KB-0118, A novel BET bromodomain inhibitor, suppresses Th17-mediated inflammation in inflammatory bowel disease.

Inflammatory bowel disease (IBD) presents complex pathologies and remains challenging to treat, highlighting the urgent need for innovative therapeutics. This study evaluates KB-0118, a novel BET bromodomain inhibitor targeting BRD4, for its immunomodulatory effects in IBD. KB-0118 effectively inhibited pro-inflammatory cytokines, including TNF, IL-1β, and IL-23a, and selectively suppressed Th17 cell differentiation, a critical driver of IBD pathology.

A Novel BD2-Selective Inhibitor of BRDs Mitigates ROS Production and OA Pathogenesis.

Bromodomain and extra-terminal domain (BET) family proteins regulate transcription and recognize lysine residues in histones. Selective BET inhibitors targeting one domain have attracted attention because they maintain normal physiological activities, whereas pan (nonselective) BET inhibitors do not. Osteoarthritis (OA) is a joint disorder characterized by cartilage degeneration for which no treatment currently exists.

BRD2-specific inhibitor, BBC0403, inhibits the progression of osteoarthritis pathogenesis in osteoarthritis-induced C57BL/6 male mice.

Background And Purpose: The discovery of new bromo- and extra-terminal inhibitors presents new drugs to treat osteoarthritis (OA).

Experimental Approach: The new drug, BBC0403, was identified in the DNA-encoded library screening system by searching for compounds that target BRD (bromodomain-containing) proteins. The binding force with BRD proteins was evaluated using time-resolved fluorescence energy transfer (TR-FRET) and binding kinetics assays.

Novel molecule BBC0901 inhibits BRD4 and acts as a catabolic regulator in the pathogenesis of osteoarthritis.

Osteoarthritis (OA) is induced by matrix degradation and inflammation mediated by bromo-domain-containing protein 4 (BRD4)-dependent catabolic factors. BRD4 acts as both a transcriptional regulator and an epigenetic reader. BBC0901 was identified as an inhibitor of BRD4 using a DNA-encoded library screening system.

Streamlined DNA-encoded small molecule library screening and validation for the discovery of novel chemotypes targeting BET proteins.

Targeting aberrant epigenetic programs that drive tumorigenesis is a promising approach to cancer therapy. DNA-encoded library (DEL) screening is a core platform technology increasingly used to identify drugs that bind to protein targets. Here, we use DEL screening against bromodomain and extra-terminal motif (BET) proteins to identify inhibitors with new chemotypes, and successfully identified BBC1115 as a selective BET inhibitor.

Tissue pharmacokinetics of DHP107, a novel lipid-based oral formulation of paclitaxel, in mice and patients by positron emission tomography.

DHP107 is a newly developed lipid-based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope-labeled [ H]DHP107 and [ F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107.

Use of oral paclitaxel for the treatment of bladder tumors in dogs.

An oral paclitaxel formulation that overcomes the hypersensitivity reaction of paclitaxel has been evaluated for safety and efficacy in humans, but not in dogs. We present the first case report on the use of oral paclitaxel in dogs. In this study, oral paclitaxel was well-tolerated in four dogs with either transitional cell carcinoma or prostate cancer; adverse effects were limited to mild neutropenia.

DHP23002 as a next generation oral paclitaxel formulation for pancreatic cancer therapy.

Objective: This study aimed to develop a new oral paclitaxel formulation (DHP23002) and to evaluate its absorption and antitumor effects in a pancreatic tumor mouse model.

Methods: To investigate the oral absorption of DHP23002, a newly developed lipid-based orally active paclitaxel formulation, a pharmacokinetic study of DHP23002, was conducted in mice (62.5 and 125 mg/kg).

Subacute toxicity and toxicokinetics study of DHP107, an oral paclitaxel formulation with once-weekly dosing in mice.

DHP107, an oral formulation of paclitaxel, is effectively and systemically absorbed in intestinal endothelial cells. Although the in vivo efficacy of DHP107 has been reported, the potential toxicity of DHP107 has not been evaluated. Therefore, this study was conducted to evaluate the toxicity and toxicokinetics of DHP107 orally administered to ICR mice at 25, 50, and 100 mg/kg via once-weekly dosing for six weeks.

Targeted Nanotherapeutics Encapsulating Liver X Receptor Agonist GW3965 Enhance Antiatherogenic Effects without Adverse Effects on Hepatic Lipid Metabolism in Ldlr Mice.

The pharmacological manipulation of liver X receptors (LXRs) has been an attractive therapeutic strategy for atherosclerosis treatment as they control reverse cholesterol transport and inflammatory response. This study presents the development and efficacy of nanoparticles (NPs) incorporating the synthetic LXR agonist GW3965 (GW) in targeting atherosclerotic lesions. Collagen IV (Col IV) targeting ligands are employed to functionalize the NPs to improve targeting to the atherosclerotic plaque, and formulation parameters such as the length of the polyethylene glycol (PEG) coating molecules are systematically optimized.

A solvent-free thermosponge nanoparticle platform for efficient delivery of labile proteins.

Protein therapeutics have gained attention recently for treatment of a myriad of human diseases due to their high potency and unique mechanisms of action. We present the development of a novel polymeric thermosponge nanoparticle for efficient delivery of labile proteins using a solvent-free polymer thermo-expansion mechanism with clinical potential, capable of effectively delivering a range of therapeutic proteins in a sustained manner with no loss of bioactivity, with improved biological half-lives and efficacy in vivo.

Gold nanoparticles displaying tumor-associated self-antigens as a potential vaccine for cancer immunotherapy.

