A principal purpose of targeting or triggering is to improve the active agents’ therapeutic indices by preferentially increasing their concentrations at the desired site of effect.

A principal purpose of targeting or triggering is to improve the active agents’ therapeutic indices by preferentially increasing their concentrations at the desired site of effect. Ideally, a drug delivery system would deliver drugs only where they are needed, when they are needed, and to the degree that they are needed. Over the past many years, there has been increasing interest in targeted and triggered nanomaterials to achieve those goals. Targeted nanoparticles refer to those that can selectively accumulate in a targeted tissue relative to others. Triggered drug delivery systems achieve a drug delivery event (drug release or triggered targeting) in a tissue in response to a stimulus. Some systems rely on endogenous environmental properties such as pH, hypoxia, and/or enzyme activity, to provide the stimulus that causes the drug delivery event;(1) these are often referred to as “passive”. Others depend on external triggering sources, such as light, ultrasound, and chemicals.(2) Targeting of a tissue can also be achieved by attaching a specific ligand to the nanoparticle surface.(3) Those systems that do not rely on simple tissue properties are often referred to as “active”. The goal is to increase the therapeutic effect of a given drug by maximizing the fraction of free drug accumulating (targeting) or being released (triggering) at the intended site of action, enhancing efficacy and minimizing toxicity. Despite a body of experimental data suggesting that such approaches could work, and some nanoencapsulated drugs having obtained FDA approval or entered clinic trials,(4) there is still a lot of room for development. Some diseases have tissue properties that enable targeting and triggering of drug release, so that nanomaterials show improved efficacy and reduced toxicity compared to conventional formulations. As an example of tissue properties driving targeting, the enhanced permeability and retention (EPR) effect has been used to target PEGylated liposomal doxorubicin (Doxil) to tumors. With EPR, the relatively leaky vasculature of tumors allows the preferential accumulation of drug-loaded nanoparticles of a given size on-target, improving efficacy in relation to toxicity.(5) (The relevance to and reliability of EPR in human disease is debated.(6)) As an example of tissue properties enabling triggering, the mild acidity at tumor sites (and in specific cell compartments) has been used to trigger pH-responsive nanomaterials to degrade or dissolve at the site of interest, achieving high local drug concentrations.(7) The fact that selectivity is not absolute remains a major challenge. Only a small percentage (∼1%) of systemically administered nanoparticles reach the diseased site,(8) and perhaps equally important, the amount reaching off-target sites and causing toxicity remains substantial, that is, the therapeutic index (the ratio of the toxic to the efficacious dose) has not been optimized. Therefore, it is still of great interest to develop novel strategies to enhance targeting. Triggering by an external source can further enhance delivery to or release at a specific location, perhaps in the absence of tissue properties that might trigger such events, and can enable targeting even in the absence of a specific ligand. One approach is to decorate a nanoparticle with a ligand that works on most cell surfaces, such as arginine-glycine-aspartate (RGD) derivatives, or cell-penetrating peptides. Inactivation of the ligand by a photosensitive moiety renders that ligand phototriggerable, allowing accumulation of the nanoparticle in response to irradiation.(9) As an example of application in vivo, irradiation of the eye increased accumulation of intravenously administered nanoparticles (and drug) modified with a cell penetrating peptide inactivated with a diethylamino-coumarin caging group in a murine model of choroidal neovascularization.(10) In our experience, targeting, especially triggered targeting of this type, works much better in the context of an existing endogenous condition that enhances accumulation. In the preceding example, accumulation in the eye in the absence of the EPR-like state engendered by neovascularization was minimal. External triggering can also provide temporal control of drug release, for example, to allow drug release to be actuated by a hand-held device held by a patient, on-demand, and to allow the patient to dial in exactly how much drug is released by adjusting the intensity of the stimulus. Liposomes loaded with local anesthetics were rendered photosensitive by decorating their surfaces with gold nanorods which would heat upon irradiation with near-infrared light, via surface plasmon resonance.