Jyoti Amar, Fugit Kyle D, Sethi Pallavi, McGarry Ronald C, Anderson Bradley D, Upreti Meenakshi
Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY.
Department of Radiation Medicine, University of Kentucky Chandler Hospital, Lexington, KY.
Sci Rep. 2015 Oct 15;5:15236. doi: 10.1038/srep15236.
Low dose metronomic chemotherapy (LDMC) refers to prolonged administration of low dose chemotherapy designed to minimize toxicity and target the tumor endothelium, causing tumor growth inhibition. Topotecan (TPT) when administered at its maximum tolerated dose (MTD) is often associated with systemic hematological toxicities. Liposomal encapsulation of TPT enhances efficacy by shielding it from systemic clearance, allowing greater uptake and extended tissue exposure in tumors. Extended release of TPT from liposomal formulations also has the potential to mimic metronomic therapies with fewer treatments. Here we investigate potential toxicities of equivalent doses of free and actively loaded liposomal TPT (LTPT) and compare them to a fractionated low dose regimen of free TPT in tumor-endothelial spheroids (TES) with/without radiation exposure for a prolonged period of 10 days. Using confocal microscopy, TPT fluorescence was monitored to determine the accumulation of drug within TES. These studies showed TES, being more reflective of the in vivo tumor microenvironment, were more sensitive to LTPT in comparison to free TPT with radiation. More importantly, the response of TES to low-dose metronomic TPT with radiation was comparable to similar treatment with LTPT. This TES study suggests nanoparticle formulations designed for extended release of drug can simulate LDMC in vivo.
低剂量节拍化疗（LDMC）是指长时间给予低剂量化疗，旨在将毒性降至最低并靶向肿瘤内皮，从而抑制肿瘤生长。拓扑替康（TPT）在其最大耐受剂量（MTD）下给药时，常伴有全身血液学毒性。TPT的脂质体包封通过使其免受全身清除，增强了疗效，从而在肿瘤中实现更大的摄取和更长时间的组织暴露。从脂质体制剂中持续释放TPT也有可能以更少的治疗次数模拟节拍疗法。在此，我们研究了等量的游离型和主动载药脂质体TPT（LTPT）的潜在毒性，并将它们与游离TPT的分次低剂量方案在有/无长时间（10天）辐射暴露的肿瘤内皮球体（TES）中的毒性进行比较。使用共聚焦显微镜监测TPT荧光，以确定药物在TES中的积累情况。这些研究表明，TES更能反映体内肿瘤微环境，与接受辐射的游离TPT相比，其对LTPT更敏感。更重要的是，TES对低剂量节拍TPT联合辐射的反应与LTPT的类似治疗相当。这项TES研究表明，设计用于药物持续释放的纳米颗粒制剂可以在体内模拟LDMC。
