Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space.

Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea.

Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea.

A self-assembled nanophotosensitizer targets lysosomes and induces lysosomal membrane permeabilization to enhance photodynamic therapy.

We report the self-assembly of amphiphilic BDQ photosensitizers into lysosome-targeting nanophotosensitizer BDQ-NP for highly effective photodynamic therapy (PDT). Molecular dynamics simulation, live cell imaging, and subcellular colocalization studies showed that BDQ strongly incorporated into lysosome lipid bilayers to cause continuous lysosomal membrane permeabilization. Upon light irradiation, the BDQ-NP generated a high level of reactive oxygen species to disrupt lysosomal and mitochondrial functions, leading to exceptionally high cytotoxicity.

Metal-Organic Layer Delivers 5-Aminolevulinic Acid and Porphyrin for Dual-Organelle-Targeted Photodynamic Therapy.

The efficacy of photodynamic therapy (PDT) depends on the subcellular localization of photosensitizers. Herein, we report a dual-organelle-targeted nanoparticle platform for enhanced PDT of cancer. By grafting 5-aminolevulinic acid (ALA) to a Hf -based nanoscale metal-organic layer (Hf-MOL) via carboxylate coordination, ALA/Hf-MOL enhanced ALA delivery and protoporphyrin IX (PpIX) synthesis in mitochondria, and trapped the Hf-MOL comprising 5,15-di-p-benzoatoporphyrin (DBP) photosensitizers in lysosomes.

Pharmacological ascorbate potentiates combination nanomedicines and reduces cancer cell stemness to prevent post-surgery recurrence and systemic metastasis.

Conventional chemotherapy targets proliferative cancer cells to halt tumor progression or regress tumors. However, the plasticity of tumor cells enables their phenotypical changes to acquire chemo-resistance, leading to treatment failure or tumor recurrence after a successful treatment course. Here, we report the use of high-dose pharmacologic ascorbate to potentiate treatment efficacy of nanoscale coordination polymers (NCPs) delivering two clinical combinations of chemotherapeutics, carboplatin/docetaxel and oxaliplatin/SN38, and to target metabolic plasticity of tumor cells.

A Three-in-One Nanoscale Coordination Polymer for Potent Chemo-Immunotherapy.

The addition of immune checkpoint blockade to standard chemotherapy has changed the standards of care for some cancer patients. However, current chemo-immunotherapy strategies do not benefit most colorectal cancer patients and many triple-negative breast cancer patients. Here, the design of a three-in-one nanoscale coordination polymer (NCP), OX/GC/CQ, comprising prodrugs of oxaliplatin (OX), gemcitabine (GC), and 5-carboxy-8-hydroxyquinoline (CQ) for triple-modality chemo-immunotherapy is reported.

A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy.

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects.

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

The binding of plasma proteins to nanomedicines is widely considered detrimental to their delivery to tumors. Here, the design of OxPt/SN38 nanoparticle containing a hydrophilic oxaliplatin (OxPt) prodrug in a coordination polymer core and a hydrophobic cholesterol-conjugated SN38 prodrug on the lipid shell for active tumor targeting is reported. OxPt/SN38 hitchhikes on low-density lipoprotein (LDL) particles, concentrates in tumors via LDL receptor-mediated endocytosis, and selectively releases SN38 and OxPt in acidic, esterase-rich, and reducing tumor microenvironments, leading to 6.

Dimensional Reduction Enhances Photodynamic Therapy of Metal-Organic Nanophotosensitizers.

Herein we report that dimensional reduction from three-dimensional nanoscale metal-organic frameworks (nMOFs) to two-dimensional nanoscale metal-organic layers (nMOLs) increases the frequency of encounters between photosensitizers and oxygen and facilitates the diffusion of singlet oxygen from the nMOL to significantly enhance photodynamic therapy. The nMOFs and nMOLs share the same M-oxo (M = Zr, Hf) secondary building units and 5,15-di--benzoatoporphyrin (DBP) ligands but exhibit three-dimensional and two-dimensional topologies, respectively. Molecular dynamics simulations and experimental studies revealed that the nMOLs with a monolayer morphology enhanced the generation of reactive oxygen species and exhibited over an order of magnitude higher cytotoxicity over the nMOFs.

