激光引发喷酒HpD增强肿瘤的光动力效应

光动力学疗法主要副作用之一是皮肤光敏反应。我们研制了激光引发微型喷药装置，直接喷射给药以减少皮肤光敏反应。以小鼠Ｓ－１８０实体移植瘤为模型。腹腔注射和肿瘤表面喷药两种给药方法，但剂量相同。用荧光分光光度法检测给药后不同时间内肿瘤、血液和皮肤的ＨｐＤ浓度，发现给药后３ｈ￣１６８ｈ肿瘤内ＨｐＤ浓度，Ｓ．Ｔ．法明显高于Ｉ．Ｐ法，而皮肤ＨｐＤ浓度恰好相反，Ｉ．Ｐ．法高于Ｓ．Ｔ．法，肿瘤与皮肤ＨｐＤ浓度之比     

氩离子激光＋HpD照射血管瘤动物模型的组织学变化

本文用氩离子激光照射鸡垂（ｗａｔｔｌｅ）．分为注射ＨｐＤ和对照组，在１、３、７、１４、２８天取材，观察了肉眼和组织学变化，并对ＨｐＤ组的血清荧光进行了监测。组织学结果表明：ＨｐＤ组病变反应完全，坏死层、渗出层均较对照组显著，对血管的破坏更完全。血清中的荧光随时间衰减，至２４小时基本排泄完。鸡垂组织匀浆上清液中的荧光在２４小时内衰减较快，后趋于平缓。正常组的血清荧光和鸡垂组织匀浆上清液荧光在同样测试条件下均无荧光峰值出现，表现为一低水平的直线。     

光动力作用对活体肝组织损伤研究

目的 研究光动力作用对活体肝组织的损伤,探讨光动力治疗肝癌的可行性,为临床治疗提供实验依据。方法 动物实验：将小鼠分成光动力疗法（ＰＤＴ）组、单血卟啉衍生物（ＨｐＤ）组、浙江组和空白对照组。光敏药物选用血卟啉衍生物,给药量每公拆体重１０ｍｇ,药物用１ｍｌ生理盐水稀释,于实验前４８ｈ将药物注射入ＰＤＴ组和ＨｐＤ组小鼠腹腔内,避光饲养。将ＰＤＴ组和激光组小鼠固定于褓反上。麻醉后,剖腹暴露右肝前叶,激光     

激光引发喷洒HpD增强肿瘤的光动力效应

光动力学疗法（ＰＤＴ）主要副作用之一是皮肤光敏反应。我们研制了激光引发微型喷药装置，直接喷射给药以减少皮肤光敏反应。以小鼠Ｓ－１８０实体移植瘤为模型。腹腔注射（Ｉ．Ｐ．）和肿瘤表面喷药（Ｓ．Ｔ．）两种给药方法，但剂量相同。用荧光分光光度法检测给药后不同时间内肿瘤、血液和皮肤的ＨｐＤ浓度，发现给药后３ｈ～１６８ｈ肿瘤内ＨｐＤ浓度，Ｓ．Ｔ．法明显高于Ｉ．Ｐ．法（Ｐ＜０．０１），而皮肤ＨｐＤ浓度恰好相反，Ｉ．Ｐ．法高于Ｓ．Ｔ．法。肿瘤与皮肤ＨｐＤ浓度之比，Ｓ．Ｔ．法明显高于Ｉ．Ｐ．法（Ｐ＜０．０１），提示此方法可能提高肿瘤的光动力学效果，减轻皮肤光敏反应和全身损害。两种方法给药３ｈ及２４ｈ后的ＰＤＴ治疗，较对照组均能延迟肿瘤生长（Ｐ＜０．０１），其中以Ｓ．Ｔ．法３ｈ后照光效果最佳，说明该方法确能增强光动力学效应，其机理可能主要是对肿瘤的直接损伤。     

^131I标记血卟啉衍生物及其在膀胱癌放射显象中的应用

为了解血卟啉衍生物（ＨｐＤ）在体内的分布情况，利用放射性核素１３１Ｉ标记ＨｐＤ，制备成１３１Ｉ－ＨｐＤ，将其静脉注入带有膀胱移行细胞癌的裸小鼠体内，显示１３１Ｉ－ＨｐＤ在裸小鼠体内相对稳定，并随着时间延长，肿瘤组织中相对放射性强度逐渐增高。对６例膀胱癌患者静脉注射１３１Ｉ－ＨｐＤ后２４、４８、７２小时膀胱区γ闪烁显象，其中５例表现为放射性浓聚区，其位置与手术中所见肿瘤位置相同；１例显象阴性，术中见散在的小肿瘤。说明ＨｐＤ对肿瘤定位、导向治疗有一定意义。     

