Interpretable CT Radiomics-based Machine Learning Model for Preoperative Prediction of Ki-67 Expression in Clear Cell Renal Cell Carcinoma.

Rationale And Objectives: To develop and externally validate interpretable CT radiomics-based machine learning (ML) models for preoperative Ki-67 expression prediction in clear cell renal cell carcinoma (ccRCC).

Methods: 506 patients were retrospectively enrolled from three independent institutes and divided into the training (n=357) and external test (n=149) sets. Ki67 expression was determined by immunohistochemistry (IHC) and categorized into low (<15%) and high (≥15%) expression groups.

Phthalocyanine aggregates as semiconductor-like photocatalysts for hypoxic-tumor photodynamic immunotherapy.

Photodynamic immunotherapy (PIT) has emerged as a promising approach for efficient eradication of primary tumors and inhibition of tumor metastasis. However, most of photosensitizers (PSs) for PIT exhibit notable oxygen dependence. Herein, a concept emphasizing on transition from molecular PSs into semiconductor-like photocatalysts is proposed, which converts the PSs from type II photoreaction to efficient type I photoreaction.

The Discovery of a Novel AXL/Triple Angiokinase Inhibitor Based on 6-Chloro-Substituted Indolinone and Side Chain Methyl Substitution Inhibiting Pancreatic Cancer Growth and Metastasis.

In this study, we discovered and identified a novel AXL/triple angiokinase inhibitor by rational structural modification based on the structure of triple angiokinase inhibitor Nintedanib. We found that potently inhibited AXL expression with the IC value of 3.75 nM and possessed similar inhibitory activity on KDR as Nintedanib.

Synthesis of novel deuterated EGFR/ALK dual-target inhibitors and their activity against non-small cell lung cancer.

EGFR and ALK are common driver genes in NSCLC, and more patients with these mutations are being identified due to medical advances. Thus, developing dual-target EGFR/ALK inhibitors is crucial. In this study, 10 novel small molecules were designed and synthesized.

A tumor-pH-responsive phthalocyanine as activatable type I photosensitizer for improved photodynamic immunotherapy.

The development of a simple drug formulation capable of achieving both activatable type I photoreaction and tumor-responsive release of immunomodulator is crucial for advancing photodynamic immunotherapy (PDIT). Herein, we present a nanostructured photosensitizer (NP5) that is activated by the acidic tumor microenvironment to produce type I reactive oxygen species (ROS) under light irradiation and release the immunomodulator demethylcantharidin (DMC) for PDIT. The NP5 is formed by self-assembly of a versatile phthalocyanine molecule which is composed of DMC and phthalocyanine linked via a pH-responsive amide bond.

Efficient hydroxyl radical generation of an activatable phthalocyanine photosensitizer: oligomer higher than monomer and nanoaggregate.

It remains a challenge to develop a single-component organic photosensitizer that efficiently produces hydroxyl radicals (˙OH) without oxygen involvement, especially while maintaining tumor-targeting capability. Herein, we propose an intelligent molecular design strategy whereby a tumor-targeted phthalocyanine is initially ˙OH-free and can be activated by overexpressed β-nicotinamide adenine dinucleotide sodium salt hydrate (NAD(P)H) in hypoxic tumors to efficiently produce ˙OH under light irradiation. Furthermore, the oligomer models based on the phthalocyanine molecules were constructed by a supramolecular regulation strategy, which were in an intermediate state between monomer and nanoaggregate, to achieve enhanced ˙OH generation.

A Renal Clearable Nano-Assembly with Förster Resonance Energy Transfer Amplified Superoxide Radical and Heat Generation to Overcome Hypoxia Resistance in Phototherapeutics.

Given that type I photosensitizers (PSs) possess a good hypoxic tolerance, developing an innovative tactic to construct type I PSs is crucially important, but remains a challenge. Herein, we present a smart molecular design strategy based on the Förster resonance energy transfer (FRET) mechanism to develop a type I photodynamic therapy (PDT) agent with an encouraging amplification effect for accurate hypoxic tumor therapy. Of note, benefiting from the FRET effect, the obtained nanostructured type I PDT agent (NanoPcSZ) with boosted light-harvesting ability not only amplifies superoxide radical (O ) production but also promotes heat generation upon near-infrared light irradiation.

Discovery of new cyclopropane sulfonamide derivatives as EGFR inhibitors to overcome C797S-mediated resistance and EGFR double mutation.

