Elsevier

Advanced Drug Delivery Reviews

Volume 138, 1 January 2019, Pages 117-132
Advanced Drug Delivery Reviews

Remotely controlled opening of delivery vehicles and release of cargo by external triggers

https://doi.org/10.1016/j.addr.2018.10.003Get rights and content

Abstract

Tremendous efforts have been devoted to the development of future nanomedicines that can be specifically designed to incorporate responsive elements that undergo modification in structural properties upon external triggers. One potential use of such stimuli-responsive materials is to release encapsulated cargo upon excitation by an external trigger. Today, such stimuli-response materials allow for spatial and temporal tunability, which enables the controlled delivery of compounds in a specific and dose-dependent manner. This potentially is of great interest for medicine (e.g. allowing for remotely controlled drug delivery to cells, etc.). Among the different external exogenous and endogenous stimuli used to control the desired release, light and magnetic fields offer interesting possibilities, allowing defined, real time control of intracellular releases. In this review we highlight the use of stimuli-responsive controlled release systems that are able to respond to light and magnetic field triggers for controlling the release of encapsulated cargo inside cells. We discuss established approaches and technologies and describe prominent examples. Special attention is devoted towards polymer capsules and polymer vesicles as containers for encapsulated cargo molecules. The advantages and disadvantages of this methodology in both, in vitro and in vivo models are discussed. An overview of challenges associate with the successful translation of those stimuli-responsive materials towards future applications in the direction of potential clinical use is given.

Graphical abstract

Release of encapsulated molecular cargo upon (external) triggers.

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Introduction

Controlled delivery of small and macromolecular drugs into cells, still remains a major challenge concerning future applications of nanoparticle-based delivery systems. There are several approaches described for delivery of cargo to intracellular regions, including viral and nonviral chemical methods [1]. However, as most nanoparticle-based delivery vehicles will enter intracellular endosomes/lysosomes, cargo release into the cytosol imposes an important experimental hurdle [2]. Thus, release of encapsulated cargo from a container upon external triggers typically would release the cargo inside endosomes/lysosomes, and subsequent endosomal escape is needed. In fact, a desired delivery strategy would involve both opening of containers and endosomal release upon the same applied external trigger.

Starting from a general point of view, control of the site and kinetics of release is important. Today, several biomedical applications, especially those related to treatment and sensing, rely on the effective lateral and temporal control of releasing the active cargo/element, e.g. drugs for treatment and reporter molecules for sensing. Targeted delivery combined with controlled release thus has gained increased attention. From this perspective, therapeutic delivery systems should aim to deliver agents to the site of interest in an efficient, safe, and control manner. In general, controlled release systems are designed i) to prevent the degradation and elimination of the cargo before it has reached the target site, ii) to enhance delivery to the desired region by minimizing the exposure to non-targeted sites, and iii) to provide greater control of the local concentration of delivered cargo over the time [3]. One appealing approach to control the release of cargo from the delivery vehicle is to design an external trigger. Upon stimulation, triggering would regulate the delivery in terms of time, release, and dose at the site of action.

There are several stimuli-responsive vehicles allowing for triggering release. A variety of stimuli have been investigated to promote the release of encapsulated cargo including i) chemical cues such as local redox-conditions, pH, salt-concentrations, presence of certain DNA sequences, etc. [[4], [5], [6]] and ii) those using stimuli by physical triggers such as ultrasound, light, electric fields, magnetic fields, microwaves, heat, etc. [[6], [7], [8], [9], [10]]. In particular, the opportunities for controlled release using light and alternating magnetic fields as stimuli have attracted considerable attention, to which focus in this review will be given. For the use of the other triggers we refer to the literature [[11], [12], [13], [14], [15]]. For instance, light can induce local heating of plasmonic nanoparticles (NPs) entrapped in hybrid matrix, which may trigger thermal degradation of the matrix leading to controlled release of encapsulated cargo [6,16]. In a similar manner, heating can also be achieved by magnetic NPs exposed to alternating magnetic fields, also resulting in controlled release of encapsulated cargo [17]. It needs to be mentioned that the intrinsic magnetoelectricity of some magnetic NPs also enables remotely controlled delivery without employing heat [18].

