Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: Rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors
Metronomic photodynamic therapy as a new paradigm for photodynamic therapy: Rationale and preclinical evaluation of technical feasibility for treating malignant brain tumors
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DOI：
10.1562/2004-03-05-ra-100.1
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发表时间：
2004-07-01
影响因子：
3.3
通讯作者：
Wilson, BC
中科院分区：
文献类型：
--
作者：
Bisland, SK;Lilge, L;Wilson, BC
提出了节律性光动力疗法(MPDT)的概念，在该疗法中，光敏剂和光在较长时间内以低速率连续输送，通过凋亡来增加肿瘤细胞的选择性杀伤力。目前临床前研究的重点是mPDT治疗恶性脑肿瘤，其中选择性杀伤肿瘤细胞和损伤正常脑组织是至关重要的。以往的研究表明，使用5-氨基乙酰丙酸(ALA)诱导的原卟啉IX(PpIX)的小剂量光动力疗法可以诱导肿瘤细胞凋亡，而不会导致肿瘤或正常脑组织的坏死，也不会导致后者的细胞凋亡。根据已达到的细胞凋亡水平和脑肿瘤生长速度的模型计算，节律传递或多种PDT治疗，如超分割，可能需要产生足够的肿瘤细胞杀伤才能成为有效的治疗方法。体外研究证实，与急性高剂量方案(ALA-APDT)相比，ALA-mPDT诱导更高的细胞凋亡率(末端脱氧核苷酸转移酶介导的2‘-脱氧尿苷5’-三磷酸，钠盐缺口末端标记阳性)。在体内，mPDT带来了两个重大的技术挑战：延长ALA的传递和植入延长光传递的装置，同时允许不受阻碍的运动。在大鼠模型中，ALA通过饮用水以非常高的剂量(高达治疗剂量的10倍)给药长达10天，肿瘤(9L胶质肉瘤)和正常脑的体外荧光光谱显示，PpIX浓度的肿瘤与脑比率增加了3-4倍，没有毒性证据。在mPDT治疗后，组织学染色显示肿瘤周边和周围微侵袭集落内广泛的细胞凋亡，这在治疗前的正常脑或肿瘤中并不明显。原型光源和传输装置被发现是实用的，无论是使用激光二极管或发光二极管(LED)耦合到大鼠模型中植入的光纤，还是使用直接植入的LED(使用兔模型)。证明了在不影响动物生存的情况下，药物和光在较长时间内的联合输送。初步证据表明，在这些条件下，肿瘤发生了选择性的凋亡。
The concept of metronomic photodynamic therapy (mPDT) is presented, in which both the photosensitizer and light are delivered continuously at low rates for extended periods of time to increase selective tumor cell kill through apoptosis. The focus of the present preclinical study is on mPDT treatment of malignant brain tumors, in which selectivity tumor cell killing versus damage to normal brain is critical. Previous studies have shown that low-dose PDT using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) can induce apoptosis in tumor cells without causing necrosis in either tumor or normal brain tissue or apoptosis in the latter. On the basis of the levels of apoptosis achieved and model calculations of brain tumor growth rates, metronomic delivery or multiple PDT treatments, such as hyperfractionation, are likely required to produce enough tumor cell kill to be an effective therapy. In vitro studies confirm that ALA-mPDT induces a higher incidence of apoptotic (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate, sodium salt nick-end labeling positive) cells as compared with an acute, high-dose regimen (ALA-aPDT). In vivo, mPDT poses two substantial technical challenges: extended delivery of ALA and implantation of devices for extended light delivery while allowing unencumbered movement. In rat models, ALA administration via the drinking water has been accomplished at very high doses (up to 10 times therapeutic dose) for up to 10 days, and ex vivo spectro-fluorimetry of tumor (9L gliosarcoma) and normal brain demonstrates a 3-4 fold increase in the tumor-to-brain ratio of PpIX concentration, without evidence of toxicity. After mPDT treatment, histological staining reveals extensive apoptosis within the tumor periphery and surrounding microinvading colonies that is not evident in normal brain or tumor before treatment. Prototype light sources and delivery devices were found to be practical, either using a laser diode or light-emitting diode (LED) coupled to an implanted optical fiber in the rat model or a directly implanted LED using a rabbit model. The combined delivery of both drug and light during an extended period, without compromising survival of the animals, is demonstrated. Preliminary evidence of selective apoptosis of tumor under these conditions is presented.