Formulation, stabilisation and encapsulation of bacteriophage for phage therapy
Formulation, stabilisation and encapsulation of bacteriophage for phage therapy
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DOI：
10.1016/j.cis.2017.05.014
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发表时间：
2017-11-01
影响因子：
15.6
通讯作者：
Kirpichnikova, Anna
中科院分区：
文献类型：
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作者：
Malik, Danish J.;Sokolov, Ilya J.;Kirpichnikova, Anna
在全球抗生素耐药性和人们对人类微生物群重要性的认识不断提高的背景下，人们对噬菌体用于治疗目的的潜在用途（即噬菌体疗法）重新产生了兴趣。许多噬菌体疗法 I 期和 II 期临床试验已经结束，并表明噬菌体不会带来重大的不良安全问题。这些临床试验使用简单的噬菌体悬浮液，没有任何制剂，噬菌体稳定性是次要问题。噬菌体在溶液中的稳定性有限，并且在加工和储存过程中噬菌体滴度显着下降，如果噬菌体要成为受管制的药物，则这是不可接受的，其中稳定的剂量和明确的药代动力学和药物动力学是必需的。动物研究表明，噬菌体治疗的效果取决于感染部位的噬菌体浓度（即剂量）及其靶向和杀死细菌、阻止细菌生长和清除感染的能力。此外，体外和动物研究表明，使用噬菌体混合物而不是单一噬菌体制剂对于获得更好的治疗效果非常重要。由于与宿主抗体或其他清除机制的相互作用导致噬菌体浓度在体内降低，可能需要重复给予噬菌体或持续释放方法。噬菌体-细菌种群动态的建模强化了这些观点。令人惊讶的是，考虑到对噬菌体鸡尾酒的需求，鸡尾酒中的每种噬菌体可能需要显着不同的配方才能保留足够高的感染剂量，因此很少有人关注配方对噬菌体治疗结果的影响。本综述首先着眼于与急性和慢性感染治疗以及噬菌体封装驱动因素相关的临床需求和挑战（通过对评估噬菌体疗法的关键动物研究进行回顾）。配制和封装的一个重要驱动因素是噬菌体的保质期和储存，以确保可重复的剂量。其他驱动因素包括封装在微米和纳米颗粒中以实现有效递送的噬菌体制剂、封装在刺激响应系统中以在感染的目标部位触发受控或持续释放。噬菌体的封装（例如在脂质体中）也可用于增加噬菌体的循环时间，用于治疗全身感染、用于预防性治疗或用于治疗细胞内感染。然后，我们继续记录已发表文献中使用的关于噬菌体的配制和稳定化的方法，这些方法用于使用冷冻干燥（冻干）、喷雾干燥、在乳液中将噬菌体储存和封装在微米和纳米结构材料中。软膏、聚合物微粒、纳米颗粒和脂质体。随着噬菌体疗法迈向 III 期临床试验，该综述的结论是研究了有前景的噬菌体微米和纳米封装新方法，以及这些方法如何解决该领域的空白。
Against a backdrop of global antibiotic resistance and increasing awareness of the importance of the human microbiota, there has been resurgent interest in the potential use of bacteriophages for therapeutic purposes, known as phage therapy. A number of phage therapy phase I and II clinical trials have concluded, and shown phages don't present significant adverse safety concerns. These dinical trials used simple phage suspensions without any formulation and phage stability was of secondary concern. Phages have a limited stability in solution, and undergo a significant drop in phage titre during processing and storage which is unacceptable if phages are to become regulated pharmaceuticals, where stable dosage and well defined pharmacokinetics and phamiacodynamics are de rigueur. Animal studies have shown that the efficacy of phage therapy outcomes depend on the phage concentration (i.e. the dose) delivered at the site of infection, and their ability to target and kill bacteria, arresting bacterial growth and clearing the infection. In addition, in vitro and animal studies have shown the importance of using phage cocktails rather than single phage preparations to achieve better therapy outcomes. The in vivo reduction of phage concentration due to interactions with host antibodies or other clearance mechanisms may necessitate repeated dosing of phages, or sustained release approaches. Modelling of phage-bacterium population dynamics reinforces these points. Surprisingly little attention has been devoted to the effect of formulation on phage therapy outcomes, given the need for phage cocktails, where each phage within a cocktail may require significantly different formulation to retain a high enough infective dose.This review firstly looks at the clinical needs and challenges (informed through a review of key animal studies evaluating phage therapy) associated with treatment of acute and chronic infections and the drivers for phage encapsulation. An important driver for formulation and encapsulation is shelf life and storage of phage to ensure reproducible dosages. Other drivers include formulation of phage for encapsulation in micro- and nanoparticles for effective delivery, encapsulation in stimuli responsive systems for triggered controlled or sustained release at the targeted site of infection. Encapsulation of phage (e.g. in liposomes) may also be used to increase the circulation time of phage for treating systemic infections, for prophylactic treatment or to treat intracellular infections. We then proceed to document approaches used in the published literature on the formulation and stabilisation of phage for storage and encapsulation of bacteriophage in micro- and nanostructured materials using freeze drying (lyophilization), spray drying, in emulsions e.g. ointments, polymeric microparticles, nanoparticles and liposomes. As phage therapy moves forward towards Phase III clinical trials, the review concludes by looking at promising new approaches for micro- and nanoencapsulation of phages and how these may address gaps in the field.