Tissue distribution and retention drives efficacy of rapidly clearing VHL-based PROTACs.

Background: Proteolysis-targeting chimeras (PROTACs) are being developed for therapeutic use. However, they have poor pharmacokinetic profiles and their tissue distribution kinetics are not known.

Methods: A typical von Hippel-Lindau tumor suppressor (VHL)-PROTAC C-A947 (BRM degrader)-was synthesized and its tissue distribution kinetics was studied by quantitative whole-body autoradiography (QWBA) and tissue excision in rats following IV dosing.

Pharmacologic Treatments in Acute Respiratory Failure.

Acute respiratory failure relies on supportive care using non-invasive and invasive oxygen and ventilatory support. Pharmacologic therapies for the most severe form of respiratory failure, acute respiratory distress syndrome (ARDS), are limited. This review focuses on the most promising therapies for ARDS, targeting different mechanisms that contribute to dysregulated inflammation and resultant hypoxemia.

Early Stage Preclinical Formulation Strategies to Alter the Pharmacokinetic Profile of Two Small Molecule Therapeutics.

Early stage chemical development presents numerous challenges, and achieving a functional balance is a major hurdle, with many early compounds not meeting the clinical requirements for advancement benchmarks due to issues like poor oral bioavailability. There is a need to develop strategies for achieving the desired systemic concentration for these compounds. This will enable further evaluation of the biological response upon a compound-target interaction, providing deeper insight into the postulated biological pathways.

Utilizing Molecular Simulations to Examine Nanosuspension Stability.

Drug nanosuspensions offer a promising approach to improve bioavailability for poorly soluble drug candidates. Such formulations often necessitate the inclusion of an excipient to stabilize the drug nanoparticles. However, the rationale for the choice of the correct excipient for a given drug candidate remains unclear.

Tissue factor targeting peptide enhances nanoparticle binding and delivery of a synthetic specialized pro-resolving lipid mediator to injured arteries.

Background: Specialized pro-resolving lipid mediators (SPM) such as resolvin D1 (RvD1) attenuate inflammation and exhibit vasculo-protective properties.

Methods: We investigated poly-lactic-co-glycolic acid (PLGA)-based nanoparticles (NP), containing a peptide targeted to tissue factor (TF) for delivery of 17R-RvD1 and a synthetic analog 17-R/S-benzo-RvD1 (benzo-RvD1) using in vitro and in vivo models of acute vascular injury. NPs were characterized in vitro by size, drug loading, drug release, TF binding, and vascular smooth muscle cell migration assays.

Development of Liposome Systems for Enhancing the PK Properties of Bivalent PROTACs.

Proteolysis-Targeting Chimeras (PROTACs) are a promising new technology in drug development. They have rapidly evolved in recent years, with several of them in clinical trials. While most of these advances have been associated with monovalent protein degraders, bivalent PROTACs have also entered clinical trials, although progression to market has been limited.

Fast and versatile analysis of liposome encapsulation efficiency by nanoParticle exclusion chromatography.

Liposomes are an attractive drug delivery platform for a wide variety of pharmaceutical molecules. Encapsulation efficiency, which refers to the amount of drug contained inside liposomes compared with the total amount of drug, is a critical quality attribute of liposome products, as the free drug in a liposomal formulation may cause toxicity or undesired biodistribution. The determination of encapsulation efficiency requires the measurement of at least two of the three drug populations: total drug, encapsulated drug and free drug.

A Systematic Approach for Liposome and Lipodisk Preclinical Formulation Development by Microfluidic Technology.

Lipid nanoparticles have transformed the drug delivery field enhancing the therapeutic drug performance of small molecules and biologics with several approved drug products. However, in industry, these more complex drug delivery systems such as liposomes require more material and time to develop. Here, we report a liposome and lipodisk decision tree with model compounds of diverse physicochemical properties to understand how to resourcefully optimize encapsulation efficiency (EE) for these lipid-based drug delivery systems.

Adherence to Lung Protective Ventilation in Patients With Coronavirus Disease 2019.

Unlabelled: Prior studies have demonstrated suboptimal adherence to lung protective ventilation among patients with acute respiratory distress syndrome. A common barrier to providing this evidence-based practice is diagnostic uncertainty. We sought to test the hypothesis that patients with acute respiratory distress syndrome due to coronavirus disease 2019, in whom acute respiratory distress syndrome is easily recognized, would be more likely to receive low tidal volume ventilation than concurrently admitted acute respiratory distress syndrome patients without coronavirus disease 2019.

Multi-Immune Agonist Nanoparticle Therapy Stimulates Type I Interferons to Activate Antigen-Presenting Cells and Induce Antigen-Specific Antitumor Immunity.

Cancer immunity is mediated by a delicate orchestration between the innate and adaptive immune system both systemically and within the tumor microenvironment. Although several adaptive immunity molecular targets have been proven clinically efficacious, stand-alone innate immunity targeting agents have not been successful in the clinic. Here, we report a nanoparticle optimized for systemic administration that combines immune agonists for TLR9, STING, and RIG-I with a melanoma-specific peptide to induce antitumor immunity.

An Injectable Cytokine Trap for Local Treatment of Autoimmune Disease.

Systemic cytokine therapy is limited by toxicity due to activation of unwanted immune cells in off-target tissues. Injectable nanomaterials that interact with the immune system have potential to offer improved pharmacokinetics and cell specificity compared to systemic cytokine therapy by instead capturing and potentiating endogenous cytokine. Here we demonstrate the use of high aspect ratio polycaprolactone nanowires conjugated to cytokine-binding antibodies that assemble into porous matrices when injected into the subcutaneous space.

