CN106488766A - 利用氧气疗法的分割放疗和化疗 - Google Patents
利用氧气疗法的分割放疗和化疗 Download PDFInfo
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- CN106488766A CN106488766A CN201580023252.9A CN201580023252A CN106488766A CN 106488766 A CN106488766 A CN 106488766A CN 201580023252 A CN201580023252 A CN 201580023252A CN 106488766 A CN106488766 A CN 106488766A
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Abstract
一种用于分割放疗和化疗的氟碳乳剂，其中所述氟碳包含4～8个碳原子。
Description
新型所属之技术领域
本创作系指一种氧气疗法的使用并结合化疗给药和/或放疗的反复运用。
创作背景
放射增敏剂是一种使肿瘤细胞对放射治疗更加敏感的药物。放疗的一大主要限制作用就是让实体肿瘤的细胞在氧气中变得稀少。实体肿瘤的增长速度超过血液供应速度，因而会造成一种低氧状态(称为组织缺氧)。氧气是一种强有力的放射增敏剂，通过形成损坏DNA的自由基来增加一次放射的有效性。缺氧环境中的肿瘤细胞可能比正常氧气环境下的细胞对辐照损伤具有超出3倍的耐受力。
创作图式的简要描述
为让本创作更能明显易懂，下文特配合所附图式和标示的内含元素作详细说明如下：其中，
图1A显示了在老鼠中9个Hs-766T胰腺癌肿瘤异种移植物的氧气水平。不同的迹线代表了在9个不同老鼠中的9种肿瘤。每个老鼠都被注射了一个剂量的NVX-108：0.3mL/kg(蓝色迹线)，0.45mL/kg(绿色迹线)或0.6mL/kg(红色迹线)；
图1B显示了3种不同剂量NVX-108水平下，老鼠中Hs-766T胰腺癌肿瘤异种移植物的平均和标准差氧气水平：0.3mL/kg(蓝色迹线，n＝2)，0.45mL/kg(绿色迹线，n＝3)或0.6mL/kg(红色迹线，n＝4)；
图2A显示了3组老鼠中肿瘤增长百分比对比图；
图2B系图2A中两个治疗组的放大图。
较佳实施例的详细描述
本创作在下文中通过较佳实施例并参考图表进行了描述，在图表中同类数字代表相同或相似的元素。本说明书中所指“一个实施例”，“某实施例”或类似用语系指本实施例描述的某个具体特征、结构或特点被包含在本创作的至少一个实施例中。因此，“一实施例”，“某实施例”和贯穿本说明书的类似用语均可能(但不一定)指同一实施例。
本创作中描述的特征，结构或特点可能以任何合适的方式与一个或多个实施例相结合。在下列描述中，许多具体细节被反复引用以便于充分理解本创作的实施例。不过，熟悉此项技术之人士当可在缺乏一个或多个具体细节的情况下，或采用其他方法，成分和材料等实施本创作。在其他情况下，熟知的结构，材料或操作并未详细展示或描述，以避免对本创作引起歧义。
十二氟戊烷乳剂(DDFPe)曾作为一种放疗增敏剂在单次放疗中进行测试。肿瘤(异种移植)被辐射，然后从动物中移除，细胞被分解并测试其生存能力。肿瘤的增长或存活都没有被评估，并且，肿瘤pO2也没有被直接评估。化疗中实施DDFPe的效果也没有被评估。分割放疗中DDFPe的多剂量实施也没有被评估。
在某些实施例中，被治疗的动物是哺乳动物。在某些实施例中，被治疗的动物是人。在某些实施例中，剂量在大约0.01cc/kg到大约1.0cc/kg(2％w/vol DDFPe)之间变化。在某些实施例中，剂量在大约0.05cc/kg到0.3cc/kg之间变化，并通过长达30分钟的注入或单次弹丸推注的方式给药。熟悉此项技术之人士应当会承认，如果乳剂中DDFP的浓度增加(例如5％或10％，按体重计)，则用药量一般会随之减少。优选情况下，研究对象吸入氧气或氧气与二氧化碳的混合气体，例如碳合气，其比例为95％氧气混合5％二氧化碳与98％氧气混合2％二氧化碳之间。
申请人发现碳合气和氧气的使用效果相当，但碳合气有些问题。它必须专门订购，而氧气随处可得。
每次放疗前都静脉注射DDFPe。在某些实施例中，DDFPe作为一种当前临床研发中的用药产品以NVX-108命名。
在先前技术中，相对较高分子量的碳氟化合物已经作为放射增敏剂进行研究。已经作为放射增敏剂研究的材料包括：F-1,3-二甲基金刚烷，F-trimethylbicyclo[3.3.1]壬烷，F-三丁胺(FC-43,3M公司)，全氟萘烷和液态氟碳。
