Light-switchable systems for remotely controlled drug delivery
Graphical abstract
Introduction
Nanotechnology-based drug formulations have been intensively exploited for decades to improve therapeutic index, modulate distribution, and control drug release at disease sites [1], [2]. In cancer therapy, pathophysiology-based targeting strategies have been studied as a means to control anticancer drug delivery for increased distribution to tumor tissues and cancer cells [3], [4]. The enhanced permeability and retention (EPR) effect, which is based on the unusual physiological aspects of a rapidly forming tumor [5], [6], [7], has been regarded as a basic means for enhancing the delivery of anticancer drug-carrying nanoparticles to tumor tissues. The ligand modification of nanomedicines has also been extensively studied as a way to enhance the uptake of anticancer drugs by cancer cells via the specific interaction of a ligand with a marker molecule that is overexpressed on the target cell surface [8]. The next logical step, targeting the specific biophysical environment of target cells (e.g., the tumor microenvironment), considers the complexity of target tissues [9], [10], [11].
Despite these many efforts, however, physiology-based delivery systems have several drawbacks for controlled drug delivery [2], [12]. Although numerous approaches and designs of sophisticated delivery systems have shown genuinely positive and promising results, the results obtained in animal models have rarely translated to clinical outcomes. With respect to the tumor accumulation of nanotechnology-based drugs, the tumor delivery rates are less than 5% of the total injection dose, suggesting that the values of EPR-based passive targeting and modified ligand-based active targeting have been overstated in the nanomedical community. Ligand-modified nanomedicines that target overexpressed receptors or marker molecules on target cells are limited because the levels of unique markers may change with time and/or differ among heterogeneous cells [12]. They may also cause side effects when the target molecules are not exclusive to the target cell surfaces [13]. Recently, tumor microenvironments have emerged as new targets that may be used to activate the delivery of anticancer drugs [10]. The very slow progress in the well-studied realm of pathophysiology-based approaches indicates that we need a paradigm shift in the design of controlled drug delivery systems.
Remotely controlled delivery, which has emerged as an alternative modality to overcome or complement the limitations of pathophysiology-based drug delivery systems, offers the advantage of being unaffected by the heterogeneous natures of target cells, tissues, and microenvironments. One potential remote stimulus source for remotely controlled delivery is light [14], [15]. Light-switchable systems are composed of photoresponsive molecules or nanostructures, which absorb irradiated light and transduce it to heat (in a photothermal mechanism) or reactive oxygen species (ROS; in a photodynamic mechanism) to activate drug release [14].
This review will briefly assess the current status of pathophysiology-based drug delivery technologies, cover the potentials of various light-switchable systems for remotely controlled delivery, examine the main mechanisms of light-based activation, and address the current status of light-switchable systems. Finally, the challenges and future directions of remotely controlled delivery will be explored.
Section snippets
Limitations of pathophysiology-based drug delivery
The concept of pathophysiology-based drug targeting has been intensively studied for neoplastic diseases with theoretical base on the EPR effect, which has been widely accepted in nanomedicine. Vascular endothelial growth factor (VEGF), which is secreted from most neoplastic cells during their abnormal growth, activates VEGF receptor signaling to induce rapid angiogenesis and increase blood vessel permeability [6], [7]. According to the EPR effect, macromolecules and nanoparticles readily
Advantages of light switches for remotely controlled delivery
The field of remotely controlled delivery needs attention in that drug release would be controlled by external stimulus, rather than pathophysiological features. Remote stimuli may include light, ultrasound, and electric pulse. In this review, we will focus on light as a source of remote control.
The use of light stimulus for remotely controlled delivery has various advantages. First, the external application of light enables drug release to be activated in a controlled manner. In
Light-switchable mechanisms of remote controlled delivery
The release mechanisms of light-switchable systems can be divided into three types: physical disruption of the carrier by a photothermal effect [27], [28], [29]; chemical degradation of the carriers by a photochemical effect [30]; and molecular structure change of the carriers by a photoisomerization effect [31] (Fig. 1).
Light-switchable spatio-temporal release
In spatio-temporal release, the remote light stimulus has been used to elaborately control the release kinetics of drug in cascade pathways at irradiated sites. These systems can minimize the initial burst of drug at non-target sites before light exposure. Light-switchable spatio-temporal release systems been studied for chemical drugs such as doxorubicin [35], [61], carbon monoxide [62], and phenylethylenesulfonamide [63], as well as biological drugs including proteins [64] and nucleic acids
Light-switchable enhancement of endosomal escape
Efforts to deliver active agents intracellularly to the cytoplasm or nucleus are often frustrated by the endosomal pathway. Many nanoparticles enter the cell via endocytosis, whereupon they are located in endosomes, which can traffic to lysosomes. Under the acidic and digestive-enzyme-rich conditions of endolysosomes, macromolecular drugs such as proteins and nucleic acids can be easily degraded before they reach their intracellular targets. To overcome this issue, researchers have tested the
Perspectives and future directions
Most of the light-activatable systems reported to date have focused on treating cancers, and have been designed to be intravenously injected on a nanoscale. Most of these studies have assumed that the EPR effect will distribute the light-activatable nanoscale systems to cancer tissues, which may not be the case in patients with heterogeneous tumor vasculatures [1]. Given the feasibility of light-switchable systems for endosomal escape and spatio-temporal release, additional formulations (e.g.,
Conclusion
Pathophysiology-based drug delivery leaves few options for controlling the rate and extent of drug release at target sites. In contrast, light-switchable systems may enable drugs to undergo spatio-temporal delivery under remote control. Photothermal, photochemical, and photoisomerization-based mechanisms have been used with NIR as strategies to control the release of drugs. Moreover, the endosomal escape feature of some light-switchable systems could prove useful for biological drugs, which are
Acknowledgement
This work was supported by research grants from the Ministry of Science and ICT, Republic of Korea (NRF-2015R1A2A1A01005674), and the Korean Health Technology R&D project, Ministry of Health and Welfare, Republic of Korea (No. HI15C2842).
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