光动力治疗过程中组织内光衰减的实时测量

采用计算机辅助的光子计数装置实时测量了ＰＤＴ过程中实验肿瘤Ｓ１80内透射光密度的变化，结果观察到透射光密度呈下降趋势，应用ＨｐＤ的肿瘤内光密度变化与无ＨｐＤ肿瘤内光密度变化相比，有显著性差异（Ｐ＜０．０１）。     

光动力疗法联合局部化疗治疗上消化道癌的研究

为了提高光动力疗法（ＰＤＴ）的治癌效果，应用ＰＤＴ与瘤内注射氟尿嘧啶（５－Ｆｕ）治疗小鼠前胃癌移植瘤。治疗后各组移植瘤细胞ＤＮＡ含量和标记指数（ＬＩ）均较治疗前明显减少，而联合治疗组的减少较单纯ＰＤＴ或瘤内注射５－Ｆｕ组更为显著。又应用ＰＤＴ治疗进展期食管、贲门癌患者８０例，并对其中４０例联合应用内镜下局部注射５－Ｆｕ。结果：ＰＤＴ组的近期显效率为２２．５％（９／４０），联合治疗组显效率为４５．０％（１８／４０），高于ＰＤＴ组（Ｐ＜０．０５）。病例随访１２月～１８月，联合治疗组的平均生存期（３７４天）较ＰＤＴ组（２６６天）延长（Ｐ＜０．０１）。认为ＰＤＴ与局部注射５－Ｆｕ联合治疗上消化道癌，能协同提高ＰＤＴ的治疗效果。     

放射性碘标记CL—3体外肿瘤细胞结合及瘤内注射动物实验研究

为评价瘤内注射＾１３１Ｉ标记单抗对提高肿瘤放射免疫治疗效果的作用。用＾１２５Ｉ标记抗人结肠癌单抗ＣＬ－３，测定与人结肠癌细胞系ＬＳ１７４Ｔ及人胃印细胞癌细胞系（ＫＡＴＯⅢ的结合率。用３４只ＬＳ１７４Ｔ荷瘤裸鼠，在瘤内注射＾１３１Ｉ－ＣＬ－３后１、３、５、１７天进行体内分布与放射免疫显像，以腹腔注射及＾１３１Ｉ－正常鼠ＩｇＧ瘤内注射组作对照，结果：＾１２５Ｉ－ＣＬ－３与ＬＳ１７４Ｔ及ＫＡＴＯⅢ细胞结     

放射自显影术用于裸鼠LS174T移植瘤瘤内注射^125I—CL—3后的分…

为经瘤内注射途径进行肿瘤放射免疫治疗提供组织学实验依据，在裸鼠ＬＳ１７４Ｔ移植瘤生长至－１ｃｍ时，瘤内分别注射＆１２５Ｉ标记的小鼠抗人结肠癌单发和正常小鼠ＩｇＧ或腹腔注射ＣＬ－３，３天后取出肿瘤并制备连续切片，用放射自显影术观察＾１２５Ｉ标记抗体的分布。     

光动力疗法合并化学疗法治疗恶性肿瘤的实验研究

我们对人癌ＨｅＬａ细胞株的裸鼠接种瘤进行了光动力疗法（ＰＤＴ）联合应用肿瘤ＤＮＡ合成酶抑制剂，目的在于探讨增强ＰＤＴ作用的有效途径。观察到在本实验条件下，仅做激光照射或单纯采用抗癌剂，对这种移植癌均无抗肿瘤作用；ＰＤＴ组的肿瘤生长阻止率为３５．１％～４７．９％，而ＰＤＴ并用化疗组的肿瘤生长阻止率达８０％～９５％。研究表明，ＰＤＴ合并应用化学疗法比单独实施ＰＤＴ对抑制肿瘤生长、破坏肿瘤组织的效应显著     

Tumor therapy with hematoporphyrin derivative and lasers via a percutaneous fiberoptic technique: preclinical experiments

