Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain.
J Control Release. 2018 Apr 10;275:162-176. doi: 10.1016/j.jconrel.2018.02.015. Epub 2018 Feb 13.
Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab', to the polymers covering the surface of liposomes. The combination of this targeting strategy together with drug encapsulation in a single formulation may contribute to enhance the efficacy of these associated agents, reducing their toxicities. In this paper we will consider how factors such as particle size, lipid composition and charge, lipid-polymer conjugation, method of production and type of ligand for liposome coupling influence the efficacy of these formulations. Furthermore, the high inter-individual variability in the tumor microenvironment, as well as the poor experimental designs for the PK characterization of liposomes, make the establishment of the relationship between plasma or tumor concentrations and efficacy difficult. Thus, adequate dosing regimens and patient stratification regarding the target expression may contribute to enhance the possibility of incorporating these immunoliposomes into the therapeutic arsenal for cancer treatments. All these issues will be briefly dealt with here, together with a section showing the state of the art of those targeted liposomes that are coming up for testing in clinical trials. Finally, some insights into future developments such as the combination of specificity and controlled release, based on the application of different stimuli, for the manipulation of stability and cargo release, will be offered. This has been included in order to highlight the new opportunities for targeted liposomes, including immunoliposomes.
脂质体制剂可以包裹大量分子，从而改善癌症治疗，克服某些药代动力学（PK）和药效学限制，其中许多限制与肿瘤特征有关。在这种情况下，免疫脂质体代表了一种新的策略，已在临床前癌症模型中得到广泛研究，取得了有希望的结果，尽管很少有达到临床试验阶段。这与单克隆抗体（mAbs）的新兴临床应用形成对比。这种制剂允许将不同的 mAbs 或抗体衍生物，如单价可变片段 Fab'，与覆盖脂质体表面的聚合物连接。这种靶向策略与单一制剂中药物包封的结合可能有助于增强这些相关药物的疗效，降低其毒性。在本文中，我们将考虑颗粒大小、脂质组成和电荷、脂质-聚合物缀合、生产方法和脂质体偶联配体类型等因素如何影响这些制剂的疗效。此外，肿瘤微环境中的个体间高度变异性，以及脂质体 PK 特征的较差实验设计，使得很难建立这些制剂在血浆或肿瘤浓度与疗效之间的关系。因此，适当的剂量方案和针对靶表达的患者分层可能有助于增加将这些免疫脂质体纳入癌症治疗的治疗武器库的可能性。在这里，我们将简要讨论所有这些问题，并展示那些正在临床试验中进行测试的靶向脂质体的最新进展。最后，我们将提供一些关于未来发展的见解，例如基于不同刺激的应用，对稳定性和货物释放的控制释放和特异性的结合，以操纵稳定性和货物释放。这包括在内是为了突出靶向脂质体，包括免疫脂质体的新机会。