创作者发现，低分子量的碳氟化合物(FC)，尤其是沸点在大约-4摄氏度到大约100摄氏度之间的FC，比更高分子量、更高沸点的FC更加有效。更优选的是沸点在大约20到80摄氏度之间的FC，而更为优选的是沸点在大约28到60摄氏度之间的FC。本创作中使用的FC包括：全氟丁烷，全氟戊烷，全氟己烷，全氟庚烷和全氟辛烷。在最优选的全氟戊烷和全氟己烷中，最优选的是全氟戊烷。
最优选情况下，FC通过高压、温控同质化被制成一种乳剂。多种表面活化剂可以被用来制备乳剂。优选的表面活化剂是磷脂，而优选的磷脂成分包括dioleoylphosphatidylcholine(DOPC)和二油酰磷脂酰乙醇胺-PEG-5000(DOPE-PEG 5k)。另一种优选的磷脂混合物包括二棕榈酰磷脂酰胆碱(DPPC)和二棕榈酰磷脂酰乙醇胺-PEG-5000(DPPE-PEG 5k)。油脂的优选比例是92分子百分数DPPC和8分子百分数DPPE-PEG。同比例的油脂也可优选用于未饱和磷脂酰基团。其他磷脂，例如胆固醇，磷脂酸，硬脂酸，棕榈酸，油酸和磷脂酰乙醇胺，可以与上述油脂混合。其他有用的表面活化剂包括含氟表面活性剂，如PEG调聚物B和CAPSTONE(杜邦)。可以使用磷脂和含氟表面活性剂的混合物。其他表面活化剂包括聚氧乙烯-聚氧丙烯共聚物表面活化剂，例如“普朗尼克”F-68。
优选情况下，将黏精纳入配方中来增加产品中的粘性以减少纳米乳剂的沉淀。黏精包括蔗糖，羧甲基纤维素，海藻糖，淀粉，人造血浆溶液黄原胶，丙二醇，甘油和聚乙二醇，其分子量在大约400到8000MV之间。优选情况下，配方包含一种缓冲剂，如磷酸钠，以此将pH值稳定在中性左右，也就是pH＝7.0。
由于本创作使用更低沸点的FC来获得更大的功效，用更低的剂量就可以有效逆转耐辐照性。例如，NVX-108只有2％w/vol的DDFP。先前的材料拥有大于10％w/vol的FC。对于本创作而言，优选的FC重量范围是从大约1％到5％w/vol，其中最优选的是2％w/vol的FC，例如2％w/vol的DDFP或全氟。
在患有异种移植肿瘤的动物身上的实验表明，对于呼吸碳合气和氧气的动物来说NVX-108对pO2肿瘤的效果相当。但是对于呼吸室内空气的动物来说对pO2肿瘤产生的效果会降低。因此，就本创作而言，研究对象在给予乳剂过程之中和之后，以及在放疗或化疗用药期间，都可以呼吸碳合气或者补充氧气。
这种材料可以与放疗同时施用，或者在放疗前施用，例如，在放疗前多达120分钟时施用。作为一种选项，除了放疗或者单独使用以外，化疗可以与DDFPe同时施用。各种抗肿瘤药都可以在本创作中使用，包括但不限于：烷化剂，抗代谢药物，蒽环类药物，拓扑异构酶抑制剂，有丝分裂抑制剂，皮质类固醇，各种各样的化疗药物，靶向治疗，激素治疗和免疫治疗药物。
NVX-108包含的一种剂型由表1中所列的组分组成。
表1
| 成分 | 规格 | 作用 | 浓度(毫克/毫升) |
| 戊烷 | 医用级 | 活性 | 20 |
| 蔗糖 | 医用级 | 辅药 | 300 |
| PEG聚合物B | 纯化的化学级 | 辅药 | 3 |
| 注射用水 | USP | 溶剂 | 适量至1毫升 |
| 氮 | 医用级 | 头部空间吹气 | 适量 |
| 磷酸钠 | USP | 缓冲剂 | 0.01M |
| 盐酸 | USP | 辅药 | 适量 |
一般情况下，申请人的氟碳乳液不包含任何酰氨基胺氧化合物。更具体而言，申请人的氟碳乳液不包含任何氟化酰胺基胺氧化物。
烷化剂包括但不限于氮芥：例如二氯甲基二乙胺(氮芥)，苯丁酸氮芥，环磷酰胺(环磷酰胺)，异环磷酰胺和苯丙氨酸氮芥；亚硝基脲：包括链脲佐菌素，亚硝(基)脲氮芥(BCNU)，和环己亚硝脲；烷基磺酸盐：甲磺酸丁二醇二酯；三嗪：氮烯唑胺(DTIC)和替莫唑胺(TEMODAR)；乙烯亚胺:噻替哌和六甲蜜(六甲蜜胺)。铂类药物(顺铂，卡铂，奥沙利铂)有时和烷化剂归为一类，因为它们以相似的方式杀死细胞。
抗代谢物的样例包括：5-氟尿嘧啶(5-FU)，6-巯嘌呤(6-MP)，卡培他滨(XELODA)，克拉屈滨，氯法拉滨，阿糖胞苷(ARA-C)，氟尿苷，氟达拉滨，吉西他滨(GEMZAR)，羟基脲，氨甲叶酸，培美曲塞(ALIMTA)，喷司他丁和硫鸟嘌呤。蒽环类包括：柔红霉素，阿霉素(ADRIAMYCIN)和表柔比星。非蒽环霉素的伊达比星抗肿瘤抗生素包括：放线菌素博莱霉素和丝裂霉素-C。米托蒽醌是一种许多方面都和阿霉素相似的抗肿瘤抗生素。拓扑异构酶I抑制剂的样例包括拓扑替康和依立替康(CPT-11)。拓扑异构酶II抑制剂的样例包括依托泊苷(VP-6)和替尼泊苷。米托蒽醌也抑制拓扑异构酶II。有丝分裂抑制剂的样例包括：紫杉烷类：紫杉醇(TAXOI)和多西他赛(TAXOTERE)。埃博霉素包括伊沙匹隆(IXEMPRA)。长春花生物碱包括长春花碱(VELBAN)，长春新碱(ONCOVIN)，和长春瑞滨(NAVELBINE)和雌莫司汀(EMCYT)。皮质类固醇样例包括泼尼松，甲泼尼龙(SOLUMEDROL)，和地塞米松(DECADRON)。射靶疗法样例包括伊马替尼(GLEEVEC)，吉非替尼(IRESSA)，舒尼替尼(SUTENT)和硼替佐米(VELCADE)。