Reversible inhibition of efflux transporters by hydrogel microdevices.

Oral drug delivery is a preferred administration route due to its low cost, high patient compliance and fewer adverse events compared to intravenous administration. However, many pharmaceuticals suffer from poor solubility and low oral bioavailability. One major factor that contributes to low bioavailability are efflux transporters which prevent drug absorption through intestinal epithelial cells.

Human intestinal spheroids cultured using Sacrificial Micromolding as a model system for studying drug transport.

In vitro models of the small intestine are crucial tools for the prediction of drug absorption. The Caco-2 monolayer transwell model has been widely employed to assess drug absorption across the intestine. However, it is now well-established that 3D in vitro models capture tissue-specific architecture and interactions with the extracellular matrix and therefore better recapitulate the complex in vivo environment.

Continuous-wave upconverting nanoparticle microlasers.

Reducing the size of lasers to microscale dimensions enables new technologies that are specifically tailored for operation in confined spaces ranging from ultra-high-speed microprocessors to live brain tissue. However, reduced cavity sizes increase optical losses and require greater input powers to reach lasing thresholds. Multiphoton-pumped lasers that have been miniaturized using nanomaterials such as lanthanide-doped upconverting nanoparticles (UCNPs) as lasing media require high pump intensities to achieve ultraviolet and visible emission and therefore operate under pulsed excitation schemes.

Energy-Looping Nanoparticles: Harnessing Excited-State Absorption for Deep-Tissue Imaging.

Near infrared (NIR) microscopy enables noninvasive imaging in tissue, particularly in the NIR-II spectral range (1000-1400 nm) where attenuation due to tissue scattering and absorption is minimized. Lanthanide-doped upconverting nanocrystals are promising deep-tissue imaging probes due to their photostable emission in the visible and NIR, but these materials are not efficiently excited at NIR-II wavelengths due to the dearth of lanthanide ground-state absorption transitions in this window. Here, we develop a class of lanthanide-doped imaging probes that harness an energy-looping mechanism that facilitates excitation at NIR-II wavelengths, such as 1064 nm, that are resonant with excited-state absorption transitions but not ground-state absorption.

Far-field optical nanothermometry using individual sub-50 nm upconverting nanoparticles.

We demonstrate far-field optical thermometry using individual NaYF4 nanoparticles doped with 2% Er(3+) and 20% Yb(3+). Isolated 20 × 20 × 40 nm(3) particles were identified using only far-field optical imaging, confirmed by subsequent scanning electron microscopy. The luminescence thermometry response for five such single particles was characterized for temperatures from 300 K to 400 K.

Near-IR mediated intracellular uncaging of NO from cell targeted hollow gold nanoparticles.

We demonstrate modulation of nitric oxide release in solution and in human prostate cancer cells from a thiol functionalized cupferron (TCF) absorbed on hollow gold nanoshells (HGNs) using near-infrared (NIR) light. NO release from the TCF-HGN conjugates occurs through localized surface heating due to NIR excitation of the surface plasmon. Specific HGN targeting is achieved through cell surface directed peptides, and excitation with tissue penetrating NIR light provides unprecedented spatio-temporal control of NO delivery to biological targets.

Rationally Designed Energy Transfer in Upconverting Nanoparticles.

Significant advances in the analysis and theoretical modeling of upconverting nanoparticles (UCNPs) are beginning to reveal the complex details of their energy transfer (ET) pathways. UCNPs combine multiple NIR photons to emit at higher energies in the NIR or visible, and are an ideal system for the rational design and precise engineering of optical processes. The ET pathways that drive photon upconversion can be tuned by varying the combination of lanthanide co-dopants, their concentrations, and their spatial distribution within the nanocrystal.

Resolvin D1 attenuates polyinosinic-polycytidylic acid-induced inflammatory signaling in human airway epithelial cells via TAK1.

The respiratory epithelium consists of lung sentinel cells, which are the first to contact inhaled inflammatory insults, including air pollutants, smoke, and microorganisms. To avoid damaging exuberant or chronic inflammation, the inflammatory process must be tightly controlled and terminated once the insult is mitigated. Inflammation resolution is now known to be an active process involving a new genus of lipid mediators, called "specialized proresolving lipid mediators," that includes resolvin D1 (RvD1).

Parathyroid hormone 1-84 alters circulating vascular endothelial growth factor levels in hypoparathyroidism.

Context: We previously reported on four patients treated with PTH(1-84) who recovered from postoperative hypoparathyroidism many years after onset. Because vascular endothelial growth factor (VEGF) has been shown to be necessary for the induction of PTH-mediated angiogenesis, we postulated a possible role for VEGF in the recovery of parathyroid function in these subjects.

Objective: Our objective was to measure VEGF levels in subjects with hypoparathyroidism who regained parathyroid gland function and matched controls.

PTH(1-84) is associated with improved quality of life in hypoparathyroidism through 5 years of therapy.

Context: In hypoparathyroidism, quality of life (QOL) is compromised as compared to normal subjects. We previously reported our results showing an association with recombinant human PTH(1-84) therapy in hypoparathyroidism and improvement in QOL measures for 1 year.

Objective: We tested the hypothesis that PTH(1-84) therapy in hypoparathyroidism through 5 years would be associated with continued improvement in QOL measures.