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首页> 外文学位 >Pharmacokinetics, biodistribution, toxicity and therapeutic efficacy of liposomal doxorubicin formulations in mice.
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Pharmacokinetics, biodistribution, toxicity and therapeutic efficacy of liposomal doxorubicin formulations in mice.

机译：脂质体阿霉素制剂在小鼠中的药代动力学，生物分布，毒性和治疗功效。

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摘要

Mice bearing the orthotopically implanted 4T1 murine mammary carcinoma were used as a model system to explore the therapeutic and toxicological implications of different dosing schedules and dose intensities of STEALTHRTM liposomal doxorubicin (SL-DXR). The pharmacokinetics, biodistribution, and therapeutic efficacy of SL-DXR were studied as a function of liposome size, drug release rate, dose, and dose intensity. In humans the dose-limiting toxicities of CaelyxRTM (the clinical formulation of SL-DXR) are mucocutaneous, resulting, e.g., in palmar-plantar erythrodysesthesia (PPE). Therefore, the tissue distribution of STEALTHRTM liposomes and total doxorubicin (DXR) into cutaneous tissues (skin and paws) and tumors was determined for naive or orthotopically implanted mice after single or multiple injections of SL-DXR.; Liposomes larger than approximately 150 nm in diameter showed reduced tissue uptake in all tissues and reduced therapeutic activity against the 4T1 murine mammary carcinoma in mice. Compared to liposomes with faster drug release rates, liposomes with slower release rates resulted in higher concentrations of DXR in tissues and had greater therapeutic efficacy against the 4T1 murine mammary carcinoma. In mice receiving four doses of CaelyxRTM (9 mg/kg) in short intervals (q1wk), drug concentrations in cutaneous tissues were sustained at high levels, or increased during the course of the experiment, even though plasma levels returned close to baseline between subsequent doses. Drug accumulation in cutaneous tissues was correlated with the development of PPE-like lesions. Lengthening the dose interval to q2wk resulted in lower concentrations of DXR in cutaneous tissues and fewer PPE-like lesions. When the dose interval was extended to q4wk, drug was cleared from all tissues between doses, but therapeutic activity was reduced compared to q1wk or q2wk dose schedules. For identical dose intensities of CaelyxRTM (9 mg/kg/week), infrequent larger doses appeared to have superior therapeutic activity compared to frequent smaller doses. Overall, the results show that the mouse is a valuable animal model for the development of optimal liposomal drug delivery systems.
机译：将带有原位植入4T1鼠乳腺癌的小鼠用作模型系统，以探讨STEALTHRTM脂质体阿霉素（SL-DXR）的不同给药方案和剂量强度的治疗和毒理学意义。研究了SL-DXR的药代动力学，生物分布和治疗效果与脂质体大小，药物释放速率，剂量和剂量强度的关系。在人类中，CaelyxRTM（SL-DXR的临床配方）的剂量限制性毒性是粘膜皮肤的，例如会导致掌plant红斑感觉异常（PPE）。因此，对于单次或多次注射SL-DXR的幼稚或原位植入的小鼠，要确定STEALTHRTM脂质体和总阿霉素（DXR）在皮肤组织（皮肤和爪子）和肿瘤中的组织分布。直径大于约150 nm的脂质体在所有组织中均显示出组织摄取减少，并且对小鼠的4T1鼠乳腺癌的治疗活性降低。与具有较快药物释放速率的脂质体相比，具有较慢释放速率的脂质体会导致组织中DXR的浓度更高，并且对4T1鼠乳癌的治疗效果更高。在短期间隔（q1wk）内接受四剂CaelyxRTM（9 mg / kg）的小鼠中，即使随后两次之间血浆水平恢复至基线水平，皮肤组织中的药物浓度仍保持较高水平，或在实验过程中有所增加剂量。皮肤组织中的药物积累与PPE样病变的发展有关。将剂量间隔延长至q2wk导致皮肤组织中DXR的浓度降低，PPE样病变更少。当剂量间隔延长至q4wk时，在两次剂量之间从所有组织中清除药物，但与q1wk或q2wk剂量时间表相比，治疗活性降低。对于相同剂量强度的CaelyxRTM（9 mg / kg /周），与频繁的较小剂量相比，较小的较大剂量似乎具有更好的治疗活性。总体而言，结果表明，小鼠是开发最佳脂质体药物递送系统的有价值的动物模型。

著录项

  • 作者

    Charrois, Gregory John Robert.;

  • 作者单位

    University of Alberta (Canada).;

  • 授予单位 University of Alberta (Canada).;
  • 学科 Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 164 p.
  • 总页数 164
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

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