Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial).
Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial).
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DOI：
10.1186/1471-2407-11-337
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发表时间：
2011-08-04
期刊：
影响因子：
3.8
通讯作者：
Pütz G
中科院分区：
文献类型：
--
作者：
Eckes J;Schmah O;Siebers JW;Groh U;Zschiedrich S;Rautenberg B;Hasenburg A;Jansen M;Hug MJ;Winkler K;Pütz G
化疗药物的治疗成功常常受到严重不良反应的限制。为了降低这些药物的毒性，使用纳米级颗粒基给药系统（DDS）。DDS在肿瘤组织中会有一定程度的积累，但在给定剂量下，只有很小一部分能达到这一目标。DDS在肿瘤组织中的积累应该比在某些其他会产生副作用的组织中的积累要快得多（“动力学靶向”）。一旦肿瘤组织达到饱和，大多数给药的DDS仍在血浆中循环。体外清除这些循环纳米颗粒可能会降低毒性。在carl试验（脂质体化疗药物的控制应用和去除）中，使用聚乙二醇化脂质体阿霉素（PLD）作为化疗药物，并进行双滤过血浆置换（DFPP）体外清除脂质体。PLD为每3周40 mg/m2联合长春瑞滨2 × 25 mg/m2（乳腺癌新辅助治疗12例），或每4周40 mg/m2（复发性卵巢癌3例）。主要终点是DFPP的有效性和安全性，次要终点是副作用和肿瘤反应。DFPP消除了~62%的循环PLD，相当于总剂量的~45% （n = 57个循环）。阿霉素AUC降低50%。消除过程中未检测到阿霉素泄漏，也未发生与dppp相关的副作用。10/12（新辅助）和1/3（复发）患者的肿瘤大小减少了30%。仅有5例2级事件和1例3级事件（粘膜炎、中性粒细胞减少或白细胞减少）和1例2级掌跖红肿。DFPP体外清除PLD安全有效。CARL可以减少PLD的主要剂量限制副作用，可能许多不同的DDS也一样。DRKS00000163
The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle-based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. For the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m2 every 3 weeks in combination with vinorelbine 2 × 25 mg/m2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. DFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported. Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike. DRKS00000163
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