Department of Engineering Science, Institute of Biomedical Engineering, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Old Road Campus, Oxford OX3 7DQ, UK.
J Control Release. 2020 Mar 10;319:222-233. doi: 10.1016/j.jconrel.2019.12.045. Epub 2019 Dec 28.
The purpose of this exploratory study was to investigate the combination of a radiopharmaceutical, nanoparticles and ultrasound (US) enhanced delivery to develop a clinically viable therapeutic strategy for tumours overexpressing the epidermal growth factor receptor (EGFR). Molecularly targeted radionuclides have great potential for cancer therapy but are sometimes associated with insufficient delivery resulting in sub-cytotoxic amounts of radioactivity being delivered to the tumour. Liposome formulations are currently used in the clinic to reduce the side effects and improve the pharmacokinetic profile of chemotherapeutic drugs. However, in contrast to non-radioactive agents, loading and release of radiotherapeutics from liposomes can be challenging in the clinical setting. US-activated cavitation agents such as microbubbles (MBs) have been used to release therapeutics from liposomes to enhance the distribution/delivery in a target area. In an effort to harness the benefits of these techniques, the development of a liposome loaded radiopharmaceutical construct for enhanced delivery via acoustic cavitation was studied. The liposomal formulation was loaded with peptide, human epidermal growth factor (HEGF), coupled to a chelator for subsequent radiolabelling with Indium ([In]In), in a manner designed to be compatible with preparation in a radiopharmacy. Liposomes were efficiently radiolabelled (57%) within 1 h, with release of ~12% of the radiopeptide following a 20 s exposure to US-mediated cavitation in vitro. In clonogenic studies this level of release resulted in cytotoxicity specifically in cells over-expressing the epidermal growth factor receptor (EGFR), with over 99% reduction in colony survival compared to controls. The formulation extended the circulation time and changed the biodistribution compared to the non-liposomal radiopeptide in vivo, although interestingly the biodistribution did not resemble that of liposome constructs currently used in the clinic. Cavitation of MBs co-injected with liposomes into tumours expressing high levels of EGFR resulted in a 2-fold enhancement in tumour uptake within 20 min. However, owing to the poor vascularisation of the tumour model used the same level of uptake was achieved without US after 24 h. By combining acoustic-cavitation-sensitive liposomes with radiopharmaceuticals this research represents a new concept in achieving targeted delivery of radiopharmaceuticals.
这项探索性研究的目的是研究放射性药物、纳米颗粒和超声（US）增强传递的结合，以开发针对过度表达表皮生长因子受体（EGFR）的肿瘤的临床可行的治疗策略。分子靶向放射性核素在癌症治疗方面具有巨大潜力，但有时与传递不足有关，导致放射性活度的亚细胞毒性剂量传递到肿瘤。脂质体制剂目前在临床上用于减少副作用并改善化疗药物的药代动力学特性。然而，与非放射性药物相比，从脂质体中加载和释放放射性药物在临床环境中可能具有挑战性。超声激活的空化剂（如微泡（MB））已被用于从脂质体中释放治疗剂，以增强目标区域的分布/传递。为了利用这些技术的优势，研究了通过声空化增强传递的负载放射性药物的脂质体制剂的开发。脂质体制剂以与放射性药物制备兼容的方式负载肽，即人表皮生长因子（HEGF），与螯合剂偶联，随后用铟（[In]In）进行放射性标记。脂质体在 1 小时内有效地进行放射性标记（57%），在体外超声介导的空化作用下暴露 20 秒后，约有 12%的放射性肽被释放。在集落形成研究中，这种释放水平导致 EGFR 过度表达的细胞产生细胞毒性，与对照组相比，集落存活率降低超过 99%。与非脂质体放射性肽相比，该制剂在体内延长了循环时间并改变了生物分布，尽管有趣的是，生物分布与目前临床上使用的脂质体构建体不同。将高表达 EGFR 的肿瘤中注射的 MB 与脂质体共空化导致肿瘤摄取在 20 分钟内增加 2 倍。然而，由于所使用的肿瘤模型的血管化不良，在没有 US 的情况下，24 小时后达到了相同的摄取水平。通过将声敏脂质体与放射性药物结合，这项研究代表了实现放射性药物靶向传递的新概念。
