Cationized extracellular vesicles for gene delivery.

Last decade, extracellular vesicles (EVs) attracted a lot of attention as potent versatile drug delivery vehicles. We reported earlier the development of EV-based delivery systems for therapeutic proteins and small molecule chemotherapeutics. In this work, we first time engineered EVs with multivalent cationic lipids for the delivery of nucleic acids.

Poly(2-oxazoline)-Based Polyplexes as a PEG-Free Plasmid DNA Delivery Platform.

The present study expands the versatility of cationic poly(2-oxazoline) (POx) copolymers as a polyethylene glycol (PEG)-free platform for gene delivery to immune cells, such as monocytes and macrophages. Several block copolymers are developed by varying nonionic hydrophilic blocks (poly(2-methyl-2-oxazoline) (pMeOx) or poly(2-ethyl-2-oxazoline) (pEtOx), cationic blocks, and an optional hydrophobic block (poly(2-isopropyl-2-oxazoline) (iPrOx). The cationic blocks are produced by side chain modification of 2-methoxy-carboxyethyl-2-oxazoline (MestOx) block precursor with diethylenetriamine (DET) or tris(2-aminoethyl)amine (TREN).

Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease.

Extracellular vesicles (EVs) are cell-derived nanoparticles that facilitate transport of proteins, lipids, and genetic material, playing important roles in intracellular communication. They have remarkable potential as non-toxic and non-immunogenic nanocarriers for drug delivery to unreachable organs and tissues, in particular, the central nervous system (CNS). Herein, we developed a novel platform based on macrophage-derived EVs to treat Parkinson disease (PD).

Atmospheric waves and global seismoacoustic observations of the January 2022 Hunga eruption, Tonga.

The 15 January 2022 climactic eruption of Hunga volcano, Tonga, produced an explosion in the atmosphere of a size that has not been documented in the modern geophysical record. The event generated a broad range of atmospheric waves observed globally by various ground-based and spaceborne instrumentation networks. Most prominent was the surface-guided Lamb wave (≲0.

Biodistribution of Biomimetic Drug Carriers, Mononuclear Cells, and Extracellular Vesicles, in Nonhuman Primates.

Discovery of novel drug delivery systems to the brain remains a key task for successful treatment of neurodegenerative disorders. Herein, the biodistribution of immunocyte-based carriers, peripheral blood mononuclear cells (PBMCs), and monocyte-derived EVs are investigated in adult rhesus macaques using longitudinal PET/MRI imaging. Cu-labeled drug carriers are introduced via different routes of administration: intraperitoneal (IP), intravenous (IV), or intrathecal (IT) injection.

Extracellular Vesicles as Drug Delivery System for Treatment of Neurodegenerative Disorders: Optimization of the Cell Source.

Extracellular vesicles (EVs) represent a next generation drug delivery system that combines nanoparticle size with extraordinary ability to cross biological barriers, reduced immunogenicity, and low offsite toxicity profiles. A successful application of this natural way of delivering biological compounds requires deep understanding EVs intrinsic properties inherited from their parent cells. Herein, we evaluated EVs released by cells of different origin, with respect to drug delivery to the brain for treatment of neurodegenerative disorders.

Brain Targeting and Toxicological Assessment of the Extracellular Vesicle-Packaged Antioxidant Catalase-SKL Following Intranasal Administration in Mice.

The antioxidant enzyme catalase represents an important therapeutic target due to its role in mitigating cellular reactive oxygen species that contribute to the pathogenesis of many disease states. Catalase-SKL (CAT-SKL), a genetically engineered, peroxisome-targeted, catalase derivative, was developed in order to increase the therapeutic potential of the enzyme, and has previously been shown to be effective in combating oxidative stress in a variety of in vitro and in vivo models, thereby mitigating cellular degeneration and death. In the present study we addressed important considerations for the development of an extracellular vesicle-packaged version of CAT-SKL (evCAT-SKL) as a therapeutic for neurodegenerative diseases by investigating its delivery potential to the brain when administered intranasally, and safety by assessing off-target toxicity in a mouse model.

Mannosylated Cationic Copolymers for Gene Delivery to Macrophages.

Macrophages are desirable targets for gene therapy of cancer and other diseases. Cationic diblock copolymers of polyethylene glycol (PEG) and poly-L-lysine (PLL) or poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (pAsp(DET)) are synthesized and used to form polyplexes with a plasmid DNA (pDNA) that are decorated with mannose moieties, serving as the targeting ligands for the C type lectin receptors displayed at the surface of macrophages. The PEG-b-PLL copolymers are known for its cytotoxicity, so PEG-b-PLL-based polyplexes are cross-linked using reducible reagent dithiobis(succinimidyl propionate) (DSP).

Genetically modified macrophages accomplish targeted gene delivery to the inflamed brain in transgenic Parkin Q311X(A) mice: importance of administration routes.

Cell-based drug delivery systems have generated an increasing interest in recent years. We previously demonstrated that systemically administered macrophages deliver therapeutics to CNS, including glial cell line-derived neurotrophic factor (GDNF), and produce potent effects in Parkinson's disease (PD) mouse models. Herein, we report fundamental changes in biodistribution and brain bioavailability of macrophage-based formulations upon different routes of administration: intravenous, intraperitoneal, or intrathecal injections.

Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes.

CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs).

Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy.

Efficient targeted delivery of anticancer agents to TNBC cells remains one of the greatest challenges to developing therapies. The lack of tumor-specific markers, aggressive nature of the tumor, and unique propensity to recur and metastasize make TNBC tumors more difficult to treat than other subtypes. We propose to exploit natural ability of macrophages to target cancer cells by means of extracellular vesicles (EVs) as drug delivery vehicles for chemotherapeutic agents, paclitaxel (PTX) and doxorubicin (Dox).

Mechanically transformative electronics, sensors, and implantable devices.

Traditionally, electronics have been designed with static form factors to serve designated purposes. This approach has been an optimal direction for maintaining the overall device performance and reliability for targeted applications. However, electronics capable of changing their shape, flexibility, and stretchability will enable versatile and accommodating systems for more diverse applications.

GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson's disease in transgenic Parkin Q311X(A) mice.

There is an unmet medical need in the area of Parkinson's disease (PD) to develop novel therapeutic approaches that can stop and reverse the underlying mechanisms responsible for the neuronal death. We previously demonstrated that systemically administered autologous macrophages transfected ex vivo to produce glial cell line-derived neurotrophic factor (GDNF) readily migrate to the mouse brain with acute toxin-induced neuroinflammation and ameliorate neurodegeneration in PD mouse models. We hypothesized that the high level of cytokines due to inflammatory process attracted GDNF-expressing macrophages and ensured targeted drug delivery to the PD brain.

TPP1 Delivery to Lysosomes with Extracellular Vesicles and their Enhanced Brain Distribution in the Animal Model of Batten Disease.

Extracellular vesicles (EVs) are promising natural nanocarriers for delivery of various types of therapeutics. Earlier engineered EV-based formulations for neurodegenerative diseases and cancer are reported. Herein, the use of macrophage-derived EVs for brain delivery of a soluble lysosomal enzyme tripeptidyl peptidase-1, TPP1, to treat a lysosomal storage disorder, Neuronal Ceroid Lipofuscinoses 2 (CLN2) or Batten disease, is investigated.

Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: in vitro and in vivo evaluations.

Exosomes have recently emerged as a promising drug delivery system with low immunogenicity, high biocompatibility, and high efficacy of delivery. We demonstrated earlier that macrophage-derived exosomes (exo) loaded with a potent anticancer agent paclitaxel (PTX) represent a novel nanoformulation (exoPTX) that shows high anticancer efficacy in a mouse model of pulmonary metastases. We now report the manufacture of targeted exosome-based formulations with superior structure and therapeutic indices for systemic administration.

Macrophage exosomes as natural nanocarriers for protein delivery to inflamed brain.

Recent work has stimulated interest in the use of exosomes as nanocarriers for delivery of small drugs, RNAs, and proteins to the central nervous system (CNS). To overcome the blood-brain barrier (BBB), exosomes were modified with brain homing peptides that target brain endothelium but likely to increase immune response. Here for the first time we demonstrate that there is no need for such modification to penetrate the BBB in mammals.

Microfluidic neural probes: in vivo tools for advancing neuroscience.

Microfluidic neural probes hold immense potential as in vivo tools for dissecting neural circuit function in complex nervous systems. Miniaturization, integration, and automation of drug delivery tools open up new opportunities for minimally invasive implants. These developments provide unprecedented spatiotemporal resolution in fluid delivery as well as multifunctional interrogation of neural activity using combined electrical and optical modalities.

Risk of ventricular tachyarrhythmias following improvement of left ventricular ejection fraction in patients with implantable cardiac defibrillators implanted for primary prevention of sudden cardiac death.

Purpose: In patients who undergo implantable cardiac defibrillator (ICD) implantation for primary prevention of sudden cardiac death (SCD), data is unclear whether their ICD generator needs to be replaced at end of life if their left ventricular ejection fraction (EF) improves. Despite improvement in EF, the underlying scar may represent a potential substrate for ventricular arrhythmias.

Methods: Data on 280 patients who underwent ICD implantation for primary prevention of SCD was obtained from two centers.

Volcanic tremor and plume height hysteresis from Pavlof Volcano, Alaska.

The March 2016 eruption of Pavlof Volcano, Alaska, produced an ash plume that caused the cancellation of more than 100 flights in North America. The eruption generated strong tremor that was recorded by seismic and remote low-frequency acoustic (infrasound) stations, including the EarthScope Transportable Array. The relationship between the tremor amplitudes and plume height changes considerably between the waxing and waning portions of the eruption.

Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells.

Unlabelled: Exosomes have recently come into focus as "natural nanoparticles" for use as drug delivery vehicles. Our objective was to assess the feasibility of an exosome-based drug delivery platform for a potent chemotherapeutic agent, paclitaxel (PTX), to treat MDR cancer. Herein, we developed different methods of loading exosomes released by macrophages with PTX (exoPTX), and characterized their size, stability, drug release, and in vitro antitumor efficacy.