Dongyoon Kim

Delivery of ofloxacin to the lung and alveolar macrophages via hyaluronan microspheres for the treatment of tuberculosis.

Microspheres containing ofloxacin (HMO) with a mean diameter of 2-5 mum were prepared by the co-spray drying of ofloxacin and the sodium salt of hyaluronic acid (hyaluronan). Recovery of lactose blends of HMO from stage II of the twin-stage impinger (TSI) reached 43%, indicating favorable delivery of the drug to the lung via inhalation. The area under the ofloxacin concentration curve from time zero to infinity (AUC) was estimated for plasma and lungs in rats following intratracheal (it), intravenous (iv), and oral (po) administration of HMO, ofloxacin microspheres (MO), and an aqueous solution of ofloxacin (OS), at an equivalent ofloxacin dose of 8 mg/kg rat. The AUC ratio between the lung and plasma for it-administered HMO was.10.9-, 9.3- and 1.8-fold greater than iv OS, po OS, and it MO, respectively, suggesting that the most efficient delivery of ofloxacin to the lung is feasible via HMO. Moreover, in vitro uptake of ofloxacin from HMO by air-surface cultured alveolar macrophages (RAW 264.7) was 2.1- and 1.7-fold higher than ofloxacin uptake from OS and MO (P<0.05). Taken together, the results of the present study demonstrate that pulmonary administration of ofloxacin via HMO would improve the treatment efficacy of ofloxacin against tuberculosis, compared to other forms of ofloxacin (OS and MO) and to other routes of administration (iv and po).

Therapeutic gene editing: delivery and regulatory perspectives

Gene-editing technology is an emerging therapeutic modality for manipulating the eukaryotic genome by using target-sequence-specific engineered nucleases. Because of the exceptional advantages that gene-editing technology offers in facilitating the accurate correction of sequences in a genome, gene editing-based therapy is being aggressively developed as a next-generation therapeutic approach to treat a wide range of diseases. However, strategies for precise engineering and delivery of gene-editing nucleases, including zinc finger nucleases, transcription activator-like effector nuclease, and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-associated nuclease Cas9), present major obstacles to the development of gene-editing therapies, as with other gene-targeting therapeutics. Currently, viral and non-viral vectors are being studied for the delivery of these nucleases into cells in the form of DNA, mRNA, or proteins. Clinical trials are already ongoing, and in vivo studies are actively investigating the applicability of CRISPR/Cas9 techniques. However, the concept of correcting the genome poses major concerns from a regulatory perspective, especially in terms of safety. This review addresses current research trends and delivery strategies for gene editing-based therapeutics in non-clinical and clinical settings and considers the associated regulatory issues.

Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics.

Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a new modality for cancer immunotherapy due to their potent efficacy against terminal cancers. CAR-Ts are reported to exert higher efficacy than monoclonal antibodies and antibody–drug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors. CAR-Ts are classified as first-, second- and third-generation, depending on the intracellular signaling domain number of T cell receptors. This review covers the current status of CAR-T research, including basic proof-of-concept investigations at the cell and animal levels. Currently ongoing clinical trials of CAR-T worldwide are additionally discussed. Owing to the lack of existing approved products, several unresolved concerns remain with regard to safety, efficacy and manufacturing of CAR-T, as well as quality control issues. In particular, the cytokine release syndrome is the major side-effect impeding the successful development of CAR-T in clinical trials. Here, we have addressed the challenges and regulatory perspectives of CAR-T therapy.

Light-switchable systems for remotely controlled drug delivery

ABSTRACT Light‐switchable systems have recently received attention as a new mode of remotely controlled drug delivery. In the past, a multitude of nanomedicine studies have sought to enhance the specificity of drug delivery to target sites by focusing on receptors overexpressed on malignant cells or environmental features of diseases sites. Despite these immense efforts, however, there are few clinically available nanomedicines. We need a paradigm shift in drug delivery. One strategy that may overcome the limitations of pathophysiology‐based drug delivery is the use of remotely controlled delivery technology. Unlike pathophysiology‐based active drug targeting strategies, light‐switchable systems are not affected by the heterogeneity of cells, tissue types, and/or microenvironments. Instead, they are triggered by remote light (i.e., near‐infrared) stimuli, which are absorbed by photoresponsive molecules or three‐dimensional nanostructures. The sequential conversion of light to heat or reactive oxygen species can activate drug release and allow it to be spatio‐temporally controlled. Light‐switchable systems have been used to activate endosomal drug escape, modulate the release of chemical and biological drugs, and alter nanoparticle structures to control the release rates of drugs. This review will address the limitations of pathophysiology‐based drug delivery systems, the current status of light‐based remote‐switch systems, and future directions in the application of light‐switchable systems for remotely controlled drug delivery. Graphical abstract Figure. No caption available.

Nanoformulation-based sequential combination cancer therapy

&NA; Although combining two or more treatments is regarded as an indispensable approach for effectively treating cancer, the traditional cocktail‐based combination therapies are seriously limited by coordination issues that fail to account for differences in the pharmacokinetics and action sites of each drug. The careful manipulation of dosing regimens, such as by the sequential application of combination treatments, may satisfy the temporal and spatial needs of each drug and achieve successful combination antitumor therapy. Nanotechnology‐based carriers might be the best tools for sequential combination therapy, as they can be loaded with multiple cargos and may provide targeted and sustained delivery to target tumor cells. Single nanoformulations capable of sequentially releasing drugs have shown synergistic anticancer activity, such as by sensitizing tumor cells through cascaded drug delivery or remodeling the tumor vasculature and microenvironment to enhance the tumor distribution of nanotherapeutics. This review highlights the use of nanotechnology‐based multistage drug delivery for cancer treatment, focusing on the ability of such formulations to enhance antitumor efficacy by applying sequential treatment and modulating dosing regimens, which are challenges currently being faced in the clinic. Graphical abstract Figure. No caption available.

