Apical integrins as a switchable target to regulate the epithelial barrier.

Tight junctions regulate epithelial barrier function and have been shown to be influenced by multiple classes of proteins. Apical integrins have been identified as potential regulators of epithelial barrier function; however, only indirect approaches have been used to measure integrin regulation of the epithelial barrier. Here, we used polymeric nanowires conjugated with anti-integrin β1 antibodies to specifically target apically localized integrins in either their closed or open conformation.

Encapsulation of β-NGF in injectable microrods for localized delivery accelerates endochondral fracture repair.

Currently, there are no non-surgical FDA-approved biological approaches to accelerate fracture repair. Injectable therapies designed to stimulate bone healing represent an exciting alternative to surgically implanted biologics, however, the translation of effective osteoinductive therapies remains challenging due to the need for safe and effective drug delivery. Hydrogel-based microparticle platforms may be a clinically relevant solution to create controlled and localized drug delivery to treat bone fractures.

Codelivery of synergistic antimicrobials with polyelectrolyte nanocomplexes to treat bacterial biofilms and lung infections.

Bacterial biofilm infections, particularly those of (PA), have high rates of antimicrobial tolerance and are commonly found in chronic wound and cystic fibrosis lung infections. Combination therapeutics that act synergistically can overcome antimicrobial tolerance; however, the delivery of multiple therapeutics at relevant dosages remains a challenge. We therefore developed a nanoscale drug carrier for antimicrobial codelivery by combining approaches from polyelectrolyte nanocomplex (NC) formation and layer-by-layer electrostatic self-assembly.

Bioinspired Polymeric High Aspect Ratio Particles with Asymmetric Janus Functionalities.

Polymeric particles with intricate morphologies and properties have been developed based on bioinspired designs for applications in regenerative medicine, tissue engineering, and drug delivery. However, the fabrication of particles with asymmetric functionalities remains a challenge. Janus polymeric particles are an emerging class of material with asymmetric functionalities; however, they are predominantly spherical in morphology, made from non-biocompatible materials, and made using specialized fabrication techniques.

Impact of Microdevice Geometry on Transit and Retention in the Murine Gastrointestinal Tract.

Oral protein delivery technologies often depend on encapsulating or enclosing the protein cargo to protect it against pH-driven degradation in the stomach or enzymatic digestion in the small intestine. An emergent methodology is to encapsulate therapeutics in microscale, asymmetric, planar microparticles, referred to as microdevices. Previous work has shown that, compared to spherical particles, planar microdevices have longer residence times in the GI tract, but it remains unclear how specific design choices (e.

Networks of High Aspect Ratio Particles to Direct Colloidal Assembly Dynamics and Cellular Interactions.

Injectable colloids that self-assemble into three-dimensional networks are promising materials for applications in regenerative engineering, as they create open systems for cellular infiltration, interaction, and activation. However, most injectable colloids have spherical morphologies, which lack the high material-biology contact areas afforded by higher aspect ratio materials. To address this need, injectable high aspect ratio particles (HARPs) were developed that form three-dimensional networks to enhance scaffold assembly dynamics and cellular interactions.

Micro and nanoscale technologies in oral drug delivery.

Oral administration is a pillar of the pharmaceutical industry and yet it remains challenging to administer hydrophilic therapeutics by the oral route. Smart and controlled oral drug delivery could bypass the physiological barriers that limit the oral delivery of these therapeutics. Micro- and nanoscale technologies, with an unprecedented ability to create, control, and measure micro- or nanoenvironments, have found tremendous applications in biology and medicine.

Engineering the drug carrier biointerface to overcome biological barriers to drug delivery.

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery.

Evaluation of Three Morphologically Distinct Virus-Like Particles as Nanocarriers for Convection-Enhanced Drug Delivery to Glioblastoma.

Glioblastoma is a particularly challenging cancer, as there are currently limited options for treatment. New delivery routes are being explored, including direct intratumoral injection via convection-enhanced delivery (CED). While promising, convection-enhanced delivery of traditional chemotherapeutics such as doxorubicin (DOX) has seen limited success.

Supramolecular strategies for protein immobilization and modification.

