Jason Olejniczak, Carl-Johan Carling, and Adah Almutairi

Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

IEM Center for Nanomedicine and Engineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

Department of Nanoengineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

Department of Materials Science and Engineering, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, USA

Publication Date: December 2015

Abstract

Light is an excellent means to externally control the properties of materials and small molecules for many applications. Light's ability to initiate chemistries largely independent of a material's local environment makes it particularly useful as a bio-orthogonal and on-demand trigger in living systems. Materials responsive to UV light are widely reported in the literature; however, UV light has substantial limitations for in vitro and in vivo applications. Many biological molecules absorb these energetic wavelengths directly, not only preventing substantial tissue penetration but also causing detrimental photochemical reactions. The more innocuous nature of long-wavelength light (> 400 nm) and its ability at longer wavelengths (600–950 nm) to effectively penetrate tissues is ideal for biological applications. Multi-photon processes (e.g. two-photon excitation and upconversion) using longer wavelength light, often in the near-infrared (NIR) range, have been proposed as a means of avoiding the negative characteristics of UV light. However, high-power focused laser light and long irradiation times are often required to initiate photorelease using these inefficient non-linear optical methods, limiting their in vivo use in mammalian tissues where NIR light is readily scattered. The development of materials that efficiently convert a single photon of long-wavelength light to chemical change is a viable solution to achieve in vivo photorelease. However, to date only a few such materials have been reported. Here we review current technologies for photo-regulated release using photoactive organic materials that directly absorb visible and NIR light.

Introduction

Light is widely employed as a triggering stimulus to release bioactive effectors from small molecules [1], [2], [3], [4] and nanomaterials [5], [6], [7]. Because light can be externally applied and easily tuned to a desired wavelength and power, it provides excellent spatial and temporal control over photoactive systems [7], [8], [9], [10], [11], [12]. Light's ability to activate chemistries on-demand independently of biological environments provides an enhanced level of control compared to chemical systems that are activated by biological cues such as pH [13], [14], [15], [16], [17], [18], oxidative environment [19], [20], [21], [22], [23], [24] and enzymes [25], [26], [27]. The great potential of light for controlled release has direct applications for drug delivery [5], [6], [7]. A majority of platforms for light-controlled drug delivery employ nanocarriers as they offer advantages over photocaged molecules, including protection of the payload from degradation and from off-target interactions [28], [29], [30].

Most materials capable of photorelease described in the literature rely on one-photon excitation by UV light, primarily due to the prevalence and synthetic accessibility of photoactive chromophores with direct absorption of these wavelengths [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41] UV light has sufficient energy to break [33], [34], isomerize, and rearrange [42] a variety of molecules. However, although the photochemistry is often rapid and efficient, many endogenous molecules both absorb and are degraded by UV light; the resulting damage and poor penetration limit the in vivo applicability of such materials. The wavelength range with the best tissue penetration is between 600 and 950 nm (Fig. 1) [43], [44], commonly referred to as the near-infrared (NIR) window, although 600–750 nm is visible light. Though shorter wavelength visible light (400–600 nm) has lower tissue penetration than that in the NIR window, it is still less damaging than UV. Wavelengths between 600 and 950 nm penetrate biological tissues well because the abundant endogenous chromophores heme, melanin, and water do not appreciably absorb them. However, there are very few known photoresponsive chromophores capable of bond cleavage or isomerization that absorbs this low energy light directly. To overcome this challenge and still utilize NIR to break, isomerize and rearrange molecules, non-linear optical phenomena such as two-photon excitation [45], [46] and NIR-to-UV upconversion [47], [48] have been developed and utilized. However, these non-linear optical reactions are quite inefficient and require high-power, focused lasers to occur at an appreciable rate. This prerequisite limits the practical use of such photoactive systems for in vivo applications because mammalian tissue scatters and defocuses NIR laser light, leading to a decreased power density.

Photochemistry such as bond cleavage, isomerization, and rearrangement triggered by one-photon excitation is often very fast and efficient. By developing new longer-wavelength absorbing chromophores and utilizing and improving existing photoactive chromophores with direct visible and NIR light absorption, many of the problems associated with UV light (non-specific reactivity and poor penetration depth) and non-linear excitation with NIR light (high-power and inefficiency) can be overcome. For example, photodynamic therapy, in which long-wavelength-absorbing photosensitizers convert triplet oxygen into cytotoxic singlet oxygen upon irradiation, has a long history in oncological and dermatological practice [49], [50]. Controlled photorelease of more complex bioactive effectors in vivo using long wavelength light may prove very useful in healthcare and in basic research. Molecules and materials sensitive to one-photon absorption of visible or NIR light may be used to treat disease, create photodegradable scaffolds for tissue engineering, and gain a better understanding of fundamental biological processes.

However, the array of long-wavelength one-photon-absorbing light-responsive materials and molecules capable of releasing molecules is rather limited. Here we review the current state of one-photon visible and NIR light-absorbing materials, the photoactive moieties they employ, and their application to light-triggered release. The photoactive organic materials and molecules described in this review rely primarily on three mechanisms of photoreactivity: covalent bond cleavage, isomerization, and photo-induced energy conversion (i.e. singlet oxygen generation for subsequent bond cleavage, photothermal effects and energy transfer), or a combination thereof. All mechanisms can be used to substantially change the properties of a material to trigger release using low power visible or NIR light. The review is divided into two parts: a review of one-photon visible/NIR photoactive materials with a focus on their applications in drug delivery and a review of promising one-photon visible/NIR photoactive molecules whose potential for light-triggered release has not yet been fully explored. The contents of the review were collected from a wide array of databases to be as comprehensive as possible covering publications prior to June 2015 on long wavelength light triggered release. The review does not cover photothermal effects by inorganic materials, such as gold nanoparticles, which have been reviewed extensively elsewhere [51], [52], [53].