Photodynamic therapy relies on uptake of a photosensitizer (hematoporphyrin derivative [HpD]) by tumor cells and subsequent interaction of the photosensitizer with penetrating light. This technique has been applied in multiple animal systems and several clinical trials. The therapeutic results in large, deep tumors are limited by poor uptake and distribution of the HpD and limited penetration of tumors by light, even at high wavelengths. In various experiments with mice, HpD was injected into tumors, and light was applied via laser fiberoptics inserted through a sheath catheter. Preliminary findings indicated that intratumoral injection enables excellent distribution of HpD in high concentrations, thus optimizing the sensitivity of the tumor cells. The sheath catheter and fiberoptics enable excellent distribution of light. Experiments with T-cell lymphomas demonstrated significant response of the tumors to the combination of intratumoral HpD and interstitial light application.     

应用三磺酸铝酞菁进行实验性光动力治疗和荧光定位诊断的初步观察

本文总结了激光与三磺酸铝酞菁（ＡＩＳＰｃ）诊断治疗移植瘤的系列研究，实验共分三部分：实验一以小鼠移植瘤──乳腺癌为实验模型、处死后荧光光谱分析的诊断研究；实验二小鼠移植瘤──肝癌为实验模型的活体荧光检测的诊断研究；实验三小鼠移植瘤──肝癌为实验模型的光敏治疗研究。结果证明ＡＩＳＰｃ在体内清除速度快，光毒反应低，特征荧光峰的相对荧光强度在ＡＩＳＰｃ注入机体后２４～４８小时时肿瘤与正常组织的反差最大。分别与胃内、皮肤内荧光强度比较，经ｔ检验Ｐ＜０．０５，差异有显著性。注射ＡＩＳＰｃ的小鼠移植瘤经激光照射后２４小时照光部位结痂变黑，肿瘤生长速度明显受抑，较对照组照光前、后５天肿瘤面积差值经秩和检验多组比较得Ｐ＜０．０５，差异显著，证明ＡＩＳＰｃ既可用于恶性肿瘤的诊断，又可用于治疗，是一种很有发展前途的新光敏剂。     

Improved radiolabeled monoclonal antibody uptake by lavage of intraperitoneal carcinomatosis in mice

The effect of peritoneal lavage with saline on tumor and systemic uptake of intraperitoneally administered tumor-specific (131I-5G6.4) and nonspecific (125I-UPC-10) radiolabeled monoclonal antibodies was evaluated in a nude mouse model of human intraperitoneal ovarian carcinomatosis (IP3 model). Peritoneal lavage at 2 or 6 hr postintraperitoneal antibody injection significantly improves intraperitoneal tumor/nontumor uptake ratios of specific antibody apparently by limiting systemic exposure to antibody. This enhancement tends to be more dramatic if lavage is performed within 2 hr, rather than 6 hr, of intraperitoneal antibody administration, though both times result in significant improvements in target/background ratios over no lavage. Twenty-four-hour tumor/nontumor ratios for specific antibody 5G6.4 generally are 1.5-fourfold higher following lavage than those achieved in control animals, without decreasing absolute tumor uptake of specific radiolabeled antibody. By contrast, nonspecific antibody UPC-10 binding is lower in tumor and normal tissues following lavage, with no lavage-induced improvement in tumor/nontumor ratios seen. Peritoneal lavage is a simple method to allow for specific antibody binding to accessible intraperitoneal tumors yet to limit systemic exposure thus increasing the therapeutic margin. This method may have considerable applicability in the enhancement of intraperitoneal immunoconjugate delivery to intraperitoneal tumors.     

Properties of [(111)In]-labeled HIV-1 tat peptide radioimmunoconjugates in tumor-bearing mice following intravenous or intratumoral injection

