Biomedical Engineering Reference
In-Depth Information
in the last 15 years (Schmers et al., 2010). However, to date the majority of these publications have
focused on the unique chemistry of activation, and have not thoroughly investigated the biocom-
patibility of the novel material. While obvious proof of concept studies are critical to furthering
the field of stimuli-responsive drug delivery systems, these studies need to be accompanied by a
thorough investigation into the biocompatibility of the novel material if they are to translate to a
clinically relevant solution for drug delivery. While many reports have been made regarding the
design and potentials of stimuli-responsive drug delivery systems, the issues of biocompatibility
and safety concerns have not been properly addressed. For this reason, this chapter will focus on
presenting key points on stimuli-responsive biomaterials and nanocarriers while assessing the need
for biocompatibility testing of new stimuli-responsive materials as well as the safety concerns of
stimulus that are used to trigger the system.
4.2 PHOTORESPONSIVE MATERIALS
The use of light as the activating stimulus has many potential advantages over other forms of
stimuli. The intrinsic properties of light allow for precise temporal and spatial control of system
activation due to the inherent ability to tune such systems to respond according to a multitude of
parameters, including wavelength, intensity, duration, and location of exposure. Additionally, since
photoresponsive materials utilize an externally applied light source for activation, these systems
have the potential to function as generic platforms, which can be used to treat a variety of diseases
through manipulation of the therapeutic payload. Photoresponsive materials have been developed
for numerous applications including selective drug delivery (Lu et al., 2008), photothermal ablation
therapy (Boca et al., 2011), and micropatterning of implantable devices (Sun et al., 2012). For those
systems aimed at providing selective drug delivery, a variety of approaches have been investigated,
including nanoimpellers, polymer scission, isomer switching, micelle/nanoparticle (NP) disruption,
and even pulsed (on-off) release—capable of turning drug release “on” or “off” based on the wave-
length of light used to irradiate the system.
Lu et al. (2008) developed a system for selective drug delivery using a photo-activated nanoim-
peller that controlled the release of the anticancer drug camptothecin from mesoporous silica NPs.
In this system, azobenzene was linked to organosilane, which was subsequently attached to meso-
porous silica NPs such that it covered the surface of the pores. Drug molecules loaded into these
pores could then be selectively released inside cancer cells upon photoactivation due to the switch-
ing of azobenzene between the
cis
and
trans
isomers when irradiated with visible light. The bio-
compatibility of this system was investigated following 72 h incubation by performing a cell count
after staining the cells with propidium iodide and Hoechst 33342. At the concentrations tested (10
and 100 μg/mL), the cellular viabilities were near 100% for both cell lines (PANC-1 and SW480),
which demonstrated
in vitro
biocompatibility of the system. This system utilized visible light (vio-
let, 413 nm) for activation of the chromophore. Irradiation of the cells with 413 nm light was found
to not inhibit cellular proliferation even at the maximum exposure time of 10 min.
Fomina et al. (2011) took a different approach in the development of a photo-activated NP-based
system for selective drug delivery. In their system, irradiation with ultraviolet (UV) or near-infrared
(NIR) light resulted in the photolysis of the protecting group 4-bromo-7-hydroxycoumarin (Bhc).
This triggered a cascade of rearrangement reactions and cyclizations that ultimately resulted in
complete breakdown of the polymer and release of entrapped drug. Using the 3-(4,5-dimethyl-
thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the authors were able to claim bio-
compatibility of both the intact NPs as well as the scission products over a concentration range of
1.17-30 0 μg/mL. The authors also stated that the dose of NIR light required to activate the system
was below the previously published limits for safe irradiation of living systems, but did not provide
any experimental evidence to validate this claim.
The biocompatibility of micelles constructed from a novel comb-like poly(ethylene glycol)
(CPEG) derivative functionalized with the photoresponsive 2-diazo-1,2-naphthoquinone (DNQ)