Chitosan-derived nanoparticles impede signal transduction in T790M lung cancer therapy.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treated patients ultimately develop disease progression, about 50% of which are involved in the emergence of a p.Thr790Met (T790M) mutation acquiring drug resistance. In order to solve the aforementioned problem, a therapeutic nanoparticles DGA is developed to overcome EGFR-T790M resistance downstream anti-apoptotic signal transduction blocking by a combination with persuading mitochondrial dysfunction and inhibiting miRNA expression.

Reprogramming of Neutrophils as Non-canonical Antigen Presenting Cells by Radiotherapy-Radiodynamic Therapy to Facilitate Immune-Mediated Tumor Regression.

Ineffective antigen cross-presentation in the tumor microenvironment compromises the generation of antitumor immune responses. Radiotherapy-radiodynamic therapy (RT-RDT) with nanoscale metal-organic frameworks (nMOFs) induces robust adaptive immune responses despite modest activation of canonical antigen presenting dendritic cells. Here, using transplantable and autochthonous murine tumor models, we demonstrate that RT-RDT induces antitumor immune responses early neutrophil infiltration and reprogramming.

Monte Carlo Simulations Reveal New Design Principles for Efficient Nanoradiosensitizers Based on Nanoscale Metal-Organic Frameworks.

Nanoscale metal-organic frameworks (nMOFs) have recently been shown to provide better radiosensitization than solid nanoparticles (NPs) when excited with X-rays. Here, a Monte Carlo simulation of different radiosensitization effects by NPs and nMOFs using a lattice model consisting of 3D arrays of nanoscale secondary building units (SBUs) is reported. The simulation results reveal that lattices outperform solid NPs regardless of radiation sources or particle sizes via enhanced scatterings of photons and electrons within the lattices.

Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate.

The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared.

A Hybrid Eukaryotic-Prokaryotic Nanoplatform with Photothermal Modality for Enhanced Antitumor Vaccination.

Cytomembrane-derived nanoplatforms are an effective biomimetic strategy in cancer therapy. To improve their functionality and expandability for enhanced vaccination, a eukaryotic-prokaryotic vesicle (EPV) nanoplatform is designed and constructed by fusing melanoma cytomembrane vesicles (CMVs) and attenuated Salmonella outer membrane vesicles (OMVs). Inheriting the virtues of the parent components, the EPV integrates melanoma antigens with natural adjuvants for robust immunotherapy and can be readily functionalized with complementary therapeutics.

A zipped-up tunable metal coordinated cationic polymer for nanomedicine.

Incorporating metal elements into polymers is a feasible means to fabricate new materials with multiple functionalities. In this work, a metal coordinated cationic polymer (MCCP) was developed. Ferric ions were incorporated into the polyethyleneimine-β-cyclodextrin (PC) polymer chain via coordination to produce a zipped-up polymer with a micro-ordered and macro-disordered topological structure.

General Approach To Construct Azepino[2,3-:4,5-']diindoles, Azocino[2,3-:4,5-']diindoles, and Azonino[2,3-:4,5-']diindoles via Rh(II)-Catalyzed Reactions of 3-Diazoindolin-2-imines with 3-(Bromoalkyl)indoles.

Rh(II)-catalyzed reactions of 3-diazoindolin-2-imines with 3-(2-bromoethyl)indoles, 3-(3-bromopropyl)indoles, and 3-(4-bromobutyl)indoles, followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in a one-pot operation furnished azepino[2,3-:4,5-']diindoles, azocino[2,3-:4,5-']diindoles, and azonino[2,3-:4,5-']diindoles, respectively.

A copper-catalyzed reaction of 3-diazoindolin-2-imines with 2-(phenylamino)ethanols: convenient access to spiro[indoline-3,2'-oxazolidin]-2-imines.

3-Diazoindolin-2-imines reacted with chiral 2-(phenylamino)ethanols under copper catalysis to furnish chiral spiro[indoline-3,2'-oxazolidin]-2-imines in good yields with excellent diastereoselectivity. The reaction undergoes a copper-catalyzed cascade process involving the formation of copper carbene, C-N coupling, and C-O coupling.