Sapra Puja, Moase Elaine H, Ma Jie, Allen Theresa M
Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Clin Cancer Res. 2004 Feb 1;10(3):1100-11. doi: 10.1158/1078-0432.ccr-03-0041.
Monoclonal antibody-mediated targeting of liposomal anticancer drugs to surface antigens expressed on malignant B cells can be an effective strategy for treating B-cell malignancies. In a murine model of human B-cell lymphoma, we have made in vitro and in vivo comparisons of long-circulating sterically stabilized (Stealth) immunoliposome (SIL) formulations of two anticancer drugs, vincristine (VCR) and doxorubicin (DXR), with different mechanisms of action and drug release rates.
SIL formulations of VCR or DXR were conjugated to the monoclonal antibody anti-CD19 (SIL[alphaCD19]) or its Fab' fragments (SIL[Fab']). Specific binding of SILs to Namalwa cells was studied using radiolabeled liposomes, and cytotoxicities of DXR- or VCR-loaded SILs were quantitated by a tetrazolium assay. Pharmacokinetic and drug leakage experiments were performed in mice using dual-labeled liposomes, and the therapeutic responses of SILs were evaluated in a Namalwa (human B lymphoma) cell xenograft model.
SIL[alphaCD19] or SIL[Fab'] had higher association with and cytotoxicity against Namalwa cells than nontargeted liposomes. SIL[Fab'] had longer circulation times than SIL[alphaCD19], and VCR had faster release rates from the liposomes than DXR. SIL formulations of either VCR or DXR had significantly better therapeutic outcomes than nontargeted liposomes or free drugs. SILs loaded with VCR were superior to those loaded with DXR. SIL[Fab'] had better therapeutic outcomes than SIL[alphaCD19] for the drug DXR but were equally efficacious for the drug VCR.
Treatment of a B lymphoma model with single injections of anti-CD19-targeted liposomal formulations of VCR resulted in high levels of response and long-term survivors. Responses to anti-CD19-targeted liposomal DXR were more modest, although the longer circulation times of SIL[Fab'] versus SIL[alphaCD19] led to superior therapeutics for DXR-loaded immunoliposomes.
单克隆抗体介导的脂质体抗癌药物靶向作用于恶性B细胞表面表达的抗原，可能是治疗B细胞恶性肿瘤的有效策略。在人B细胞淋巴瘤的小鼠模型中，我们对两种作用机制和药物释放速率不同的抗癌药物长春新碱（VCR）和阿霉素（DXR）的长循环空间稳定（隐形）免疫脂质体（SIL）制剂进行了体外和体内比较。
将VCR或DXR的SIL制剂与单克隆抗体抗CD19（SIL[αCD19]）或其Fab'片段（SIL[Fab']）偶联。使用放射性标记的脂质体研究SIL与Namalwa细胞的特异性结合，并通过四唑盐测定法定量负载DXR或VCR的SIL的细胞毒性。使用双标记脂质体在小鼠中进行药代动力学和药物渗漏实验，并在Namalwa（人B淋巴瘤）细胞异种移植模型中评估SIL的治疗反应。
与非靶向脂质体相比，SIL[αCD19]或SIL[Fab']与Namalwa细胞的结合力更高，细胞毒性更强。SIL[Fab']的循环时间比SIL[αCD19]长，VCR从脂质体中的释放速率比DXR快。VCR或DXR的SIL制剂的治疗效果明显优于非靶向脂质体或游离药物。负载VCR的SIL优于负载DXR的SIL。对于药物DXR，SIL[Fab']的治疗效果优于SIL[αCD19]，但对于药物VCR，二者疗效相当。
单次注射抗CD19靶向的VCR脂质体制剂治疗B淋巴瘤模型可产生高水平的反应和长期存活者。抗CD19靶向的脂质体DXR的反应较为温和，尽管SIL[Fab']与SIL[αCD19]相比循环时间更长，使得负载DXR的免疫脂质体具有更好的治疗效果。