分化诱导剂样例包括维甲酸，维A酸(ATRA或ATRALIN)和贝沙罗汀(TARGRETIN)，以及三氧化二砷(ARSENOX)。激素治疗剂样例包括抗雌激素：氟维司群(FASLODEX)，他莫昔芬，和托瑞米芬(FARESTON)。芳香抑制剂包括：阿那曲唑(ARIMIDEX)，依西美坦(AROMASIN)，和来曲唑(FEMARA)。孕激素包括醋酸甲地孕酮(MEGACE)和雌激素。抗雄激素包括比卡鲁胺(CASODEX)，氟他胺(EULEXIN)，和尼鲁米特(NILANDRON)。促性腺激素释放激素(GnRH)，也叫作促黄体生成激素释放激素(LHRH)激动剂或类似物，包括亮丙瑞林(LUPRON)和戈舍瑞林(ZOLADEX)。
免疫治疗种类及其样例包括：单克隆抗体疗法(被动免疫治疗)，例如利妥昔单抗(RITUXAN)和阿仑单抗(CAMPATH)。非特定免疫治疗和佐剂(提高免疫反应的其他物质和细胞)包括BCG，白细胞介素-2(IL-2)，和α-干扰素。免疫调节药，例如，沙利度胺和来那度胺(REVLIMID)。癌症疫苗(特定主动免疫治疗)，如针对晚期前列腺癌的PROVENGE疫苗，可以和DDFPe以及其他当前研制中的疫苗一起使用。FC的使用增加了免疫治疗的活力，例如作为免疫细胞的(易普利姆玛)在通过肿瘤复氧获得的氧化环境下变得更加活跃。其他可以和FC乳剂一起使用的免疫调节药物包括PD-L1表达抑制剂。单克隆抗体在本创作中尤其有用。这些抗体可以被用作疫苗来激发排斥癌症的免疫反应。免疫系统的非特定刺激物可以在本创作中使用。样例包括细胞因子，如白细胞介素和干扰素(如干扰素-α和白介素-2)。在本创作中有用的抗体包括阿仑单抗，贝伐单抗，Brentuximab vedotin，西妥昔单抗，吉妥珠单抗奥佐米星，替伊莫单抗，易普利姆玛，Nivolumab，Ofatumumab，帕尼单抗，利妥昔单抗，托西莫单抗和曲妥珠单抗。本创作可以与过继性T细胞疗法抗-CD47抗体，抗-GD2抗体，免疫反制点阻断剂和EGF受体抗体一起使用。乳剂的使用可以增加肿瘤组织中的氧气，以便通过氧化应激促进免疫机制，并使得免疫系统更加有效，当然也可以通过改变基因表达来实现。通过减少缺氧相关的基因表达，这种氧气疗法将侵略性缺氧介导的表型转换成更容易被免疫系统击败的低侵略性表型。在某些实施例中，申请人的创作包括一种改变基因表达的方法，即通过给有需要的病人施用有效治疗剂量的氧气治疗剂，例如，但不限于NVX-108。
优选情况下，在呼吸补充氧气或碳合气的同时使用DDFPe，这会增加肿瘤氧化，使得化疗药物的作用更加有效。同时进行放疗则可以获得协同优势。
以下案例旨在向熟悉此项技术之人士进一步证明如何作出和使用本创作。不过，这些案例无意限制本创作所界定的范围。
案例1
十二氟戊烷乳剂的制备
在室温下通过在注射用水中溶入适量USP等级的蔗糖制备一种30％蔗糖溶液，随后加入磷酸二氢钠加以中和，使系统pH值为7。在第二个容器中，一种DDDFP：PEG调聚物B比例为7：1的DDFP(十二氟戊烷)Peg调聚物B的悬浮液按如下方法制备出来。在一个冷却至4℃的夹套容器中，PEG调聚物B通过搅拌分散在注射用水中。预冷(4℃)的DDFP被加入到搅拌好的PEG调聚物B中，然后进行搅拌直至获得一种均匀的乳状悬浮液。在一个Avestin型C50均质器中对这种悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。这种乳剂通过均质器在低压下被转移到一个包含30％蔗糖的水溶液容器中；对产生的溶液进行长达20分钟的搅拌，然后通过均质器在低压下转移至第二个容器中。然后，这种溶液通过一个0.2微米的过滤器转移至第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(DDFP)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。所产生的产品包含2％w/vol DDPE。Nycomps提供的粒度测量显示平均颗粒尺寸大约为250纳米。
案例2
在老鼠上实施了Hs-766t胰腺癌异种移植物的移植实验。用于此研究的Hs-766T(胰腺；ATCC Cat#HTB-134)细胞系来自美国菌种保藏中心(ATCC，位于弗吉尼亚州马纳萨斯)，由亚利桑那大学实验鼠共享服务中心(EMSS，亚利桑那大学)进行处理，存储和管理。细胞在DMEM(Mediatech)中用高葡萄糖，L-谷氨酰胺和10％胎牛血清进行培养，并保持在37摄氏度条件下，二氧化碳浓度为5％。肿瘤细胞由ATCC细胞认证检测服务部门通过PCR/短串联重复序列位点(STR)进行认证。运用通用支原体检测试剂盒(ATCC,30-1012K)对细胞进行支原体常规检测，没有发现污染。