Protein immobilization and modification are widely used techniques in the fields of chemical biology and biomaterials science. While covalent strategies based on small molecules are traditionally used, supramolecular chemistry offers numerous useful opportunities for guiding the modification locations on complex protein landscapes and introducing different degrees of reversibility into the products. In this opinion, we highlight recent advances in using supramolecular interactions, particularly host-guest chemistry, for controlling protein modification and immobilization.

Cucurbit[6]uril-Promoted Click Chemistry for Protein Modification.

Azide-alkyne cycloaddition is a powerful reaction for the formation of bioconjugates. When catalyzed by Cu(I) or strain promotion, this cycloaddition is considered to be a "click" reaction with many applications in chemical biology and materials science. We report a new type of azide-alkyne click chemistry for the synthesis of protein conjugates using cucurbit[6]uril (CB6) supramolecular chemistry.

Rotaxane probes for protease detection by Xe hyperCEST NMR.

We report a CB6 rotaxane for the Xe hyperCEST NMR detection of matrix metalloprotease 2 (MMP-2) activity. MMP-2 is overexpressed in cancer tissue, and hence is a cancer marker. A peptide containing an MMP-2 recognition sequence was incorporated into the rotaxane, synthesized via CB6-promoted click chemistry.

Stable Disk Assemblies of a Tobacco Mosaic Virus Mutant as Nanoscale Scaffolds for Applications in Drug Delivery.

Current approaches to nanoscale therapeutic delivery rely on the attachment of a drug of interest to a nanomaterial scaffold that is capable of releasing the drug selectively in a tumor environment. One class of nanocarriers receiving significant attention is protein nanomaterials, which are biodegradable and homogeneous in morphology and can be equipped with multiple functional handles for drug attachment. Although most protein-based nanocarriers are spherical in morphology, recent research has revealed that nonspherical nanomaterials may have favorable tumor uptake in comparison to their spherical counterparts.

(129)Xe NMR Relaxation-Based Macromolecular Sensing.

We report a (129)Xe NMR relaxation-based sensing approach that exploits changes in the bulk xenon relaxation rate induced by slowed tumbling of a cryptophane-based sensor upon target binding. The amplification afforded by detection of the bulk dissolved xenon allows sensitive detection of targets. The sensor comprises a xenon-binding cryptophane cage, a target interaction element, and a metal chelating agent.

Targeted Molecular Imaging of Cancer Cells Using MS2-Based (129)Xe NMR.

We have synthesized targeted, selective, and highly sensitive (129)Xe NMR nanoscale biosensors using a spherical MS2 viral capsid, Cryptophane A molecules, and DNA aptamers. The biosensors showed strong binding specificity toward targeted lymphoma cells (Ramos line). Hyperpolarized (129)Xe NMR signal contrast and hyper-CEST (129)Xe MRI image contrast indicated its promise as highly sensitive hyperpolarized (129)Xe NMR nanoscale biosensor for future applications in cancer detection in vivo.

Rotaxane-mediated suppression and activation of cucurbit[6]uril for molecular detection by (129)Xe hyperCEST NMR.

We report a method for blocking interactions between (129)Xe and cucurbit[6]uril (CB6) until activation by a specific chemical event. We synthesized a CB6-rotaxane that allowed no (129)Xe interaction with the CB6 macrocycle component until a cleavage event released the CB6, which then produced a (129)Xe@CB6 NMR signal. This contrast-upon-activation (129)Xe NMR platform allows for modular synthesis and can be expanded to applications in detection and disease imaging.

pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies.

Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively.

Potent antitumor effects of combination therapy with IFNs and monocytes in mouse models of established human ovarian and melanoma tumors.

Interferon-activated monocytes are known to exert cytocidal activity against tumor cells in vitro. Here, we have examined whether a combination of IFN-α2a and IFN-γ and human monocytes mediate significant antitumor effects against human ovarian and melanoma tumor xenografts in mouse models. OVCAR-3 tumors were treated i.

Near eradication of clinically relevant concentrations of human tumor cells by interferon-activated monocytes in vitro.

We have previously reported that low concentrations of interferon (IFN)-activated monocytes exert near-eradicative cytocidal activity against low concentrations of several human tumor cells in vitro. In the present study, we examined 7 human tumor cell lines and 3 diploid lines in the presence or absence of 10 ng/mL IFNα2a and monocytes. The results confirmed strong cytocidal activity against 4 of 7 tumor lines but none against 3 diploid lines.