(11) The heat would increase drug release from the liposomes, resulting in local anesthesia on demand, the intensity of which could be modulated by the intensity and duration of irradiation. Applying energy sources for an extended period or at high irradiance could enhance the therapeutic effect but could also cause tissue injury.(12) Therefore, the sensitivity of nanoparticles to external stimuli has emerged as a key design feature, as has using triggering modalities with less attenuation as they travel through tissue. While enhancing the triggerability of systems is important, excessive sensitivity can render them triggerable by ambient conditions (e.g., daylight), fever, airport scanners, and medical MRI. Also, often systems that are relatively easy to trigger also have more basal (i.e., untriggered) drug release. (For example, it is easier to trigger drug release from liposomes than from covalent drug-polymer conjugates, but liposomes also have greater basal drug release).(13) Systems with high basal drug release also often have significant initial (“burst”) release, and subsequent basal release can lead to continuous unwanted depletion of drug that could have been used for triggered events. Another challenge for externally stimulated systems is identifying where to apply the stimuli (e.g., the location of a tumor) or when nanoparticle accumulation reaches its maximum. Integration of traditional imaging technologies (e.g., guidance by ultrasonography in regional anesthesia(14)) with nanoimaging agents or theranostic nanoparticles could be helpful in these situations. Triggerable and targeted systems can be enhanced by applications from other subfields of drug delivery. For example, covalent and noncovalent methods of minimizing untriggered drug release could minimize off target drug effect, improving the therapeutic index. The road to translation for remotely triggered and targeted approaches is hampered by many factors. A common problem in the study of nanoparticulate delivery is the heterogeneity of different diseases or models; xenografted mouse models may not mimic human tumors; the EPR effect can vary in different tumors or within individual tumors. Consequently, efforts to understand the pathophysiology of each disease will remain important, as will the development of preclinical models that accurately reflect human disease. The discrepancy between human and animal may be particularly important in the context of external energy triggers, as the distances across which the energy has to be transmitted, and over which it can be attenuated or cause injury, are much greater. This scale issue highlights the importance of developing systems with high sensitivity to stimuli and stimuli with low attenuation. Stimuli that focus multiple beams at a given point may prove to be safer. Combinations of stimuli that are truly synergistic (a term that is very often used but rarely proven) may greatly enhance local accumulation and therefore the therapeutic index. However, combining stimuli and other improvements described above may involve more complex formulations and relatively exotic materials. As technologies using these approaches proliferate, it may become important to demonstrate that they are better than others and that they improve outcomes. In particular, it will be important to demonstrate that the therapeutic index is meaningfully affected, using relevant therapeutic and toxic end points in animal models that accurately mimic human pathophysiology and pharmacology. Such data could facilitate translation by helping to mitigate possible regulatory hurdles created by, for example, the possible complexity and unusual materials of the formulations, or the fact that in some cases the system would be a combination of a device and a drug delivery system. Successful translation could have great effect in diseases where therapeutic effect is limited, especially if by toxicity (as in cancer), and also in conditions where the patient’s ability to control drug effect in real time would be greatly beneficial (as in pain). The authors declare no competing financial interest. The authors declare no competing financial interest. We acknowledge the support from National Institutes of Health (NIH) Grant R35GM131728. This article references 14 other publications.