29只5-8周的雌性SCID老鼠被应用于这些研究。所有老鼠的喂食、饲养和兽医服务均按照IACUC批准的准则和规程由EMSS进行管理。老鼠分成4组或4组以下关在鼠笼里，以自由给饲的方式喂食和喂水。在注射之前，将老鼠剃毛，为肿瘤异种移植准备适当的位置。肿瘤细胞(10x106个细胞，MatrigelTM中；BD Bioscience公司)在每个老鼠的左后侧进行皮下注射。使用电子卡尺测定肿瘤尺寸((a2xb2)/2)，每周两次进行肿瘤负荷评估。当肿瘤达到500-700mm3的平均体积时，老鼠被随机分到6组中的一组：3组老鼠用于肿瘤氧气的测定，3组老鼠用于肿瘤生长的测定。
在9只老鼠中进行肿瘤pO2的测定。施用了0.3(2只老鼠)，0.45(3只老鼠)，和0.6(4只老鼠)mL/kg(2％w/vol乳剂)剂量的NVX-108。在其他20只老鼠中进行了肿瘤生长速度的研究。这些老鼠被分到如下3个治疗组：第1组：未治疗(4只老鼠)，第2组：呼吸碳合气并用12Gy辐照量进行治疗(8只老鼠)，第3组：使用NVX-108(0.6cc每kg，2％w/vol的DDFP静脉注射，超过30分钟以上，注射结束时进行辐照)加以治疗，并在呼吸碳合气时施用12Gy辐照量(8只老鼠)。
每只老鼠都接受了含赛拉嗪(5mg/kg IP)的氯胺酮(20mg/kg IP)以使其身体保持固定状态，并且安装了尾静脉导管以便通过尾静脉注射(TVI)给药。尾静脉导管插入通过一个装配的27号针头改造的PE 50管来完成。这根导管通过尾部两侧的3-0缝合线和专用胶带牢牢系附在每只老鼠的尾部。在导管插入之后，这些老鼠被放入定制的气室内，导入碳合气(95％氧气，5％二氧化碳)并10分钟换气一次。使用定制的约束装置将其固定以便放置在一个铅屏板下方，这些铅屏板隔离侧面的肿瘤异种移植物，以便于辐照分割。在一个引入碳合气(95％氧气，5％二氧化碳)并10分钟换气一次的定制气室内，对所有老鼠进行一次12Gy的肿瘤分割。XRT剂量持续时间的计算是基于“处方剂量/剂量率”＝(1200cGy)/(87.9cGy/min)，这等于对肿瘤进行13.65分钟(13分39秒)的单次分割。针对组别2#，200微升的无菌生理盐水通过尾静脉注射(TVI)方式注入(时间0:00)，并且用于碳合气吸入前十分钟和辐射前16.35分钟的假注射。针对组别3#，200微升的NVX-108在碳合气吸入前十分钟和辐射前16.35分钟时通过TVI(时间0:00)方式注射。尾静脉注射通过一种多注射器泵进行，以便对每组同时给药。在时间0:00分钟时同时注射NVX-108和生理盐水后，开始进行研究。然后，在10分钟时吸入碳合气，并在16.35分钟时进行辐照。
在辐照完成之后，可以让这些老鼠通过自由饮食和饮水的方式进行恢复。对肿瘤尺寸的二维测定每周进行两次。当肿瘤尺寸大于2000mm3，老鼠被处死。
肿瘤氧化和血流量水平通过定向插入所有肿瘤的OxyLab(Oxford Optronics,Oxford,UK)三参数E-系列光纤探针来监测。使用一个在WindowsTM(版本5.02ADIstuments，澳大利亚)ChartTM下运行的多通道数据采集系统(PowerLab 8SP，ADIstruments，澳大利亚)将来自这些监视器的氧分压信号实时记录下来。麻醉后的老鼠(异氟醚100％氧气)被限制在一个定制的固定平台上以防止移动，并且平台用加热垫进行改造以维持核心体温。采取了预防措施来防止缺氧探头的任何移动，并且消除外来光源的干扰以防止探头假象问题。使用19号针头穿入肿瘤约2-4毫米，探针(OD约450微米)通过针头被送入肿瘤异种移植物，并且用定向方法固定到位。所有探针被小心标记好刻度以便在所有肿瘤中达到同样深度。一旦探针稳定并被固定住，则对输出信号进行监测(5-10分钟)直至观测到稳定的基线。在基线处对碳合气进行10分钟的实时测量，随后，在动物继续吸入碳合气时以0.3,0.45或0.6cc/kg剂量的NVX-108(NuvOx Pharma Tucson，亚利桑那)进行200微升尾静脉注射。
案例3
胶质母细胞瘤(GMB)的治疗
对一位GBM病人进行手术治疗。术后钆增强MRI扫描显示存在残余的增强肿瘤。病人持续6周进行30次放疗，每次2格雷(Gy)，一共60Gy，从放疗第一天到最后一天每周七天、每天口服每平方米75mg剂量的替莫唑胺。此病人接受了一根静脉PICC导管。从每个放疗阶段前大约30分钟开始，以静脉滴注的方式和0.05cc/kg(2％w/vol)的剂量持续超过30分钟施用DDFPe。实施磁共振TOLD扫描来显示肿瘤缺氧的逆转情况。
随后通过静脉钆造影的MRI扫描显示，与没有使用DDFPe治疗的病人相比，肿瘤数量得以减少。
