Nano drug delivery system in targeted therapy for tumor

doi:10.3969/j.issn.2095-4344.2013.21.024

Abstract

Abstract:

BACKGROUND: Nano drug delivery system is an ideal drug container for targeted therapy of tumor.
OBJECTIVE: To search the ClinicalTrial.gov and Web of Science database and to perform literature metrological analysis on the clinical trials of nano drug delivery system in targeted therapy of tumor.
METHODS: The ClinicalTrial.gov was searched with the key words of “nanoparticle, cancer, drug delivery system, nanotube, nanosphere” for the clinical trials regarding nano drug delivery system in targeted therapy of tumor. At the same time, the Web of Science was searched using key words of “nanoparticle, cancer, drug delivery system, nanotube, nanosphere” for articles indexed between 2000 and 2012. According to inclusive and exclusive criteria, the search results were transferred into excel with items of National Clinical Trial number, title, recruitment, interventions, sponsor/collaborators, as well as diseases.
RESUTLS AND CONCLUSION: (1) There are 489 clinical trial registration projects related to nano drug delivery system in targeted therapy of tumor in the ClinicalTrial.gov, and 429 registration projects were included in the analysis. The United States registered 112 projects, which is greater than other countries. Canada ranked second with 24 projects. China, with 22 projects, listed the third. The registration projects begin from 1997, increased slowly, and down to a valley at 2003, with 5 projects. After that, it increased sharply, and reached a peak at 2008. (2) The sample sizes of registration projects ranked from 1 to 2 000, which mainly focuses on smaller sample size (less than 50). The most conditions of research were breast cancer, followed by endocrine gland neoplasms and lymphoma. (3) The number of literatures on nano drug delivery system in targeted therapy of tumor indexed from 2003 to 2012 in the Web of Science database was 4 497, and the amount of literatures published by the United States is accounted for the largest proportion of the total number (2 987 articles, 66.42%). The highly cited papers are mainly published on the Proceedings of the National Academy of Sciences of the United States of America.

Key words: biomaterials, biomaterial academic discussion, nano, drug carrier, cancer, targeted therapy, biomedical materials, drug loading efficiency, ClinicalTrial.gov, Web of Science database, literature metrological analysis

CLC Number:

R318

Zhang Peng, Chen Yong-zhong, Zhou Qing-bi, Bai Jing-ping, Xilin Baoleri. Nano drug delivery system in targeted therapy for tumor[J]. Chinese Journal of Tissue Engineering Research, doi: 10.3969/j.issn.2095-4344.2013.21.024.