中文翻译：

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保持纳米药物靶向

靶向或触发的主要目的是通过优先增加活性剂在所需作用部位的浓度来改善活性剂的治疗指数。

靶向或触发的主要目的是通过优先增加活性剂在所需作用部位的浓度来改善活性剂的治疗指数。理想地，药物输送系统将仅在需要的地方，需要的时候以及在需要的程度上输送药物。在过去的许多年中，人们越来越关注有针对性的触发纳米材料以实现这些目标。靶向纳米粒子是指相对于其他纳米粒子可以选择性地积累在靶向组织中的纳米粒子。触发的药物递送系统响应于刺激而在组织中实现药物递送事件（药物释放或触发的靶向）。一些系统依赖于内在的环境特性，例如pH值，缺氧和/或酶活性，以提供引起药物传递事件的刺激。（1）这些通常称为“被动”。其他依赖于外部触发源，例如光，超声和化学物质。（2）也可以通过将特定的配体附着到纳米颗粒表面来实现组织的靶向。（3）不依赖简单组织特性的系统通常称为“主动”。目的是通过最大化在预期作用部位积累（靶向）或释放（触发）的游离药物的比例，增强疗效并最小化毒性，来提高给定药物的治疗效果。尽管有大量实验数据表明这种方法可行，并且一些纳米胶囊药物已获得FDA批准或进入临床试验，[4]但仍有很大的发展空间。一些疾病具有能够靶向和触发药物释放的组织特性，因此与传统制剂相比，纳米材料显示出更高的功效和更低的毒性。作为驱动靶向的组织特性的一个示例，增强的渗透性和保留（EPR）效应已用于将PEG化脂质体阿霉素（Doxil）靶向肿瘤。使用EPR，肿瘤的相对渗漏的脉管系统可以使目标大小给定大小的载药纳米粒子优先积累，从而提高了与毒性相关的功效。（5）（关于EPR在人类疾病中的相关性和可靠性的讨论。 （6））作为触发组织特性的示例，肿瘤部位（和特定细胞室）的弱酸性已被用来触发pH响应纳米材料在感兴趣部位降解或溶解，从而达到较高的局部药物浓度。（7）选择性不是绝对的事实仍然存在。重大挑战。全身给药的纳米颗粒中只有一小部分（〜1％）到达患病部位（8），也许同样重要的是，到达脱靶部位并引起毒性的数量仍然很大，即治疗指数（对有效剂量有毒）尚未优化。因此，仍然有很大的兴趣来开发新颖的策略以增强目标。由外部来源触发可以进一步增强对特定位置的投放或释放，也许在缺乏可能触发此类事件的组织特性的情况下，甚至在没有特定配体的情况下也可以实现靶向。一种方法是用能在大多数细胞表面上起作用的配体修饰纳米颗粒，例如精氨酸-甘氨酸-天冬氨酸（RGD）衍生物或可穿透细胞的肽。通过光敏部分使配体失活，使配体可光触发，从而使纳米颗粒响应辐照而积累。（9）作为体内应用的一个实例，眼睛的辐照增加了静脉内施用的经纳米管修饰的纳米颗粒（和药物）的积累。一种在脉络膜新血管形成的鼠模型中被二乙氨基香豆素笼蔽基团灭活的细胞穿透肽。（10）根据我们的经验，靶向，尤其是触发了这种类型的靶向，在现有的内源性条件下（可以增强积累），效果会更好。在前述示例中，在不存在由新血管形成引起的EPR样状态的情况下，眼睛中的积累最小。外部触发还可以提供药物释放的时间控制，例如，允许按需由患者手持的手持设备来驱动药物释放，并允许患者准确输入释放的药物数量通过调整刺激强度。负载有局部麻醉剂的脂质体通过在其表面用金纳米棒修饰表面而变得光敏，该纳米棒会在近红外光照射下通过表面等离振子共振而加热。（11）热量会增加从脂质体释放的药物，从而导致按需进行局部麻醉，其强度可以通过照射的强度和持续时间来调节。长时间或在高辐照度下使用能源可增强治疗效果，但也可能导致组织损伤。（12）因此，纳米颗粒对外部刺激的敏感性已成为一项关键设计特征，而使用触发方式的方法则较少当它们穿过组织时衰减。尽管增强系统的可触发性很重要，但过高的灵敏度会使它们在周围环境（例如，日光），发烧，机场扫描仪和医学MRI的情况下可被触发。同样，通常相对容易触发的系统也具有更多的基础（即未触发）药物释放。（例如，从脂质体触发药物释放比从共价药物-聚合物缀合物触发更容易，（13）具有高基础药物释放的系统通常也具有显着的初始（“爆发”）释放，随后的基础释放会导致本来可以用于触发的药物持续不断地消耗掉事件。外部刺激系统的另一个挑战是确定在何处施加刺激（例如肿瘤的位置）或何时纳米颗粒积累达到最大。在这些情况下，将传统的成像技术（例如，在区域麻醉中的超声检查指导（14））与纳米成像剂或治疗性纳米颗粒的整合可能会有所帮助。可触发和针对性的系统可以通过药物输送其他子领域的应用来增强。例如，最小化未触发药物释放的共价和非共价方法可以最大程度地降低脱靶药物的作用，从而提高治疗指数。远程触发和针对性方法的翻译之路受到许多因素的阻碍。研究纳米颗粒传递的一个普遍问题是不同疾病或模型的异质性。异种移植的小鼠模型可能无法模仿人类肿瘤；在不同的肿瘤或单个肿瘤中，EPR效果可能会有所不同。因此，理解每种疾病的病理生理学的努力将仍然很重要，准确地反映人类疾病的临床前模型的开发也将保持重要。在外部能量触发的情况下，人与动物之间的差异可能尤其重要，因为必须传输能量的距离 且其衰减或造成伤害的范围要大得多。这个规模问题突出了开发对刺激具有高敏感性和低衰减的刺激系统的重要性。将多个光束聚焦在给定点的刺激可能被证明是更安全的。真正具有协同作用的刺激组合（一个经常使用但很少被证实的术语）可以大大增强局部积累，从而提高治疗指数。然而，将刺激和上述其他改进结合起来可能涉及更复杂的配方和相对奇特的材料。随着使用这些方法的技术的激增，证明它们比其他技术更好并改善结果可能变得很重要。特别重要的是，要证明治疗指数受到了有意义的影响，在动物模型中使用可精确模拟人类病理生理学和药理学的相关治疗和毒性终点。这样的数据可以通过帮助减轻可能的监管障碍来促进翻译，例如，这些障碍可能是由于配方的可能复杂性和不寻常的材料，或者在某些情况下该系统将是设备和药物输送系统的组合。成功的翻译可以在治疗效果有限的疾病中发挥巨大作用，尤其是由于毒性（例如在癌症中），以及在患者实时控制药物作用的能力将非常有益的情况下（例如在疼痛中）。作者宣称没有竞争性的经济利益。作者宣称没有竞争性的经济利益。我们感谢美国国立卫生研究院（NIH）Grant R35GM131728的支持。本文引用了其他14个出版物。