基线术后MRI扫描显示于下图左侧。白色箭头标示了左内侧颞叶内可见的残留增强肿瘤。右侧的扫描显示了完成化疗照射和DDFPe治疗4周之后的情形。白色箭头标示了残留的增强肿瘤。增强肿瘤减少了大约80％。病人现在仍然存活，并且治疗完成后6个多月康复情况良好。
案例4
胶质母细胞瘤(GBM)的治疗
另一位患有胶质母细胞瘤的病人接受了手术，在造影增强MRI上可见残余肿瘤。除了使用0.1cc/kg的DDFPe以外，此病人采用与案例1(上文)一样的方式治疗。此病人很好地接受了这次治疗。当前正在征求下一个病人的同意，该病人将会在每次化疗照射期间用0.17cc/kg剂量的DDFPe进行治疗。
预示案例1
一位患有非小细胞性肺癌的病人使用Belani等人的方案中所述的胸部放疗和合并化疗法进行治疗。序贯化疗包括两个持续3周的疗程，每个疗程中持续超过3小时施用200mg/m2的紫杉醇，紧接着通过静脉滴注的方式持续超过30分钟在血药浓度-时间曲线下面积(AUC)＝6mg/mL·min时施用卡铂。胸部放疗在第42天开始，每天剂量1.8Gy，每周5次(在5周内对初始区域施用45.0Gy目标剂量)，之后对缩减区域的初始肿瘤体积，但也包括≥2.0cm的肿大淋巴结施用，每天2.0Gy，一共18Gy剂量(全部剂量为63.0Gy，分34次在7周以上的时间内施用)。对于每次放疗，从放疗开始前30分钟，以静脉滴注方式持续超过15分钟施用DDFPe。用DDFPe治疗过的病人对治疗方案的反应有所改善。
预示案例2
一位患有阶段I非小细胞肺癌的病人在一周内按照大分割放疗计划实施三次分割放疗，每次15Gy，共45Gy。这代表112.5Gy的生物等价剂量(BED)。在每个辐照剂量前的30～60分钟，对病人施用0.17cc/kg静脉弹丸注射剂量的NVX-108(2％w/vol DDFPe)。跟进研究显示，治疗后的肿瘤比没有施用DDFPe的肿瘤消除得更多。
预示案例3
一位患有宫颈癌的女性病人同时用放疗和化疗+NVX-108进行治疗。辐照剂量为20次共计45格雷(Gy)，随后，对宫颈区腔内低剂量施用30Gy。化疗包括每周40mg/m2的静脉内注射顺铂，持续达6个疗程。在每次辐照前60分钟，对病人施用0.2cc/kg静脉弹丸推注剂量的NVX-108(2％w/vol DDFPe)。跟进研究显示了对治疗的完全反应。
预示案例4
一位患有头部和颈部鳞状上皮细胞癌的病人每周两次静脉滴注0.50单位/kg(20单位/m2)的博莱霉素。在每次施用博莱霉素期间，病人吸入碳合气(98％氧气/2％二氧化碳)的同时施用0.2cc/kg的2％w/vol全氟己烷乳剂。在肿瘤组织中获得的更高氧气水平增加了博莱霉素的活性，药物反应得到了改善。
预示案例5
一位患有生殖细胞卵巢癌的成年病人按每四周五天施用500mcg/天的更生霉素。每瓶更生霉素包含0.5mg(500mcg)的更生霉素和20mg的甘露醇，将其静脉注射给病人。每次施用更生霉素时都会静脉弹丸推注DDFPe(0.2cc/kg，2％w/vol DDFP)。在注射过程中及注射之后，病人吸入碳合气30分钟。这在肿瘤组织中获得了更高的氧气水平，增强了药物的活性。
预示案例6
一位患有横纹肌肉瘤的成年病人以1.4mg/m2的剂量静脉注射长春新碱进行治疗。在病人呼吸室内空气的同时相继施用了0.1cc/kg的DDFPe。尽管病人吸入的是室内空气，但肿瘤组织中仍然获得了更高的氧气含量，带来了药物活性的增强。
预示案例7
一位患有多骨髓瘤的病人用BiCNU(注射用亚硝(基)脲氮芥)，亚硝脲(1,3-双(2-氯)-1-亚硝脲)并结合强的松进行治疗。对此之前，这位未接受治疗的病人每六周静脉注射200mg/m2BiCNU。这些剂量被分配到连续两天，每天注射100mg/m2。在注射每剂量BiCNU的同时静脉弹丸推注(剂量＝0.2cc/kg，2％w/vol DDFP)DDFPe，在此同时病人吸入补充氧气60分钟。6周内，一旦循环血液元素重回到可接受水平(血小板高于100,000/mm3，白细胞高于4,000/mm3)，再次重复施用BiCNU，同时伴随BiCNU施用DDFPe。
预示案例8
一位患有前列腺癌的病人结合使用外部放射治疗和高临时种子植入的高剂量率近距离放射治疗。在对前列腺癌使用45Gy的外部放射治疗三周后，使用高临时种子植入及高剂量率近距离放射治疗。病人被带入手术室并麻醉。一个直肠超声探头被导入直肠，然后探头固定到一个落地式踩踏装置。一根导针/一个会阴模板系附在踩踏装置上并向上抵靠在会阴部皮肤上。二十个金属针头通过模板安装好，经过会阴部推进到中前列腺。这些针头用塑料导管替换。在恢复之后，病人被带到放射肿瘤科进行CT扫描，以确保导管安放准确。这个电脑控制的高剂量放疗装置包含一种源驱动机制，此机制根据剂量计划确定的加载模式依次移动放射性铱丝通过填隙导管。此高剂量率放射治疗耗时10-15分钟，其中放射性铱丝被推进到每一根填隙导管中。此治疗再重复一次，然后病人被转移到医院房间6个小时，然后此过程再次重复以便再进行两次高剂量率放射治疗，例如，铱丝被推进到每根导管，一共4次，早上两次，下午两次，每个阶段耗时大约30分钟。在每个治疗阶段，对病人使用0.2cc/kg剂量的DDFPe超过30分钟，在此期间吸入碳合气。
