醇负载胶束（M-PTX）可以通过增加肿瘤氧合（pO(2)）来增强肿瘤放射敏感性。我们的目标是：（i）评估“氧效应”对 PTX 放射增敏作用的贡献；（ii）证明 M-PTX 和照射联合治疗的治疗相关性；（iii）研究观察到的氧效应的潜在机制。
我们使用（PEG-p-（CL-co-TMC））聚合物胶束来溶解 PTX。使用电子顺磁共振（EPR）血氧测定法在 M-PTX（80mg/kg）治疗的 TLT 荷瘤小鼠中测量 pO(2)。在 M-PTX 治疗 24 小时后进行 10Gy 照射后的肿瘤再生长延迟测量。通过专利蓝染色评估肿瘤灌注。通过 EPR 血氧测定法和 TUNEL 测定分别评估氧消耗率和细胞凋亡。EPR 血氧测定实验表明，M-PTX 治疗后 24 小时内 pO(2)显著增加。再生长延迟实验表明 M-PTX 和照射之间存在协同作用。M-PTX 增加了肿瘤血流量，同时用 M-PTX 处理的细胞消耗的氧气减少，凋亡增加。
M-PTX 改善了肿瘤氧合，导致这种治疗与照射之间的协同作用。这种 pO(2)的增加既可以通过增加血流量，也可以通过抑制 O(2)消耗来解释。