As stated, the use of light as external stimulus is an interesting avenue due to its clinical applicability. Light can be manipulated with high control and precision, and itself has therapeutic applications. The successful use of light as trigger relies on the light source, in terms of wavelength, power, pulse length, etc. and on the physicochemical properties of the carrier NPs and the encapsulated cargo [19]. All together will determine tissue penetration, efficacy, and potential toxicity of the system. In general, light with short wavelengths has high energy. Ultraviolet (UV) light for example may cleave chemical bonds [[20], [21], [22]]. However, due to poor tissue penetration [23] and photo-damage to cells [24], applicability of UV light as a trigger for in vivo release is quite limited. In contrast, light with higher wavelength, such as in the near infrared (NIR), presents higher tissue penetration and less photo-damage to cells [23], but in general shows lower ability to disrupt chemical structures [19,25].

On the other hand, carrier vehicles comprising magnetic NPs are also prominent examples of stimulus-controlled containers, which can be remotely controlled by magnetic fields. Magnetic fields can penetrate tissue and thus stimulation deep inside tissue is possible. Controlled release can be achieved using frequencies and magnetic field settings biocompatible with the human body. For instance, magneto-electric NPs, which could be controlled by both magnetic and electric fields, have been demonstrated as on-demand release materials with a site-specific delivery of drugs, such as peptides [26], and other compounds [18,27,28] into the target site.

In this review we highlight the use of light and magnetic fields to control release of encapsulated content involving both in vitro and in vivo systems. We first provide an overview of different triggers using light stimuli. For that, prominent examples of photo-responsive hybrid materials which have been applied in that context will be described. Second, we present a summary of release upon magnetic stimuli. Finally, an overview of major advantages and disadvantages of light and magnetic fields as triggers for controlled release will be given. Future perspectives and challenges needed for the development of those approaches towards their successful clinical translation will be discussed.

Section snippets

Carrier vehicle disintegration and endo/lysosomal escape of released molecular cargo

Particulate delivery vehicles, including NPs, polyelectrolyte capsules, liposomes, polyplexes, lipoplexes, etc. are internalized by cells via different endocytic pathways [29], whereby most vehicles eventually reach lysosomes [[30], [31], [32]]. Extensive work has been focused on developing biodegradable vehicles [29], with the goal of achieving lysosomal escape without external stimuli [7,[33], [34], [35]]. As an example, self-quenched DQ-ovalbumin (DQ-OVA, ~ 45 kDa, Thermofisher) [36], which

Light-triggered release

In this section, several light-responsive materials and different approaches towards triggered release are discussed. However, as endosomal escape is a general problem [2], we start by describing first this common limitation of drug delivery systems, before discussing how light-triggered release may circumnavigate it.

Alternating magnetic field-triggered release

Magnetic NPs have been extensively investigated as heat mediators for magnetic hyperthermia under an alternating magnetic field (AMF) [[96], [97], [98], [99]]. In a similar way to photothermal release, heating of magnetic NPs also might be used for the disintegration of carrier vehicles and release of encapsulated cargo molecules [17], leading to magnetothermal release.

Magnetic NPs can generate heat under an AMF due to the hysteresis loss and Néel relaxation [100]. AMF-triggered release can be

Photo- versus magneto-thermal heating for triggered release of encapsulated molecules

Light and AMFs stimuli are based on the excitation of plasmonic and magnetic NPs through an electromagnetic field, but at different frequencies (note that AMFs are also a special form of electromagnetic fields). The frequency of light for photo-oxidation or photothermal heating is in the visible and NIR range, while the frequency of AMFs is in the radiofrequency range. AMFs are much less absorbed by tissue than light, and thus penetrate much deeper. For instance, 99% of magnetic fields at

Outlook

Today a variety of hybrid nanocomposite delivery vehicles are designed with distinctive physicochemical characteristics including size, surface functionalization, low toxicity, etc. Specific delivery of a compound to the desired site is crucial for improving the efficacy of treatment, while minimizing possible toxic effects. Materials allowing for drug release on demand would be helpful towards temporal control of the local concentration of the pharmaceutical compound. Stimuli responsive

Acknowledgments

N. F. acknowledges funding from the Swedish Innovation Agency (Vinnova). S. R. thanks Fazit Stiftung for a PhD fellowship. Z. L. is grateful to Chinese Scholarship Council (CSC) for a PhD fellowship. W. J. P. acknowledges the Deutsche Forschungsgemeinschaft for funding (DFG grant PA 794/21-1).

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