Golden vaccine for cancers. Gold nanoparticles enable efficient antigen delivery to dendritic cells and then activate the cells to facilitate cross-presentation, inducing antigen-specific cytotoxic T-lymphocyte responses for effective cancer therapy.

A specific STAT3-binding peptide exerts antiproliferative effects and antitumor activity by inhibiting STAT3 phosphorylation and signaling.

STAT3 promotes the survival, proliferation, metastasis, immune escape, and drug resistance of cancer cells, making its targeting an appealing prospect. However, although multiple inhibitors of STAT3 and its regulatory or effector pathway elements have been developed, bioactive agents have been somewhat elusive. In this report, we report the identification of a specific STAT3-binding peptide (APTSTAT3) through phage display of a novel "aptide" library.

Synthesis and therapeutic evaluation of an aptide-docetaxel conjugate targeting tumor-associated fibronectin.

Targeted delivery of anticancer drugs to tumors has attracted considerable research interest because of its potential to reduce adverse toxicity while improving therapeutic efficacy. In this study, we synthesized and evaluated the therapeutic efficacy of a conjugate of a high-affinity peptide (aptide) and the anticancer drug docetaxel (DTX). A fibronectin extra domain B (EDB)-specific aptide (APTEDB) was used as a cancer-specific targeting ligand.

Aptide-conjugated liposome targeting tumor-associated fibronectin for glioma therapy.

Aptides, developed by our laboratory, are a novel class of high-affinity peptides. Here, we describe the conjugation of an aptide targeting extra-domain B (EDB) of tumor-associated fibronectin to drug-containing liposomes and explore the potential of these aptide-conjugated liposomes as a robust and efficient targeted drug-delivery system for glioma therapy.

HER2-specific aptide conjugated magneto-nanoclusters for potential breast cancer imaging and therapy.

Here, we report a nanotheranostic system that enables simultaneous imaging and therapy of HER2-overexpressing tumors. We first screened an aptide-based phage library for HER2-specific peptide ligands, identifying a HER2-specific aptide (APT) phage clone. Chemically synthesized APT showed high affinity for its target protein (K≈ 89 nM) and specifically bound HER2-overexpressing cells (NIH3T6.

Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan.

Despite the therapeutic potential of exendin-4 as a glucagon-like peptide-1 (GLP-1) mimetic for the treatment of type 2 diabetes, its utility has so far been limited because of the low level of patient compliance due to the requirement for frequent injections. In this study, an orally available exendin-4 was produced by conjugating it to low molecular weight chitosan (LMWC). Conjugation between the LMWC and cysteinylated exendin-4 was carried out using a cleavable linker system in order to maximize the availability of the active peptide.

Fibronectin extra domain B-specific aptide conjugated nanoparticles for targeted cancer imaging.

Fibronectin extra domain B (EDB) is specifically expressed in cancer-associated blood vessels and extracellular matrix, and thus is a promising cancer biomarker. Very recently, we developed a novel class of high-affinity (<100nM) peptides, termed 'aptides', that specifically bind a variety of protein targets. Here, we describe superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with EDB-specific aptides for use in targeted magnetic resonance imaging (MRI) of cancer.

Image-guided prostate cancer therapy using aptamer-functionalized thermally cross-linked superparamagnetic iron oxide nanoparticles.

CG-rich duplex containing prostate-specific membrane antigen (PSMA) aptamer-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPIONs) is reported as prostate cancer-specific nanotheranostic agents. These agents are capable of prostate tumor detection in vivo by magnetic resonance imaging (MRI) and selective delivery of drugs to the tumor tissue, simultaneously. The prepared PSMA-functionalized TCL-SPION via a hybridization method (Apt-hybr-TCL-SPION) exhibited preferential binding towards target prostate-cancer cells (LNCaP, PSMA+) in both in vitro and in vivo when analyzed by T(2) -weighted MRI.

Targeted chemoimmunotherapy using drug-loaded aptamer-dendrimer bioconjugates.

We reported an innovative, targeted chemoimmuno drug-delivery system. Although chemoimmunotherapy, as an alternative to or in combination with conventional therapeutic systems, has been in the forefront of recent oncological research, as presently configured, such systems face several major obstacles for efficient clinical application. Here, we establish a novel nano-platform for effective chemoimmunotherapy designed to overcome the drawbacks of conventional cancer therapies, describing a delivery system based on a dendrimer and a single-strand DNA-A9 PSMA (prostate-specific membrane antigen) RNA aptamer hybrid.

A duplex oligodeoxynucleotide-dendrimer bioconjugate as a novel delivery vehicle for doxorubicin in in vivo cancer therapy.

We designed a bioconjugate between duplex oligodeoxynucleotides (dODNs) and a dendrimer (DEN) and demonstrate its feasibility as a novel delivery system for doxorubicin (Dox) in animal tumor models and against cancer cells in vitro. The dODNs-DEN conjugates formed stable complexes with Dox (~184 Dox molecules per conjugate) and the resulting Dox-loaded conjugate exhibited a sustained drug release pattern both in vitro and in vivo. Pharmacokinetic studies showed that Dox-loaded dODNs-DEN conjugates were cleared from plasma much more slowly (up to 5.

In vivo antitumor effects of chitosan-conjugated docetaxel after oral administration.

The purpose of this study is to evaluate in vivo antitumor efficacy and subacute toxicity of docetaxel (DTX) prodrug comprising a conjugate between DTX and low molecular weight chitosan (LMWC) after oral administration. DTX was covalently attached to LMWC via a cleavable linker so as to be released from LMWC-DTX conjugate in body. In vitro cytotoxicity of LMWC-DTX conjugate was evaluated by MTT assay against two human cancer cell lines, showing similar IC(50) values to the parent DTX.