Adah Almutairi

Photochemical mechanisms of light-triggered release from nanocarriers

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 are detailed, as well as the advantages and disadvantages of each system.

Biocompatible Polymeric Nanoparticles Degrade and Release Cargo in Response to Biologically Relevant Levels of Hydrogen Peroxide

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 H(2)O(2) (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 H(2)O(2) 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 H(2)O(2). Nanoparticles formulated from polymer 2 showed a 2-fold enhancement of release upon incubation with activated neutrophils, while controls showed a nonspecific response to ROS producing cells. These polymers represent a novel, biologically relevant, and biocompatible approach to biodegradable H(2)O(2)-triggered release systems that can degrade into small molecules, release their cargo, and should be easily cleared by the body.

UV and Near-IR triggered release from polymeric nanoparticles

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 pharmaceutical Nile Red. Triggered burst release of the payload upon irradiation and subsequent degradation of the nanoparticles were observed. This system is designed to be versatile where the triggering group can be sensitive to a number of wavelengths.

Biodegradable dendritic positron-emitting nanoprobes for the noninvasive imaging of angiogenesis

A biodegradable positron-emitting dendritic nanoprobe targeted at αvβ3 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 αvβ3 integrin receptors. This nanoscale design enabled a 50-fold enhancement of the binding affinity to αvβ3 integrin receptors with respect to the monovalent RGD peptide alone, from 10.40 nM to 0.18 nM IC50. Cell-based assays of the 125I-labeled dendritic nanoprobes using αvβ3-positive cells showed a 6-fold increase in αvβ3 receptor-mediated endocytosis of the targeted nanoprobe compared with the nontargeted nanoprobe, whereas αvβ3-negative cells showed no enhancement of cell uptake over time. In vivo biodistribution studies of 76Br-labeled 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 76Br-labeled dendritic nanoprobes targeted at αvβ3 integrins in angiogenic muscles, allowing highly selective imaging of this critically important process.

Physical and Chemical Strategies for Therapeutic Delivery by Using Polymeric Nanoparticles

A significant challenge that most therapeutic agents face is their inability to be delivered effectively. Nanotechnology offers a solution to allow for safe, high-dose, specific delivery of pharmaceuticals to the target tissue. Nanoparticles composed of biodegradable polymers can be designed and engineered with various layers of complexity to achieve drug targeting that was unimaginable years ago by offering multiple mechanisms to encapsulate and strategically deliver drugs, proteins, nucleic acids, or vaccines while improving their therapeutic index. Targeting of nanoparticles to diseased tissue and cells assumes two strategies: physical and chemical targeting. Physical targeting is a strategy enabled by nanoparticle fabrication techniques. It includes using size, shape, charge, and stiffness among other parameters to influence tissue accumulation, adhesion, and cell uptake. New methods to measure size, shape, and polydispersity will enable this field to grow and more thorough comparisons to be made. Physical targeting can be more economically viable when certain fabrication techniques are used. Chemical targeting can employ molecular recognition units to decorate the surface of particles or molecular units responsive to diseased environments or remote stimuli. In this review, we describe sophisticated nanoparticles designed for tissue-specific chemical targeting that use conjugation chemistry to attach targeting moieties. Furthermore, we describe chemical targeting using stimuli responsive nanoparticles that can respond to changes in pH, heat, and light.

Multiresponse strategies to modulate burst degradation and release from nanoparticles.

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.

Inflammation responsive logic gate nanoparticles for the delivery of proteins

Oxidative stress and reduced pH are important stimuli targets for intracellular delivery and for delivery to diseased tissue. However, there is a dearth of materials able to deliver bioactive agents selectively under these conditions. We employed our recently developed dual response strategy to build a polymeric nanoparticle that degrades upon exposure to two stimuli in tandem. Our polythioether ketal based nanoparticles undergo two chemical transformations; the first is the oxidation of the thioether groups along the polymer backbone of the nanoparticles upon exposure to reactive oxygen species (ROS). This transformation switches the polymeric backbone from hydrophobic to hydrophilic and thus allows, in mildly acidic environments, the rapid acid-catalyzed degradation of the ketal groups also along the polymer backbone. Dynamic light scattering and payload release studies showed full particle degradation only in conditions that combined both oxidative stress and acidity, and these conditions led to higher release of encapsulated protein within 24 h. Nanoparticles in neutral pH and under oxidative conditions showed small molecule release and swelling of otherwise intact nanparticles. Notably, cellular studies show absence of toxicity and efficient uptake of nanoparticles by macrophages followed by cytoplasmic release of ovalbumin. Future work will apply this system to inflammatory diseases.

Low Power Upconverted Near‐IR Light for Efficient Polymeric Nanoparticle Degradation and Cargo Release

By encapsulating NaYF4 :Tm.Yb upconverting nanocrystals in UV-degradable polymer capsules, it is possible to access efficient polymer photodegradation and remotely controlled release using near-IR laser light at an unprecedentedly low power.

Direct Evidence for Coupled Surface and Concentration Quenching Dynamics in Lanthanide-Doped Nanocrystals

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 (Er3+) concentrations as high as 100 mol% in NaY(Er)F4/NaLuF4 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.

Collective activation of MRI agents via encapsulation and disease-triggered release

An activation mechanism based on encapsulated ultrasmall gadolinium oxide nanoparticles (Gd oxide NPs) in bioresponsive polymer capsules capable of triggered release in response to chemical markers of disease (i.e., acidic pH, H2O2) is presented. Inside the hydrophobic polymeric matrices, the Gd oxide NPs are shielded from the aqueous environment, silencing their ability to enhance water proton relaxation. Upon disassembly of the polymeric particles, activation of multiple contrast agents generates a strong positive contrast enhancement of >1 order of magnitude.