Nonviral Delivery Systems For Cancer Gene Therapy: Strategies And Challenges

Gene therapy has been receiving widespread attention due to its unique advantage in regulating the expression of specific target genes. In the field of cancer gene therapy, modulation of gene expression has been shown to decrease oncogenic factors in cancer cells or increase immune responses against cancer. Due to the macromolecular size and highly negative physicochemical features of plasmid DNA, efficient delivery systems are an essential ingredient for successful gene therapy. To date, a variety of nanostructures and materials have been studied as nonviral gene delivery systems. In this review, we will cover nonviral delivery strategies for cancer gene therapy, with a focus on target cancer genes and delivery materials. Moreover, we will address current challenges and perspectives for nonviral delivery-based cancer gene therapeutics.

Bacteriomimetic poly-γ-glutamic acid surface coating for hemocompatibility and safety of nanomaterials

Abstract Poly-γ-glutamic acid (PGA), a major component of the bacterial capsule, is known to confer hydrophilicity to bacterial surfaces and protect bacteria from interactions with blood cells. We tested whether applying a bacteriomimetic surface coating of PGA modulates interactions of nanomaterials with blood cells or affects their safety and photothermal antitumor efficacy. Amphiphilic PGA (APGA), prepared by grafting phenylalanine residues to PGA, was used to anchor PGA to reduced graphene oxide (rGO) nanosheets, a model of hydrophobic nanomaterials. Surface coating of rGO with bacterial capsule-like APGA yielded APGA-tethered rGO nanosheets (ArGO). ArGO nanosheets remained stable in serum over 4 weeks, whereas rGO in plain form precipitated in serum within 5 minutes. Moreover, ArGO did not interact with blood cells, whereas rGO in plain form or as a physical mixture with PGA formed aggregates with blood cells. Mice administered ArGO at a dose of 50 mg/kg showed 100% survival and no hepatic or renal toxicity. No mice survived exposure at the same dose of rGO or a PGA/rGO mixture. Following intravenous administration, ArGO showed a greater distribution to tumors and prolonged tumor retention compared with other nanosheet formulations. Irradiation with near-infrared light completely ablated tumors in mice treated with ArGO. Our results indicate that a bacteriomimetic surface modification of nanomaterials with bacterial capsule-like APGA improves the stability in blood, biocompatibility, tumor distribution, and photothermal antitumor efficacy of rGO. Although APGA was used here to coat the surfaces of rGO, it could be applicable to coat surfaces of other hydrophobic nanomaterials.

Optimal storage capacity of neural networks at finite temperatures

Gardners analysis (1989) of the optimal storage capacity of neural networks is extended to study finite-temperature effects. The typical volume of the space of interactions is calculated for strongly diluted networks as a function of the storage ratio alpha , temperature T and the tolerance parameter m, from which the optimal storage capacity alpha c is obtained as a function of T and m. At zero temperature it is found that alpha c=2 regardless of m while alpha c in general increases with the tolerance at finite temperatures. The authors show how the best performance for given alpha and T is obtained, which reveals a first-order transition from high-quality performance to a low-quality one at low temperatures. An approximate criterion for recalling, which is valid near m=1, is also discussed.

Staphylococcus aureus-mimetic control of antibody orientation on nanoparticles

We designed a bacterio-mimetic nanoparticle that can noncovalently control the orientation of attached antibodies. Liposomes with Fc-binding peptide (FcBP), formulated using FcBP-conjugated PEGylated lipid, were used as model nanoparticles. Compared with control nanoparticles surface-modified with antibody covalently attached via maleimide functional groups (Mal-NPs), FcBP-capped nanoparticles (FcBP-NPs) exhibited greater binding affinity to the target protein. Human epidermal growth factor receptor 2 (HER2)-specific antibody-modified FcBP-NPs (HER2/FcBP-NPs) showed 5.3-fold higher binding affinity to HER2 than isotype IgG antibody-modified NPs, and 2.6-fold higher affinity compared with anti-HER2 antibody-conjugated Mal-NPs. Cellular uptake of HER2/FcBP-NPs in HER2-positive cells was significantly higher than that of other formulations. The biodistribution of HER2/FcBP-NPs was higher than that of antibody-conjugated NPs in HER2-positive tumor tissues, but not in HER2-negative tumors. Our findings suggest the potential of bacteriomimetic nanoparticles for controlling the orientation of antibody attachment. These nanoparticles may have diverse applications in nanomedicine, including drug delivery, molecular imaging, and diagnosis.

Femtocell channel selection in a two-tier wireless network

Interference management is a key issue of heterogeneous network where operator-deploying macro base stations and user-deploying femto base stations coexist. Due to a large number of femtocells, centralized cell planning and interference management are impractical. In this paper, we propose a distributed frequency resource selection algorithm for self-organizing femtocell networks. The algorithm deals with inter-cell interference among femtocells as well as cross-tier interference between macrocell and femtocell. Simulation results show that proposed scheme improves throughputs of femto users as well as those of macro users.