Luminescence quenching at high dopant concentrations generally limits the dopant concentration to less than 1-5 mol% in lanthanide-doped materials, and this remains a major obstacle in designing materials with enhanced efficiency/brightness. In this work, we provide direct evidence that the major quenching process at high dopant concentrations is the energy migration to the surface (i.e., surface quenching) as opposed to the common misconception of cross-relaxation between dopant ions. We show that after an inert epitaxial shell growth, erbium (Er) concentrations as high as 100 mol% in NaY(Er)F/NaLuF core/shell nanocrystals enhance the emission intensity of both upconversion and downshifted luminescence across different excitation wavelengths (980, 800, and 658 nm), with negligible concentration quenching effects. Our results highlight the strong coupling of concentration and surface quenching effects in colloidal lanthanide-doped nanocrystals, and that inert epitaxial shell growth can overcome concentration quenching. These fundamental insights into the photophysical processes in heavily doped nanocrystals will give rise to enhanced properties not previously thought possible with compositions optimized in bulk.

Over the last three decades, a handful of photochemical mechanisms have been applied to a large number of nanoscale assemblies that encapsulate a payload to afford spatio-temporal and remote control over activity of the encapsulated payload. Many of these systems are designed with an eye towards biomedical applications, as spatio-temporal and remote control of bioactivity would advance research and clinical practice. This review covers five underlying photochemical mechanisms that govern the activity of the majority of photoresponsive nanocarriers: 1. photo driven isomerization and oxidation, 2. surface plasmon absorption and photothermal effects, 3. photo driven hydrophobicity changes, 4. photo driven polymer backbone fragmentation and 5. photo driven de-crosslinking. The ways in which these mechanisms have been incorporated into nanocarriers and how they affect release is detailed, as well as the advantages and disadvantages of each system.

Oxidative stress is caused predominantly by accumulation of hydrogen peroxide and distinguishes inflamed tissue from healthy tissue. Hydrogen peroxide could potentially be useful as a stimulus for targeted drug delivery to diseased tissue. However, current polymeric systems are not sensitive to biologically relevant concentrations of H2O2 (50-100 μM). Here we report a new biocompatible polymeric capsule capable of undergoing backbone degradation and thus release upon exposure to such concentrations of hydrogen peroxide. Two polymeric structures were developed differing with respect to the linkage between the boronic ester group and the polymeric backbone: either direct (1) or via an ether linkage (2). Both polymers are stable in aqueous solution at normal pH, and exposure to peroxide induces the removal of the boronic ester protecting groups at physiological pH and temperature, revealing phenols along the backbone, which undergo quinone methide rearrangement to lead to polymer degradation. Considerably faster backbone degradation was observed for polymer 2 over polymer 1 by NMR and GPC. Nanoparticles were formulated from these novel materials to analyze their oxidation triggered release properties. While nanoparticles formulated from polymer 1 only released 50% of the reporter dye after exposure to 1 mM H2O2 for 26 h, nanoparticles formulated from polymer 2 did so within 10 h and were able to release their cargo selectively in biologically relevant concentrations of H2O2. Nanoparticles formulated from polymer 2 showed a two fold enhancement of release upon incubation with activated neutrophils while controls showed non specific response to ROS producing cells. These polymers represent a novel, biologically relevant and biocompatible approach to biodegradable H2O2-triggered release systems that can degrade into small molecules, release their cargo, and should be easily cleared by the body.

A new light-sensitive polymer containing multiple light-sensitive triggering groups along the backbone and incorporating a quinone-methide self-immolative moiety was developed and formulated into nanoparticles encapsulating a model dye Nile Red. Triggered burst-release of the payload upon irradiation and subsequent degradation of the nanoparticles was observed. This system is designed to be versatile where the triggering group can be sensitive to a number of wavelengths.

A biodegradable positron-emitting dendritic nanoprobe targeted at ␣v␤3 integrin, a biological marker known to modulate angiogenesis, was developed for the noninvasive imaging of angiogenesis. The nanoprobe has a modular multivalent core-shell architecture consisting of a biodegradable heterobifunctional dendritic core chemoselectively functionalized with heterobifunctional polyethylene oxide (PEO) chains that form a protective shell, which imparts biological stealth and dictates the pharmacokinetics. Each of the 8 branches of the dendritic core was functionalized for labeling with radiohalogens. Placement of radioactive moieties at the core was designed to prevent in vivo dehalogenation, a potential problem for radiohalogens in imaging and therapy. Targeting peptides of cyclic arginine-glycine-aspartic acid (RGD) motifs were installed at the terminal ends of the PEO chains to enhance their accessibility to ␣v␤3 integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to ␣v␤3 integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC50. Cell-based assays of the 125 I-labeled dendritic nanoprobes using ␣v␤3-positive cells showed a 6-fold increase in ␣v␤3 receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas ␣v␤3-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of 76 Brlabeled dendritic nanoprobes showed excellent bioavailability for the targeted and nontargeted nanoprobes. In vivo studies in a murine hindlimb ischemia model for angiogenesis revealed high specific accumulation of 76 Br-labeled dendritic nanoprobes targeted at ␣v␤3 integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.dendrimer ͉ molecular imaging

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We report two polymers with UV- and NIR-removable end caps that respond to a single light activated event by complete cleavage of the polymer backbone via a self-immolative mechanism. Two photocleavable protecting groups were used to cap the polymers; o-nitrobenzyl alcohol (ONB) and bromo-coumarin (Bhc). GPC and 1H NMR confirmed complete degradation of the ONB-containing polymer in response to UV. The polymers were formulated into nanoparticles; fluorescence measurements of encapsulated Nile red confirmed release upon photolysis of the endcaps. Contrary to previous work using a similar backbone structure that degrades upon hydrolysis, here, the disassembly process and burst release of the payload are only activated on demand, illustrating the powerful capacity of light to trigger release from polymeric nanoparticles. Our design allows the signal to be amplified in a domino effect to fully degrade the polymer into small molecules. Thus, polymers and nanoparticles can reach maximal degradation without having to use intense and/or long periods of irradiation.

Logic gate nanoparticles, where two chemical transformations take place one after the other, were successfully formulated from a newly synthesized random co-polymer. This polymer, 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) contains two pH responsive moieties within its backbone. As nanoparticles they function akin to an AND logic gate. The β-aminoester backbone moiety provides a pH triggered solubility switch, only when this switch is “ON” does the ketal moiety also turn “ON” to undergo rapid acid catalyzed hydrolysis. These AND logic gate polymeric nanoparticles were prepared using an oil in water emulsion method. Their degradation in the pH range of 7.4−5 was monitored by dynamic light scattering and showed excellent stability at pH 7.4 and rapid degradation at pH 5. Our results indicate that the prepared logic gate nanoparticles may prove valuable in delivering therapeutics and diagnostics to cells and diseased tissue.