Photodynamic Therapy for Prostate Cancer

前列腺癌的光动力疗法

基本信息

批准号：
6623450
负责人：
GANG ZHENG
金额：
$ 15.85万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-02 至 2005-03-31
项目状态：
已结题

项目摘要

The overall objective of this project is to develop bacteriochlorophyll- carotenoid based molecular beacons (BChl-MB) as prostate cancer (CaP)-specific photosensitizers for photodynamic therapy (PDT). The basic concept underlying this proposal is depicted in Figure 1. We propose to synthesize a molecular beacon (MB) consisting of any antisense oligodeoxynucleotide (AS-ON) sequence complementary to an mRNA specific for the target cancer cells. The MB contains a single- stranded DNA that can form a stem-loop structure. The loop sequence is an AS-ON. The stem is formed by the annealing of two complementary arm sequences that are on either side of the loop sequence. A dye (D) is attached to the end of one arm and a quencher (Q) is similarly attached to the other end. Proximity of D and Q quenches fluorescence and photoreactivity of the dye by energy transfer. In the presence of the tumor specific mRNA, the MB hybridizes with the mRNA, disrupting the hydrogen bonds of the stem. The quencher is removed from the immediate vicinity of the dyne. Upon irradiating with light, the dye emits fluorescence and generates cytotoxic singlet oxygen. The beacon serves both as a directed photodynamic therapy (PDT) agent and as a tumor specific diagnostic agent. We are proposing to synthesize BCh1-Mbs [in Fig. 1 D= bacteriochlorophyll (BCh1), Q= carotenoid (Car)] containing stem-loop AS-ON sequence targeted at the DD3 mRNA.. We have selected DD3 as the molecular target because it is one of the most CaP- specific genes described to date and is highly over-expressed in CaP. Such MB based PDT agents should be CaP-specific. We will focus on the synthesis of the BChl-MB that can hybridize with DD3 mRNA resulting in the significant increase of the fluorescence and the singlet oxygen production. We will develop cell-specific peptides as delivery reagents fort Bchl-MB and confirm that this agent reaches the target sites. Finally, we will validate the concept of MB based PDT agents in two human prostate cancer cell lines. Finally, we will validate the concept of MB based PDT agents in tow human prostate cancer cell lines, LNCaP (over-expressing DD3) and DU145 (not expressing DD3).

该项目的总体目的是开发基于细菌性类胡萝卜素的分子信标（BCHL-MB）作为前列腺癌（CAP） - 特定于光动力疗法（PDT）的特异性光敏剂。该提案的基本概念如图1所示。我们建议合成由任何反义寡脱氧核苷酸（AS-ON）序列组成的分子信标（MB）。 MB包含一个可以形成茎环结构的单链DNA。循环序列是按摩。该茎是通过在环序序列两侧的两个互补臂序列退火而形成的。染料（d）连接到一个臂的末端，淬灭剂（q）类似地连接到另一端。 D和Q的接近度淬灭染料的荧光和光反应性通过能量转移。在存在肿瘤特异性mRNA的情况下，MB与mRNA杂交，破坏了茎的氢键。淬灭者从Dyne的附近取出。用光照射后，染料会发出荧光并产生细胞毒性单线氧。该信标既可以用作定向的光动力疗法（PDT）剂，又是肿瘤特异性诊断剂。我们提议合成BCH1-MBS [在图1 d =细菌（BCH1）中，Q =类胡萝卜素（CAR）]包含靶向DD3 mRNA的STEM环AS-ON序列。我们选择了DD3作为分子靶标的DD3，因为它是对日期和表达最多的capspempterspempters capspersspersspersspersspersspersspect。此类基于MB的PDT代理应具有帽特异性。我们将专注于可以与DD3 mRNA杂交的BCHL-MB的合成，从而导致荧光和单线氧的产生显着增加。我们将开发特异性细胞特异性肽作为递送试剂BCHL-MB，并确认该药物到达目标位点。最后，我们将验证在两个人类前列腺癌细胞系中基于MB的PDT药物的概念。最后，我们将验证人类前列腺癌细胞系，LNCAP（过表达DD3）和DU145（未表达DD3）中基于MB的PDT药物的概念。