Elsevier

Journal of Controlled Release

Volume 267, 10 December 2017, Pages 67-79
Journal of Controlled Release

Light-switchable systems for remotely controlled drug delivery

https://doi.org/10.1016/j.jconrel.2017.09.009Get rights and content

Abstract

Light-switchable systems have recently received attention as a new mode of remotely controlled drug delivery. In the past, a multitude of nanomedicine studies have sought to enhance the specificity of drug delivery to target sites by focusing on receptors overexpressed on malignant cells or environmental features of diseases sites. Despite these immense efforts, however, there are few clinically available nanomedicines. We need a paradigm shift in drug delivery. One strategy that may overcome the limitations of pathophysiology-based drug delivery is the use of remotely controlled delivery technology. Unlike pathophysiology-based active drug targeting strategies, light-switchable systems are not affected by the heterogeneity of cells, tissue types, and/or microenvironments. Instead, they are triggered by remote light (i.e., near-infrared) stimuli, which are absorbed by photoresponsive molecules or three-dimensional nanostructures. The sequential conversion of light to heat or reactive oxygen species can activate drug release and allow it to be spatio-temporally controlled. Light-switchable systems have been used to activate endosomal drug escape, modulate the release of chemical and biological drugs, and alter nanoparticle structures to control the release rates of drugs. This review will address the limitations of pathophysiology-based drug delivery systems, the current status of light-based remote-switch systems, and future directions in the application of light-switchable systems for remotely controlled drug delivery.

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).

References (84)

  • J.S. Kim et al.

    ROS-induced biodegradable polythioketal nanoparticles for intracellular delivery of anti-cancer therapeutics

    J. Ind. Eng. Chem.

    (2015)
  • S.H. Lee et al.

    Current progress in reactive oxygen species (ROS)-responsive materials for biomedical applications

    Adv. Healthc. Mater.

    (2013)
  • J. Olejniczak et al.

    Photocontrolled release using one-photon absorption of visible or NIR light

    J. Control. Release

    (2015)
  • W. Chen et al.

    Light-triggerable liposomes for enhanced endolysosomal escape and gene silencing in PC12 cells

    Mol. Ther. Nucleic Acids

    (2017)
  • M. Bostad et al.

    Light-controlled endosomal escape of the novel CD133-targeting immunotoxin AC133-saporin by photochemical internalization-A minimally invasive cancer stem cell-targeting strategy

    J. Control. Release

    (2015)
  • M.M. Shi et al.

    Quinone-induced oxidative stress elevates glutathione and induces gamma-glutamylcysteine synthetase activity in rat lung epithelial L2 cells

    J. Biol. Chem.

    (1994)
  • Y. Yesuthangam et al.

    Photogeneration of reactive oxygen species and photoinduced plasmid DNA cleavage by novel synthetic chalcones

    J. Photochem. Photobiol. B

    (2011)
  • A.B. Hill et al.

    Overcoming gene-delivery hurdles: physiological considerations for nonviral vectors

    Trends Biotechnol.

    (2016)
  • S. Stolik et al.

    Measurement of the penetration depths of red and near infrared light in human “ex vivo” tissues

    J. Photochem. Photobiol. B

    (2000)
  • K. Park

    Facing the truth about nanotechnology in drug delivery

    ACS Nano

    (2013)
  • V. Sanna et al.

    Targeted therapy using nanotechnology: focus on cancer

    Int. J. Nanomedicine

    (2014)
  • Y. Matsumura et al.

    A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs

    Cancer Res.

    (1986)
  • H.L. Goel et al.

    VEGF targets the tumour cell

    Nat. Rev. Cancer

    (2013)
  • R. Bazak et al.

    Cancer active targeting by nanoparticles: a comprehensive review of literature

    J. Cancer Res. Clin. Oncol.

    (2015)
  • Y. Ding et al.

    An efficient PEGylated liposomal nanocarrier containing cell-penetrating peptide and pH-sensitive hydrazone bond for enhancing tumor-targeted drug delivery

    Int. J. Nanomedicine

    (2015)
  • M.G. Kim et al.

    Selective activation of anticancer chemotherapy by cancer-associated fibroblasts in the tumor microenvironment

    J. Natl. Cancer Inst.

    (2017)
  • B.S. Lee et al.

    Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy

    J. Natl. Cancer Inst.

    (2015)
  • A.C. Anselmo et al.

    Nanoparticles in the clinic

    Bioeng. Transl. Med.

    (2016)
  • R. Fisher et al.

    Cancer heterogeneity: implications for targeted therapeutics

    Br. J. Cancer

    (2013)
  • Y. Yang et al.

    Nanostructures for NIR light-controlled therapies

    Nanoscale

    (2017)
  • P. Zhang et al.

    Recent progress in light-triggered nanotheranostics for cancer treatment

    Theranostics

    (2016)
  • R.A. Petros et al.

    Strategies in the design of nanoparticles for therapeutic applications

    Nat. Rev. Drug Discov.

    (2010)
  • A. Gabizon et al.

    Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes

    Cancer Res.

    (1994)
  • A. Gabizon et al.

    Pharmacokinetics of PEGylated liposomal doxorubicin

    Clin. Pharmacokinet.

    (2003)
  • C.H. Kim et al.

    Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting

    J. Pharm. Invest.

    (2017)
  • X. Guo et al.

    Near infrared light-controlled therapeutic molecules release of nanocarriers in cancer therapy

    J. Pharm. Invest.

    (2017)
  • Y. Tanaka et al.

    Long-term histological comparison between near-infrared irradiated skin and scar tissues

    Clin. Cosmet. Investig. Dermatol.

    (2010)
  • Y. Tanaka et al.

    Objective assessment of skin rejuvenation using near-infrared 1064-nm neodymium: YAG laser in Asians

    Clin. Cosmet. Investig. Dermatol.

    (2011)
  • J. Su et al.

    Bioinspired nanoparticles with NIR-controlled drug release for synergetic chemophotothermal therapy of metastatic breast cancer

    Adv. Funct. Mater.

    (2016)
  • J. Song et al.

    Biodegradable theranostic plasmonic vesicles of amphiphilic gold nanorods

    ACS Nano

    (2013)
  • S.H. Hu et al.

    Photoresponsive protein-graphene-protein hybrid capsules with dual targeted heat-triggered drug delivery approach for enhanced tumor therapy

    Adv. Funct. Mater.

    (2014)
  • G. Chen et al.

    Neuroendocrine tumor-targeted upconversion nanoparticle-based micelles for simultaneous NIR-controlled combination chemotherapy and photodynamic therapy, and fluorescence imaging

    Adv. Funct. Mater.

    (2017)
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