Sensing

Functionalities that undergo chemical alterations in response to enzymatic activity or other properties such as pH or oxygen could be used as sensors to report information about the status of the tumor or efficacy of treatment. Many nanoparticle-based sensors that respond to biological triggers including proteases, DNAses, proteins, peroxidase, pH, and others have been demonstrated in vitro.67-72 These generally rely on assembly or disassembly of inorganic nanocrystals including: gold nanoparticles, nanoshells, or nanorods, which undergo a shift in their plasmon resonance when aggregated; iron-oxide nanoparticles have enhanced T2 relaxivity when clustered; and fluorescent quencher-based nanoparticle systems that dequench after triggered release.

A system using cleavable polymeric shielding of self-assembling nanoparticles has been proposed as a mechanism for translating nanoparticle-based enzyme sensors to in vivo use (Figure 5.5).73 Self-assembling, complementary iron-oxide nanoparticles are rendered latent with PEG polymers linked to the nanoparticle surface by protease-cleavable substrates that serve to both inhibit assembly and stabilize the particles in serum. Upon proteolytic removal of PEG polymers by MMP-2 expressing cancer cells, nanoparticles assemble and acquire amplified magnetic properties that can be detected with MRI. In the future, similar to thrombin-driven self-assembly of fibrin and platelets at sites of endothelial injury, this system may allow the hyper-active proteolytic processes of cancers to drive the self-assembly of nanoparticles in regions of cancer angiogenesis, invasion, and metastasis in vivo. Due to its modular design, this system can easily be modified for a number of detection schemes by substituting the complementary binding pairs, cleavable substrates

FIGURE 5.5 (See color insert following page 522.) Protease-triggered self-assembling nanoparticles with polymer-shielded coatings. (a) Schematic representation of nanoparticles that self-assemble after protease-mediated cleavage of PEG chains reveals complementary moieties (neutravidin and biotin). (b) Iron-oxide nanoparticles with cleavable linkers assemble in the presence of MMP-2, as measured by changes their light extinction, while particles with noncleavable scrambled peptides do not. (c) Atomic force micrographs of particles incubated with MMP-2 shows detectable aggregation (scale bars are 500 nm). (d) T2 maps of particles in solution using a 4.7 T MRI demonstrate enhanced T2 relaxivity for increasing concentrations of MMP-2.

FIGURE 5.5 (See color insert following page 522.) Protease-triggered self-assembling nanoparticles with polymer-shielded coatings. (a) Schematic representation of nanoparticles that self-assemble after protease-mediated cleavage of PEG chains reveals complementary moieties (neutravidin and biotin). (b) Iron-oxide nanoparticles with cleavable linkers assemble in the presence of MMP-2, as measured by changes their light extinction, while particles with noncleavable scrambled peptides do not. (c) Atomic force micrographs of particles incubated with MMP-2 shows detectable aggregation (scale bars are 500 nm). (d) T2 maps of particles in solution using a 4.7 T MRI demonstrate enhanced T2 relaxivity for increasing concentrations of MMP-2.

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(e.g., glycans, lipids, oligonucleotides), or multivalent nanoparticle cores (e.g., gold, quantum dot, dendrimer).

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