Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain; Laboratory Experimental Surgical Oncology, Department of Surgery, Erasmus MC Cancer Institute, Rotterdam 3015 GE, The Netherland.
Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain.
J Control Release. 2015 Jul 28;210:26-38. doi: 10.1016/j.jconrel.2015.05.271. Epub 2015 May 19.
Oxaliplatin (L-OH), a platinum derivative with good tolerability is currently combined with Cetuximab (CTX), a monoclonal antibody (mAb), for the treatment of certain (wild-type KRAS) metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Improvement of L-OH pharmacokinetics (PK) can be provided by its encapsulation into liposomes, allowing a more selective accumulation and delivery to the tumor. Here, we aim to associate both agents in a novel liposomal targeted therapy by linking CTX to the drug-loaded liposomes. These EGFR-targeted liposomes potentially combine the therapeutic activity and selectivity of CTX with tumor-cell delivery of L-OH in a single therapeutic approach. L-OH liposomes carrying whole CTX or CTX-Fab' fragments on their surface were designed and characterized. Their functionality was tested in vitro using four human CRC cell lines, expressing different levels of EGFR to investigate the role of CTX-EGFR interactions in the cellular binding and uptake of the nanocarriers and encapsulated drug. Next, those formulations were evaluated in vivo in a colorectal cancer xenograft model with regard to tumor drug accumulation, toxicity and therapeutic activity. In EGFR-overexpressing cell lines, intracellular drug delivery by targeted liposomes increased with receptor density reaching up to 3-fold higher levels than with non-targeted liposomes. Receptor specific uptake was demonstrated by competition with free CTX, which reduced internalization to levels similar to non-targeted liposomes. In a CRC xenograft model, drug delivery was strongly enhanced upon treatment with targeted formulations. Liposomes conjugated with monovalent CTX-Fab' fragments showed superior drug accumulation in tumor tissue (2916.0±507.84ng/g) compared to CTX liposomes (1546.02±362.41ng/g) or non-targeted liposomes (891.06±155.1ng/g). Concomitantly, CTX-Fab' targeted L-OH liposomes outperformed CTX-liposomes, which on its turn was still more efficacious than non-targeted liposomes and free drug treatment in CRC bearing mice. These results show that site-directed conjugation of monovalent CTX-Fab' provides targeted L-OH liposomes that display an increased tumor drug delivery and efficacy over a formulation with CTX and non-targeted liposomes.
奥沙利铂（L-OH）是一种耐受性良好的铂类衍生物，目前与西妥昔单抗（CTX）联合用于治疗某些（野生型 KRAS）表达表皮生长因子受体（EGFR）的转移性结直肠癌（CRC）。通过将其包裹在脂质体中，可以改善 L-OH 的药代动力学（PK），从而更有选择性地积累并递送到肿瘤部位。在这里，我们旨在通过将 CTX 连接到载药脂质体上来将这两种药物联合用于新型的脂质体靶向治疗。这些 EGFR 靶向脂质体有望将 CTX 的治疗活性和选择性与 L-OH 对肿瘤细胞的递送结合在单一治疗方法中。设计并表征了表面携带完整 CTX 或 CTX-Fab'片段的 L-OH 脂质体。使用表达不同水平 EGFR 的四种人 CRC 细胞系在体外测试了它们的功能，以研究 CTX-EGFR 相互作用在纳米载体和包封药物的细胞结合和摄取中的作用。接下来，在结直肠癌异种移植模型中评估了这些制剂在肿瘤药物积累、毒性和治疗活性方面的情况。在 EGFR 过表达的细胞系中，靶向脂质体的细胞内药物递送随受体密度的增加而增加，达到非靶向脂质体的 3 倍以上。通过与游离 CTX 的竞争证明了受体特异性摄取，这将内化降低到与非靶向脂质体相似的水平。在 CRC 异种移植模型中，用靶向制剂治疗可大大增强药物递送。与单价 CTX-Fab' 片段偶联的脂质体在肿瘤组织中的药物积累（2916.0±507.84ng/g）明显优于 CTX 脂质体（1546.02±362.41ng/g）或非靶向脂质体（891.06±155.1ng/g）。同时，CTX-Fab'靶向 L-OH 脂质体优于 CTX 脂质体，而 CTX 脂质体在 CRC 荷瘤小鼠中的疗效仍优于非靶向脂质体和游离药物治疗。这些结果表明，单价 CTX-Fab'的定点偶联提供了靶向 L-OH 脂质体，与 CTX 和非靶向脂质体的制剂相比，其显示出增加的肿瘤药物递送和疗效。
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