http://prostate-cancer.org/temporary-seed-implant-with-high-dose-rate-brachytherapy/
预示案例9
一位患有第四阶段肾母细胞瘤的儿科病人使用更生霉素，阿霉素，环磷酰胺和长春新碱治疗65周。药用量如下：更生霉素(15mcg/kg/d[IV])，长春新碱(1.5mg/m 2wk[IV])，阿霉素(阿霉素20mg/m 2/d[IV])以及环磷酰胺(10mg/kg/d[IV])。在术后以及第13，26，39，52和65周提供更生霉素疗程。每个阿霉素疗程的第1天和第8天给予长春新碱。在第6，19，32，45和58周给予三天剂量的阿霉素。除了术后的更生霉素疗程以外，在每个阿霉素和更生霉素疗程期间给予三天剂量的环磷酰胺。在每次使用更生霉素和长春新碱期间，在病人吸入补充氧气的同时施用0.2cc/kg剂量的DDFPe。见Dangio,Giulio J.等“Treatment ofWilms’tumor.Results of the third national Wilms’tumor study.”Cancer 64.2(1989):349-360.
预示案例10
一位患有不能切除的肝细胞癌的病人使用索拉非尼进行治疗。病人每天口服400mg索拉非尼(2×200mg)。在单一设置条件下病人也使用玻璃微球进行治疗。玻璃微球包括不溶的玻璃微珠，微珠内系缚有钇-90。肝动脉中插入导管，肿瘤血管床用玻璃微球进行栓塞，通过肝动脉进行注射来递送100Gy目标剂量的玻璃微球。在栓塞过程中，0.1cc/kg剂量的DDFPe与氧气混合，并且也注入到肝动脉中。
预示案例11
老鼠体内的移植瘤是用之前描述过的UTSCC33(口腔癌)，FADUDD(FaDu的亚系，一种未分化的喉咽癌)和SiHa子宫宫颈癌，HPV-阳性(从美国菌种保藏中心获得)等细胞系生成的。见Toustrup,Kasper,et al.“Development of a hypoxia gene expressionclassifier with predictive impact for hypoxic modification of radiotherapy inhead and neck cancer.”Cancer research 71.17(2011):5929-5931(下文中见“Toustrup”)。
携带各种肿瘤的老鼠被随机分成两组，DDFPe治疗组和控制组(注射相同量的生理盐水)。DDFPe治疗包括每天以静脉弹丸推注的方式施用0.3cc/kg的DDFPe，共用十四天。十四天后老鼠被处死并针对缺氧相关基因的表达进行肿瘤测定。见Toustrup RNA fromfresh-frozen tissue was extracted by using RNeasy-kit(Qiagen)according to themanufacturer’s instructions.cDNA通过使用大容量cDNA档案包生成(应用生物系统；ABI)，而基因表达通过利用qPCR进行量化。根据FFPE样本，cDNA在实时qPCR之前根据制造商的明细(TaqMan PreAmp，ABI)进行前置放大。为了检测出感兴趣的转录物，TaqMan基因表达测定(ABI)应用于所有潜在的分类器和参考基因。感兴趣的基因(被认为在缺氧肿瘤中上调并与最可能演变的肿瘤相关)包括以下几类：ADM(应激反应)，ALDOA(糖代谢)，ANKRD37(蛋白质相互作用)，BNIP3(细胞凋亡)，BNIP3L(细胞凋亡)，C3orf28(未知)，EGNL3(HIF-1活性调节)，KCTD11(细胞凋亡)，LOX(细胞外基质代谢)，NDRG1(应激反应)，P4HA1(细胞外基质代谢)，P4HA2(细胞外基质代谢)，PDK1(能量代谢)，PFKFB3(葡萄糖代谢)以及SLC2A1(葡萄糖代谢)。在使用DDFPe治疗过的动物的异种移植肿瘤中，其基因表达测定发现，缺氧相关基因的表达明显低于用盐水控制注射治疗的动物肿瘤组织样本中的表达。
预示案例12
