Microfluidized Dextran Microgels Loaded with Cisplatin/SPION Lipid Nanotherapeutics for Local Colon Cancer Treatment via Oral Administration.

Multifunctional sequential targeted delivery system is developed as an efficient therapeutic strategy against malignant tumors with selective accumulation and minimal systemic drug absorption. The therapeutic system is comprised of microfluidized dextran microgels encapsulating cisplatin/superparamagnetic iron oxide nanoparticles (SPIONs)-loaded trilaurin-based lipid nanoparticles (LNPs). The microgel system is imparted hierarchically dual targeting via dextran and folic acid (FA) residues, leading to increases both in retention of the microgels in colon and in cellular uptake of the therapeutic LNPs by colon cancer cells while being used for oral therapeutic delivery.

Tumor microenvironment-responsive and oxygen self-sufficient oil droplet nanoparticles for enhanced photothermal/photodynamic combination therapy against hypoxic tumors.

The combination of photothermal and photodynamic therapy (PTT/PDT) shows pronounced potential as a prominent therapeutic strategy for tumor treatment. However, the efficacy is limited by insufficient tumor-targeted delivery of PTT and PDT reagents and the hypoxic nature of the tumor microenvironment. To overcome these limitations, tumor acidity-responsive lipid membrane-enclosed perfluorooctyl bromide oil droplet nanoparticles (NPs) surface modified with N-acetyl histidine-modified D-α-tocopheryl polyethylene glycol 1000 succinate (PFOB@IMHNPs) were developed, capable of co-delivering oxygen, IR780 (a photothermal agent) and mTHPC (a photodynamic sensitizer) into tumors.

New combination treatment from ROS-Induced sensitized radiotherapy with nanophototherapeutics to fully eradicate orthotopic breast cancer and inhibit metastasis.

Radiotherapy (RT) is one of the most commonly employed approaches in the treatment of malignant tumors and is often combined with radiosensitizers to enhance the therapeutic efficacy for clinical use. For developing a smart therapeutic strategy leveraging local tissue response to photo-mediated reactions and the combination of multiple treatment modalities involving ROS-induced sensitization of RT, a novel nanophototherapeutic system has been developed. The nanotherapeutics prepared from the assembly of poly (thiodiethylene malonate) (PSDEM) and PEG-PSDEM-PEG and loaded with suberoylanilide hydroxamic acid (SAHA) employed as the RT sensitizer and indocyanine green (ICG) as the photothermal/photodynamic agent, demonstrated the capability of undergoing structural change and releasing therapeutic payloads in response to near-infrared irradiation and X-ray radiotherapy.

Capturing Amyloid-β Oligomers by Stirring with Microscaled Iron Oxide Stir Bars into Magnetic Plaques to Reduce Cytotoxicity toward Neuronal Cells.

Soluble amyloid-β oligomers (oAβ)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer's disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAβ into magnetic plaques (mpAβ) and activation of microglia on cellular plaque clearance was developed. With oAβ being effectively converted into mpAβ, the neurotoxicity toward neuronal cells was thus greatly reduced.

Indocyanine green/doxorubicin-encapsulated functionalized nanoparticles for effective combination therapy against human MDR breast cancer.

To overcome low therapeutic efficacy of chemotherapy against multidrug resistance (MDR) breast cancer, a combination therapy system based upon functionalized polymer nanoparticles comprising poly(γ-glutamic acid)-g-poly(lactic-co-glycolic acid) (γ-PGA-g-PLGA) as the major component was developed. The NPs were loaded with doxorubicin (DOX) and indocyanine green (ICG) for dual modality cancer treatment and coated with cholesterol-PEG (C-PEG) for MDR abrogation in treatment of human MDR breast cancer. The in vitro cellular uptake of the DOX/ICG loaded nanoparticles (DI-NPs) by MDR cancer cells was significantly enhanced owing to effective inhibition of the P-gp activity by C-PEG and γ-PGA receptor-mediated endocytosis.

Tumortropic adipose-derived stem cells carrying smart nanotherapeutics for targeted delivery and dual-modality therapy of orthotopic glioblastoma.

Chemotherapy is typically used to treat malignant brain tumors, especially for the tumors in surgically inaccessible areas. However, owing to the existence of blood-brain barrier (BBB), the tumor accumulation and therapeutic efficacy of clinical therapeutics is still of great concerns. To this end, we present herein a prominent therapeutic strategy adopting adipose-derived stem cells (ADSCs) capable of carrying nanotherapeutic payloads selectively toward brain tumors for thermo/chemotherapy.

Protein-specific scoring method for ligand discovery.

Protein-based virtual screening plays an important role in modern drug discovery process. Most protein-based virtual screening experiments are carried out with docking programs. The accuracy of a docking program highly relies on the incorporated scoring function based on various energy terms.

Structure-based inhibitors exhibit differential activities against Helicobacter pylori and Escherichia coli undecaprenyl pyrophosphate synthases.

Helicobacter pylori colonizes the human gastric epithelium and causes diseases such as gastritis, peptic ulcers, and stomach cancer. Undecaprenyl pyrophosphate synthase (UPPS), which catalyzes consecutive condensation reactions of farnesyl pyrophosphate with eight isopentenyl pyrophosphate to form lipid carrier for bacterial peptidoglycan biosynthesis, represents a potential target for developing new antibiotics. In this study, we solved the crystal structure of H.

A three-dimensional pharmacophore model for dipeptidyl peptidase IV inhibitors.

Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. In our study, 3D pharmacophore models were generated using a training set of 22 DPP-IV inhibitors. The best model consisted of important chemical features and mapped well into the active site of DPP-IV.

Structural basis for the structure-activity relationships of peroxisome proliferator-activated receptor agonists.

Type 2 diabetes has rapidly reached an epidemic proportion becoming a major threat to global public health. PPAR agonists have emerged as a leading class of oral antidiabetic drugs. We report a structure biology analysis of novel indole-based PPAR agonists to explain the structure-activity relationships and present a critical analysis of reasons for change in selectivity with change in the orientation of the same scaffolds.

Structure-based drug design and structural biology study of novel nonpeptide inhibitors of severe acute respiratory syndrome coronavirus main protease.

Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search.

Discovery of a novel family of SARS-CoV protease inhibitors by virtual screening and 3D-QSAR studies.

The severe acute respiratory syndrome-associated coronavirus (SARS-CoV) 3C-like protease (3CL(pro) or M(pro)) is an attractive target for the development of anti-SARS drugs because of its crucial role in the viral life cycle. In this study, a compound database was screened by the structure-based virtual screening approach to identify initial hits as inhibitors of SARS-CoV 3CL(pro). Out of the 59,363 compounds docked, 93 were selected for the inhibition assay, and 21 showed inhibition against SARS-CoV 3CL(pro) (IC(50) View Article and Find Full Text PDF

Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists.

Indol-1-yl acetic acids as peroxisome proliferator-activated receptor agonists: design, synthesis, structural biology, and molecular docking studies.

A series of novel indole-based PPAR agonists is described leading to discovery of 10k, a highly potent PPAR pan-agonist. The structural biology and molecular docking studies revealed that the distances between the acidic group and the linker, when a ligand was complexed with PPARgamma protein, were important for the potent activity. The hydrophobic tail part of 10k makes intensive hydrophobic interaction with the PPARgamma protein resulting in potent activity.

2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.

Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage.

Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities.

The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein.

Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.

To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.