Biomedical Engineering Reference
In-Depth Information
over a period of 1 min). When the dose was increased to 88 μJ/pulse, a significant reduction in
cellular viability was observed. This reduction in cellular viability at higher doses of NIR light was
not a problem for the system developed by Chen et al. because their DNA-gold nanorod conjugate
responded sufficiently to NIR light dosed at the 79 μJ/pulse level—which trigger the release of
DNA from the conjugate and resulted in the successful transfection of green fluorescence protein
(GFP) into HeLa cells.
4.3 pH-RESPONSIVE SYSTEMS
While light is an attractive stimulus for activation, it is not the only stimulus that has been inves-
tigated for the development of stimuli-responsive systems. Indeed, the use of an internal stimulus
sidesteps any possible biocompatibility complications that could arise through the application of an
external stimulus. Much effort has been put forth into the development of systems that respond to
changes in pH. The rationale behind this approach is twofold; first, it allows for the selective deliv-
ery of therapeutic agents to diseased tissues such as solid tumors, which exhibit a markedly reduced
pH (5.5-6.5) compared to healthy tissues (pH 7.4) due to the core of the tumor tissue being exposed
to hypoxic/anoxic conditions (Brown and Wilson, 2004). This requires the core of the tumor to
rely extensively on glycolysis and lactic acid fermentation for energy production, thus making the
tumor microenvironment acidic (Brown and Wilson, 2004). Second, the use of pH as the stimulus
allows systems to be engineered to release the drug once they are inside intracellular compartments
that exhibit a difference in pH—namely, the lysosome in which the pH is maintained around 5.5
(Liberman and Marks, 2009). The main drawback to pH-responsive systems, as well as any system
that relies on an internal stimulus, is that this approach allows for a large degree of variability at
both the intra- and interpatient levels.
Perhaps one of the most promising new materials for pH-responsive systems was that described
by Sankaranarayanan et al., which utilized the novel copolymer poly([2,2′-(propane-2,2-diylbis(oxy))
bis(ethane-2,1-diyl) diacrylate]-
co-
[hexane-1,6-diyl diacrylate]-4,4′-trimethylene dipiperidine) (poly-
β-aminoester ketal-2) (Sankaranarayanan et al., 2010). This new copolymer utilizes two pH-respon-
sive motifs in order to change its solubility as well as selectively rupture upon incubation in low
pH (5-6) environments while maintaining its stability at physiological pH. In order to evaluate the
biocompatibility of this new copolymer, the authors employed the MTT assay. Following a 20 h
incubation of the copolymer with RAW 264.7 cells, it was found that the copolymer did not induce
cytotoxic effects at concentrations of 3.7 μg/mL or lower. However, cytotoxicity was seen at the high-
est concentration tested: 11.11 μg/mL. No further tests were conducted in order to evaluate the bio-
compatibility of the copolymer at different pH values or the products of the copolymer's breakdown.
Another approach that utilizes a pH-responsive material has been investigated for NP-mediated
drug delivery to tumor tissues through the shedding of the NP's stealth (PEG) layer. The idea behind
this system is that once the outer PEG layer is shed, the positively charged core of the NP is exposed,
resulting in increased uptake of the drug-loaded NPs through the electrostatic interaction between
the NP and the plasma membrane (e.g., nonspecific adsorptive pinocytosis). This approach was
investigated by Poon et al. who utilized the pH-sensitive nature of the iminobiotin-neutravidin bond
to link PEG to a poly-l-lysine core (Poon et al., 2011). When tested
in vivo
, these NPs were able to
show stronger persistence in the tumor when utilized in two different tumor models. This supports
the authors' hypothesis that pH-responsive materials are a potentially viable means of selectively
targeting solid tumors, regardless of the type of cancer being treated. The biocompatibility of this
system was assessed through subjecting these NPs to the MTT assay. Using uncoated latex beads
as a reference, HeLa cells were incubated for 48 h with varying concentrations of the novel NPs
or latex beads. The results showed that the NPs prepared with a pH-sheddable PEG layer were not
cytotoxic; exhibiting levels of cellular viability similar to those seen for the latex beads. The promis-
ing
in vivo
results obtained by this group warrant further investigation into the biocompatibility of
this system as a novel pH-responsive system for drug delivery.