下列预示案例旨在显示DDFPe的使用如何下调在缺氧肿瘤组织中表达过度的基因表达以及上调含氧量正常组织中的基因表达(即：规范基因的表达)。Fischer 344只老鼠(F344/Ncr；美国国家癌症研究所，弗雷德里克，马里兰州)用来生成9L神经胶质瘤模型。部分9L神经胶质瘤如之前所述被嵌入上腹部动脉/静脉对中。动物每天静脉注射0.45cc/kgDDFPe或者盐水直至肿瘤大约重达1.5g，然后将动物安乐死，取下肿瘤并速冻。按照上述类似的方式对肿瘤里的基因表达进行测定。在控制组中看到的上调基因包括：BCL2/腺病毒E1B 19kDa-相互作用的蛋白质3，血红素加氧酶(decycling)1，激活转录因子3，热休克蛋白(HSP27)，N-myc下游调节基因1，碳酸酐酶9等。在控制组中下调的基因包括：Ly6-C抗原，溶质载体系列44(成员2)，包含9-L的无菌α基序域，DEAD(Asp-Glu-Ala-Asp)盒多肽60以及CD3分子δ多肽等等。对使用DDFPe治疗的动物身上的9-L神经胶质瘤组织的基因表达对比显示：控制组动物中上调的基因表达明显减少，而下调的基因表达明显增加。也就是说，使用DDFPe治疗的动物的肿瘤里具有规范化的基因表达。详见Marotta，Diane，et al.“In vivoprofiling of hypoxic gene expression in gliomas using the hypoxia markerEF5and laser-capture microdissection.”Cancer research 71.3(2011):779-789。
预示案例13
按照案例1所述制备一份30％的蔗糖溶液。在第二个容器中通过在水里加热使其温度高于所有油脂的相变温度，制备一份含下列成份的磷脂混合物悬浮液：92％DPPC和8％DPPE-PEG(摩尔比例)的DPPC和DPPE-PEG 5k。一旦油脂分散开来，则将悬浮液冷却到4℃，然后在一个夹套容器里搅拌。按照重量比7:1将预冷的(4℃)DDFP加入搅拌好的磷脂悬浮液中，然后搅拌，直到获得均匀的乳白色悬浮液。在Avestin型C50均质器中对悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。通过均质器在低压下将乳状液转移到一个装有30％蔗糖水溶液的容器里；将获得的溶液搅拌二十分钟，然后通过均质器在低压下将搅拌后的溶液转移到第二个容器中。随后，溶液通过一个0.2微米的过滤器过滤到第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(DDFP)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。
预示案例14
按照案例1所述制备一份30％的蔗糖溶液。在第二个容器中通过在水里加热使其温度高于所有油脂的相变温度，制备一份含下列成份的磷脂混合物悬浮液：DPPC和DPPE-PEG 5k。一旦油脂分散开来，则将悬浮液冷却到4℃，然后在一个夹套容器里搅拌。按照重量比7:1将预冷的(4℃)全氟己烷加入搅拌好的磷脂悬浮液中，然后搅拌，直到获得均匀的乳白色悬浮液。在Avestin型C50均质器中对悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。通过均质器在低压下将乳状液转移到一个装有30％蔗糖水溶液的容器里；将获得的溶液搅拌二十分钟，然后通过均质器在低压下将搅拌后的溶液转移到第二个容器中。随后，溶液通过一个0.2微米的过滤器过滤到第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(全氟己烷)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。
预示案例15
按照案例1所述制备一份30％的蔗糖溶液。在第二个容器中通过在水里加热使其温度高于所有油脂的相变温度，制备一份含下列成份的磷脂混合物悬浮液：DPPC，胆固醇和DPPE-PEG 5k。一旦油脂分散开来，则将悬浮液冷却到4℃，然后在一个夹套容器里搅拌。按照重量比7:1将预冷的(4℃)全氟庚烷加入搅拌好的磷脂悬浮液中，然后搅拌，直到获得均匀的乳白色悬浮液。在Avestin型C50均质器中，对悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。通过均质器在低压下将乳状液转移到一个装有30％蔗糖水溶液的容器里；将获得的溶液搅拌二十分钟，并通过均质器在低压下将搅拌后的溶液转移到第二个容器中。然后，溶液通过一个0.2微米的过滤器过滤到第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(全氟庚烷)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。
预示案例16