Figures/Tables 7

2.6 中国在北美临床试验注册中心注册的已完成的纳米给药系统在肿瘤靶向治疗相关研究的项目分析中国在北美临床试验注册中心共注册22项，其中，已完成的项目3项，中国大陆，中国香港地区，及中国台湾地区各完成1项。中国香港地区已完成的注册项目，临床注册号NCT00093444，中国和美国联合注册，以研究阿霉素脂质体联合射频消融治疗原发性及转移性肝肿瘤疗效为目的Ⅰ期临床试验，研究开始于2004年10月，结束于2010年1月，共纳入30名试验对象，主要观察注射15，30，45，60，75， 90 min，2，3，4，6，24，46 h，及 4，8 d的药代动力学及药效学水平。阿霉素脂质体治疗的最大耐受剂量；其次MRI观测 28 d后消融治疗对肿瘤血流量及肿瘤血管密度的影响。纳入的疾病特征：组织学确诊原发性或转移性肝肿瘤：≤4个病灶；单一肿瘤最大直径＜7 cm。病理学或先前手术表明不适合进行手术切除。患者的特点：年龄≥18岁, 体能状态：ECOG评分0-2分；预期寿命≥3个月, 造血系统：血小板计数≥75 000/ mm3；白细胞计数≥1 500/mm3；血红蛋白≥100 g/L的(允许输血达到水平≥100 g/L)；肝：胆红素≤34.2 μmol/L；凝血酶原时间或部分凝血致活酶时间≤1.5倍对照值(患者接受抗凝治疗除外)。肾：肌酐≤221 μmol/L。心血管：心脏放射性核素扫描射血分数≥50%；无充血性心脏衰竭；过去6个月内无心肌梗死，无脑血管意外；没有危及生命的心律失常。其他：体质量<136 kg；血糖≤16.65 mmol/L；无不受控制的糖尿病；对使用的造影剂没有不良反应史；无蛋或蛋制品过敏史；无其他严重内科疾病；非怀孕期或哺乳期；妊娠试验阴性；育龄妇女必须有效的避孕。同时疗法：生物治疗：无治疗干扰；免疫抑制患者在试验时及试验后30 d无活疫苗接种。其它：肝肿瘤治疗≥3周；全身治疗非危及生命的肝外疾病并恢复超过>3周；无其他并发全身性治疗；试验期间及试验后30 d无任何下列药物给药：环孢素、苯巴比妥、苯妥英钠、链脲佐菌素。未同时给予给下药物：注射两性霉素B、抗甲状腺剂用于甲状腺亢进、硫唑嘌呤、氯霉素、秋水仙碱、氟胞嘧啶、更昔洛韦、普卡、齐多夫定、丙磺舒、磺吡酮。临床注册号NCT00606515，中国大陆地区注册的以研究紫杉醇脂质体治疗中国实体瘤患者的Ⅳ期药代动力学研究，开始于2008年1月，结束于2008年10月。纳入标准：病理学确诊实体瘤晚期患者；仅适用醇脂质体治疗；体能状态ECOG评分0-2分；预期寿命≥3个月；血液指标，肝、肾功能正常；其他器官功能正常；过去4周内无全身化疗；无激素过敏史。排除标准：有对试验研究药物过敏史；有影响患者完成试验的严重并发症；毒性评价标准NCI CTCAE3.0规定的≥1级神经病变；怀孕期或哺乳期。共16例患者纳入分析。随机分成A，B两组，A组患者接受静脉注射紫杉醇脂质体，3 h内注射175 mg/(m2•d), 21 d 一个疗程，治疗3个疗程；B组患者接受静脉注射紫杉醇注射液，3 h内注射175 mg/(m2•d)，21 d 一个疗程，治疗3个疗程。主要观察治疗72 h 的药代动力学参数。临床注册号NCT00813072，中国台湾地区联合波黑共和国、克罗地亚、韩国、西班牙、英国的国际多中心研究PEP02, 依立替康及多西他奇治疗胃或胃食管肿瘤的Ⅱ期有效性分析。研究开始于2008年12月，结束于2010年12月。纳入标准：病理学或细胞学确诊的局部晚期(不能手术切除)或转移性胃或胃食管肿瘤患者；局部晚期或转移性疾病仅一次全身化疗失败，包括辅助化疗后6个月内疾病复发的患者，同步放化疗给药不算入全身化疗；根据RECIST标准，至少有一个可测量的病灶；有能力签署患者知情同意书；ECOG体力状态评分0-2分；预期寿命≥3个月；器官和血液指标正常。排除标准：试验开始前3周接受全身化疗；试验开始前4周接受放疗；脑转移瘤；试验前5年内接受活动性多重肿瘤或其他肿瘤的治疗(治愈的非黑色素瘤和原位宫颈癌患者除外)；曾接受伊立替康或紫杉烷类(紫杉醇，多西紫杉醇)治疗；曾接受辐射导致骨髓活性>30%；试验开始前4周内接受重大手术(剖腹手术，导管置入除外)；周围神经病变> 2级；对脂质体产品或其他含聚山梨酯成分药物有过敏史；有不受控制的并发症；试验开始前3周内接受任何药物试验；妊娠期或哺乳期女性(所有女性受试者进入研究之前都必须进行妊娠试验，结果必须是阴性)；肠梗阻患者；试验开始前2周内接受St. John's Wort, CYP3A4诱导抗痉挛药(苯妥英钠，苯巴比妥，卡马西平)、利福平和利福布汀，或试验开始前1周内接受酮康唑，伊曲康唑，醋竹桃霉素，红霉素，地尔硫卓，维拉帕米药物。135例患者随机分为2组，PEP02组：静脉注射PEP02, 90 min 内注射120 mg/(m2•d)，21 d 一个疗程，直到肿瘤恶化或出现无法耐受的毒副作用。依立替康组：静脉注射依立替康, 300 mg/(m2•d)，21 d一个疗程，直到肿瘤恶化或出现无法耐受的毒副作用。多西他奇组，静脉注射依立替康, 75 mg/(m2•d), 60 min注完，21d 一个疗程，直到肿瘤恶化或出现无法耐受的毒副作用。主要观察指标：治疗的客观有效率。次要观察指标：无进展生存期，肿瘤反应时间，肿瘤进展时间，治疗失败时间，疾病控制率，1年存活率，总存活率，以及PEP02和依立替康的药代动力学及药物遗传学检测。 2.7 Web of Science数据库纳米给药系统在肿瘤靶向治疗相关文章分析见表5。 Web of Science数据库2000-01-01/2012-12- 31共收录纳米给药系统在肿瘤靶向治疗相关文章 4 497篇，发文量最多的国家为美国，数量为2 987篇，中国发表文章134篇。被引较高的前10篇文章中有3篇发表在Proceedings of the National Academy of Sciences of the United States of America (《美国科学院院刊》)上。被引次数最高的文章为2006年在Nano Letters (《纳米快报》)由Chithrani BD, Ghazani AA, Chan WC发表的Determining the size and shape dependence of gold nanoparticle uptake into mammalian cells[21]，截止检索日止，在Web of Science数据库中共计被引用950次，年平均被引118.75次。"

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