INTRODUCTION: Our objective was to evaluate the tumor and normal tissue distribution and nuclear importation properties of [(111)In]-mouse IgG (mIgG) conjugated to tat peptides (GRKKRRQRRRPPQGYG) in athymic mice with subcutaneous BT-474 human breast cancer xenografts. METHODS: Tumor and normal tissue uptake was compared after intravenous (iv) or intratumoral injection of [(111)In]-mIgG-tat and [(111)In]-mIgG. Area under the curve (AUC) was estimated for blood, liver, spleen, kidneys and tumor. Nuclear localization was measured by subcellular fractionation and estimated by microdosimetry. Imaging studies were performed with a gamma-camera. RESULTS: [(111)In]-mIgG-tat was eliminated from the blood and normal tissues two- to threefold more rapidly after iv injection than [(111)In]-mIgG. Tumor uptake was 4-5% injected dose per gram (%ID/g). Tumor radioactivity after intratumoral injection was initially very high (146-154 %ID/g), but declined 12- to 14-fold by 144 h postinjection. There was greater retention of [(111)In]-mIgG-tat in BT-474 tumors after intratumoral than iv injection, and the AUC (610+/-157 %ID h) was threefold greater than for intratumorally injected [(111)In]-mIgG (200+/-37 %ID h). Tat peptides increased nuclear localization of [(111)In]-mIgG after iv injection in tumor, kidney and liver cells, but only in tumor cells after intratumoral injection. Tumors were not imaged after iv administration but were predominant with intratumorally injected [(111)In]-mIgG and [(111)In]-mIgG-tat. Estimated radiation doses to the nucleus of tumor cells from intratumoral [(111)In]-mIgG-tat were 2.8x10(3) mGy/MBq and were 15-fold higher than for iv injection. CONCLUSION: [(111)In]-labeled tat immunoconjugates may have potential for imaging intracellular epitopes or localized Auger electron radiotherapy of tumors.     

CT-guided laser therapy in resistant human tumors: phase I clinical trials

Photodynamic therapy was performed on ten tumors in patients who did not respond to initial therapy and for whom no additional conventional therapy was available. A sensitizing agent (hematoporphyrin derivative [HpD]) was injected directly into each tumor under computed tomographic (CT) guidance to deliver high concentrations to the tumor and to minimize systemic toxicity. Three to 6 days after the injection, a clear Teflon sheath catheter was placed into the tumor under CT guidance. The tumor was exposed to red light (630-nm wavelength) through laser fiberoptics inserted in the sheath. The initial investigation confirmed the technical feasibility of CT-guided photodynamic therapy by means of intratumoral HpD injections and laser exposure through fiberoptics inserted in sheath catheters. The toxicity from a single treatment was minor, and the tumor response was encouraging.     

32P-磷酸铬间质给药在荷人胰腺癌裸鼠的体内生物学分布及形态学表现

目的 研究^32P-磷酸铬(^32P胶体)瘤体间质给药治疗BALB／c—nu／nu裸鼠荷人胰腺癌(Pc-3)移植瘤时在体内相应组织中的分布、药代动力学特点及全身毒性反应。方法 51只荷瘤裸鼠，经瘤体给予不同剂量^32P胶体或尾静脉给药，分批处死，动态观察^32P胶体在裸鼠体内放射性分布和组织器官形态学表现，观察体重变化和计数WBC和PLT，测量瘤体表面放射性计数率。结果 ^32P胶体瘤体间质注射后其放射性计数率明显高于其他器官组织，器官组织放射性计数率瘤体给药明显低于尾静脉给药。增体给药有效半减期为13d。形态学检查显示给药后大部分Pc-3细胞被破坏，并出现分化较好的瘤细胞；肝、脾、肺及淋巴结等重要器官组织的辐射损伤为可逆性．未见明显骨髓抑制现象。结论 ^32P胶体瘤体间质给药是治疗胰腺癌安全、简便、有效的核素介入疗法。     

~(131)Ⅰ-HpD在小鼠体内的吸收、分布和排泄

血卟啉衍生物（即HpD，定位标记为131I-HpD），经小鼠尾静脉注射后，血药浓度下降较快，全身分布迅速广泛，24至32小时变化较为平缓，32小时后几无变化。肺、脾、肝分布较多，肌肉最少，其它组织介于中间，8小时后血液、甲状腺、肺、肝、大腿肌肉等组织呈下降趋势，而肿瘤组织分布相对较多。与其它组织（肺肝除外）相比，具有相对选择性吸收和潴留作用，这种作用在24小时后较为明显。该药72小时内粪排量（57．5％）大于尿排量（42．5％）。血中放射性一时间曲线符合开放二室模型。     

