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The art of falling apart: exploiting nanomaterial disassembly for health sciences
M.L. Viger, C. de Gracia Lux, C-J. Carling, V.A..Nguyen Huu, J. Olejniczak, and A. Almutairi
University of California, San Diego, US
Keywords: drug delivery, nanomaterials
Summary:
This presentation will cover several recent advances in the development of light- and inflammation-responsive polymers as tools for biological research and drug delivery. In the area of light-responsive materials, four exciting strategies will be discussed: chemically amplifying the light signal to accelerate degradation, single-photon absorption of red light, novel upconverting structures enabling efficient conversion of more biologically compatible wavelengths, and application of a previously reported polymer to the treatment of disease. The chemical amplification strategy relies on phototriggered unmasking of acidic groups that hydrolyze adjacent ketals, which overcomes ketals’ requirement of low pH for efficient degradation. Particles composed of the photocaged-acid/ ketal polymer degrade rapidly upon brief irradiation. The red light-degradable polymer incorporates a photocage not previously used in responsive materials, which cleaves in hydrophobic environments (unlike coumarins). Particles composed of this polymer, when subcutaneously injected and irradiated through tissue, release sufficient drug to significantly reduce carrageenan-induced paw inflammation in mice. Our advance in the upconversion field is the application of uniform shell deposition to overcome dopant concentration quenching, allowing unprecedented upconversion efficiencies at 800 nm. Absorption of this wavelength rather than the 980 nm employed by current structures avoids the potential for tissue heating, as water’s absorption of 800 nm infrared is much lower. Finally, we have evidence that a UV-degradable polymer (Fomina et al., J Am Chem Soc 2010) may be useful for the delivery of anti-angiogenics in the eye to treat macular degeneration. This strategy would preserve clinician control over dose timing while reducing the frequency of intravitreal injections. UV-degradable particles are stable in the eye for months and release a therapeutically effective dose of a small molecule anti-angiogenic; the irradiation required for release is well-tolerated by the eye. Inflammation-responsive materials have been recently applied in the lab towards prevention of systemic inflammatory response syndrome (SIRS) and detection of atherosclerotic plaque likely to disrupt and cause a heart attack or stroke. The first project involves delivering anti-inflammatory drugs in nanoparticles composed of our polythioether ketal (published in 2011). Using this strategy to deliver drugs 12 h prior to the bacterial toxin LPS reduces mortality in mice, suggesting that such nanoparticles could lead to a means of preventing organ failure following systemic infection or trauma. In the second, particles composed of dextran modified to be acid- and H2O2-responsive encapsulate Gd-based nanocrystals with unprecedented relaxivity, such that MRI signal is silenced until encountering inflammation, where particles loosen and nanocrystals can relax surrounding water molecules. This material’s ability to detect inflammation in vivo has been demonstrated using fluorescence activation; its applicability to atherosclerosis is currently being tested in ApoE-/- mice fed a high fat diet and implanted with a carotid cuff to reliably induce inflamed plaque.