按照案例1所述制备一份30％的蔗糖溶液。在第二个容器中通过在水里加热使其温度高于所有油脂的相变温度，制备一份含下列成份的磷脂混合物悬浮液：DPPC，磷脂酸(DPPA)和DPPE-PEG 5k。一旦油脂分散开来，则将悬浮液冷却到4℃，然后在一个夹套容器里搅拌。按照重量比7:1将预冷的(4℃)全氟辛烷加入搅拌好的磷脂悬浮液中，然后搅拌，直到获得均匀的乳白色悬浮液。在Avestin型C50均质器中，对悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。通过均质器在低压下将乳状液转移到一个装有30％蔗糖水溶液的容器里；将获得的溶液搅拌二十分钟，并通过均质器在低压下将搅拌后的溶液转移到第二个容器中。然后，溶液通过一个0.2微米的过滤器过滤到第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(全氟辛烷)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。
预示案例17
通过在水里加热使其温度高于所有油脂的相变温度制备一份含下列成份的磷脂混合物悬浮液：二油酰磷脂酰胆碱(DOPC)，胆固醇和二油酰磷脂酰乙醇胺-PEG-5,OOO。产生的油脂悬浮液悬浮在丙二醇/甘油混合物中，从而获得80:10:10重量百分比的磷酸盐缓冲盐水：丙二醇：甘油。一旦油脂分散开来，则将悬浮液冷却到4℃，然后在一个夹套容器里搅拌。按照重量比7:1将预冷的(4℃)全氟己烷加入搅拌好的磷脂悬浮液中，然后搅拌，直到获得均匀的乳白色悬浮液。在Avestin型C50均质器中，对悬浮液进行长达18分钟的高压均质化处理，并保持温度低于7℃。通过均质器在低压下将乳状液转移到一个装有30％蔗糖水溶液的容器里；将获得的溶液搅拌二十分钟，并通过均质器在低压下将搅拌后的溶液转移到第二个容器中。然后，溶液通过一个0.2微米的过滤器过滤到第三个容器中。这种产品被分配到加盖的波纹状小瓶中。由于活性成分(全氟辛烷)的挥发性，这些操作均在低于8℃的冷夹套容器中完成。处理过程中的损耗通过使用超额活性成分加以补偿。产品灌装体积也经过严格控制，以便生产的小瓶满足发送和保质期规格。
前文系针对本创作之较佳实施例进行具体之说明，不过，熟悉此项技术之人士当可在不脱离本创作之精神与原则下对本创作进行变更与修改，而此等变更与修改皆应涵盖于如下申请专利范围所界定之范畴中。
Claims (25)
1.一种用于分割放疗和化疗的氟碳乳剂，其中所述氟碳包含4～8个碳原子。
2.如申请专利范围第1项所述氟碳乳剂，其中所述氟碳包括全氟戊烷。
3.如申请专利范围第1项所述氟碳乳剂，其中所述氟碳包括全氟戊烷和全氟己烷。
4.如申请专利范围第1项所述氟碳乳剂，其中所述氟碳在乳剂中包含大约1-10％的重量/体积。
5.如申请专利范围第1项所述氟碳乳剂，其中所述氟碳包含大约20mg/mL的十二氟戊烷。
6.如申请专利范围第5项所述氟碳乳剂，其进一步包含粘度调节剂。
7.如申请专利范围第6项所述氟碳乳剂，其中所述粘度调节剂包含蔗糖。
8.如申请专利范围第7项所述氟碳乳剂，其中所述蔗糖含量大约为300mg/mL。
9.如申请专利范围第6项所述氟碳乳剂，其进一步包含PEG调聚物B。
10.如申请专利范围第8项所述氟碳乳剂，其中所述PEG调聚物B含量大约为3mg/mL。
11.一种使哺乳动物对多分割放疗或化疗敏感的方法，包括：
对哺乳动物施用氟碳乳剂；同时对所述哺乳动物施用碳合气或补充氧气；其中所述氟碳包含4-8个碳原子。
12.如申请专利范围第11项所述方法，其中所述氟碳包括全氟戊烷。
13.如申请专利范围第11项所述方法，其中所述氟碳包含全氟戊烷和全氟己烷。
14.如申请专利范围第11项所述方法，其中所述氟碳在乳剂中包含大约1-10％的重量/体积。
15.如申请专利范围第11项所述方法，其中乳剂施用方法为静脉注射。
16.如申请专利范围第11项所述方法，其中所述氟碳包含大约20mg/mL的十二氟戊烷。
17.声如申请专利范围第10项所述方法，其中所述氟碳乳剂进一步包含粘度调节剂。
18.如申请专利范围第17项所述方法，其中所述粘度调节剂包含蔗糖。
19.如申请专利范围第18项所述方法，其中所述蔗糖含量大约为300mg/mL。
20.如申请专利范围第17项所述方法，其进一步包含PEG调聚物B。
21.如申请专利范围第20项所述方法，其中所述PEG调聚物B含量大约为3mg/mL。
22.如申请专利范围第11项所述方法，其中所述乳剂包含磷脂。
23.如申请专利范围第11项所述方法，其中所述乳剂与抗癌剂共同施用。
24.如申请专利范围第23项所述方法，其中所述抗癌剂是一种抗体。
25.一种给有需要的病人施药来改变基因表达的方法，其实际为一种有效治疗剂量的氧疗方法。
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| CN102395548A (zh) * | 2009-04-15 | 2012-03-28 | 奥斯金生医公司 | 全氟化碳类乳液 |
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