血卟啉衍生物静脉注射后在皮肤中分布的实验研究

目的探讨鲜红斑痣光动力学疗法中血卟啉衍生物（ＨｐＤ）的理想剂量和理想照光时间。方法５组实验用新西兰白兔（每组６只）分别按２、３、５、７、１０ｍｇ／ｋｇ静脉注射ＨｐＤ,采用快速冰冻切片技术,于荧光显微镜下观察不同时间ＨｐＤ在真皮血管内、真皮血管外间质和表皮的分布情况。结果ＨｐＤ在真皮浅层血管内出现时间,２、３ｍｇ／ｋｇ二组为１５ｍｉｎ,５、７、１０ｍｇ／ｋｇ三组为５ｍｉｎ;ＨｐＤ在真皮血管外间质出现时间,各组依次为６０、６０、３０、１５、５ｍｉｎ;ＨｐＤ在表皮出现时间,３、５、７、１０ｍｇ／ｋｇ各组依次为９０、６０、３０、５ｍｉｎ,２ｍｇ／ｋｇ组观察至１２０ｍｉｎ未出现。结论运用光动力学疗法治疗鲜红斑痣的剂量应掌握在３～５ｍｇ／ｋｇ之间,注射完毕后即可开始照光,３ｍｇ／ｋｇ时照光时间不宜超过９０ｍｉｎ,５ｍｇ／ｋｇ时不宜超过６０ｍｉｎ。     

光动力疗法治疗鲜红斑痣的基础研究—血啉甲醚与血卟啉衍生物吸收特性的比较

目的　观察新型光敏剂——血啉甲醚(HMME)在鸡冠皮肤组织和血管内皮细胞(EC)的吸收特点。 方法　莱亨鸡12只,分为HMME组和血卟啉衍生物(HpD)组,每组6只。分别静脉注射HMME或HpD10mg/kg,每隔10min取血2.5ml和鸡冠皮肤组织2.5g。培养新生儿脐带EC,培养液中加入HMME或HpD,孵育浓度分别为20、40、60、80和100 μg/ml,孵育时间为即刻、15、30、60、120、180和240min。采用荧光分析法测定光敏剂含量,并绘制EC吸收光敏剂的浓度—含量和时间—含量关系曲线。 结果　静脉注射HMME或HpD后,其血清浓度的峰值出现在注射后10min,以后随时间迅速下降,二者的曲线形态基本一致。HMME在鸡冠组织中的含量于注射后10min显著高于HpD（P＜0.01）,以后虽然下降速率较快,但在注射后80min仍显著高于HpD（P＜0.05）。培养EC可迅速吸收HMME和HpD,30min达峰值的89%以上;其吸收量与孵育浓度呈线性关系,对HMME的吸收量显著高于HpD（P＜0.01）。 结论　HMME较HpD更容易被皮肤微血管EC摄取,这将有利于鲜红斑痣的治疗。     

Comparison of the Intraperitoneal,Retroorbital and per Oral Routes for F-18 FDG Administration as Effective Alternatives to Intravenous Administration in Mouse Tumor Models Using Small Animal PET/CT Studies

Purpose

We compared alternative routes for ¹⁸F-fluorodeoxyglucose (FDG) administration, such as the retroorbital (RO), intraperitoneal (IP) and per oral (PO) routes, with the intravenous (IV) route in normal tissues and tumors of mice.

Materials and Methods

CRL-1642 (ATCC, Lewis lung carcinoma) cells were inoculated in female BALB/c-nu/nu mice 6 to 10 weeks old. When the tumor grew to about 9 mm in diameter, positron emission tomography (PET) scans were performed after FDG administration via the RO, IP, PO or IV route. Additional serial PET scans were performed using the RO, IV or IP route alternatively from 5 to 29 days after the tumor cell injection.

Results

There was no significant difference in the FDG uptake in normal tissues at 60 min after FDG administration via RO, IP and IV routes. PO administration, however, showed delayed distribution and unwanted high gastrointestinal uptake. Tumoral uptake of FDG showed a similar temporal pattern and increased until 60 min after FDG administration in the RO, IP and IV injection groups. In the PO administration group, tumoral uptake was delayed and reduced. There was no statistical difference among the RO, IP and IV administration groups for additional serial PET scans.

Conclusion

RO administration is an effective alternative route to IV administration for mouse FDG PET scans using normal mice and tumor models. In addition, IP administration can be a practical alternative in the late phase, although the initial uptake is lower than those in the IV and RO groups.