The C797S mutation of EGFR leads to Osimertinib resistance by blocking the covalent binding of Cys797. To develop new agents that can overcome EGFR mutation resistance, thirty seven new cyclopropane sulfonamide derivatives were synthesized and evaluated as EGFR or EGFR inhibitors by structure-based screening. Most of the synthesized compounds exhibit good to excellent anti proliferation activity against to BaF3-EGFR and BaF3- cancer cell lines.

The synthesis and evaluation of novel ALK inhibitors containing the sulfoxide structure.

With ceritinib as the lead, a series of novel compounds containing the sulfoxide structure were synthesized and evaluated as anaplastic lymphoma kinase inhibitors. Among them, compounds 18a-d exhibited excellent anti-proliferation activities on H2228 EML4-ALK cancer cell lines with 14-28 nM of the IC values. In xenograft mouse models, 18a-d inhibited tumor growth with an excellent inhibitory rate of 75.

The new N, N-diphenylpyridine-2,4-diamine deuterated derivatives as EGFR inhibitors to overcome C797S-mediated resistance.

A series of new deuterated and non-deuterated N, N-diphenylpyridine - 2,4-diamine derivatives were synthesized and evaluated as EGFR C797S-mediated resistance inhibitors. Most of these compounds exhibited potent antiproliferative activity against Baf3-EGFR and Baf3-EGFR cancel cell lines, with IC values in the nanomolar concentration range. Among them, compound 14l represented the most active compound with IC values of 8-11 nM.

A novel c-Met/TRK inhibitor 1D228 efficiently inhibits tumor growth by targeting angiogenesis and tumor cell proliferation.

Multiple tumors are synergistically promoted by c-Met and TRK, and blocking their cross-signalling pathway may give better effects. In this study, we developed a tyrosine kinase inhibitor 1D228, which exhibited excellent anti-tumor activity by targeting c-Met and TRK. Models in vitro, 1D228 showed a significant better inhibition on cancer cell proliferation and migration than the positive drug Tepotinib.

A smart and visible way to switch the aromaticity of silicon(IV) phthalocyanines.

Unlike traditional methods of modifying phthalocyanines (Pcs), we herein report a smart and visible way to switch the aromaticity of silicon(IV) phthalocyanines a reversible nucleophilic addition reaction of the Pc skeleton induced by alkalis and acids, leading to an interesting allochroism phenomenon and the switching of photosensitive activities.

Discovery of potent and effective inhibitors containing sulfoxide structures targeting EML4-ALK rearrangement and EGFR mutant non-small cell lung cancer.

For non-small cell lung cancer patients with dual mutations in EGFR and ALK, there are currently no effective therapies. Consequently, novel EGFR/ALK dual-target inhibitors are urgently needed for the treatment of NSCLC. Here, we designed a series of highly effective small molecule dual inhibitors of ALK and EGFR.

Synthesis and evaluation of sulfonamide derivatives targeting EGFR mutations and ALK rearrangement as anticancer agents.

Fourteen new compounds bearing sulfonamide groups that target EGFRT mutations and ALK rearrangement were synthesized and evaluated as dual-target tumor inhibitors. The study on the anti-proliferation activity on cancer cells showed that the sulfonamide derivative with pyrimidine nucleus had much better activities compared with those with quinazoline nucleus. Among them, compound 19e exhibited excellent activity against H1975 cancer cell lines (EGFR high express) and H2228 cells (ALK rearrangement) with the IC values of 0.

Albumin-binding photosensitizer capable of targeting glioma via the SPARC pathway.

Background: Malignant glioma is among the most lethal and frequently occurring brain tumors, and the average survival period is 15 months. Existing chemotherapy has low tolerance and low blood-brain barrier (BBB) permeability; therefore, the required drug dose cannot be accurately delivered to the tumor site, resulting in an insufficient drug effect.

Methods: Herein, we demonstrate a precision photodynamic tumor therapy using a photosensitizer (ZnPcS) capable of binding to albumin in situ, which can increase the permeability of the BBB and accurately target glioma.

A Sulfur-Bridging Sulfonate-Modified Zinc(II) Phthalocyanine Nanoliposome Possessing Hybrid Type I and Type II Photoreactions with Efficient Photodynamic Anticancer Effects.

Phthalocyanines are potentially promising photosensitizers (PSs) for photodynamic therapy (PDT), but the inherent defects such as aggregation-caused quenching effects and non-specific toxicity severely hinder their further application in PDT. Herein, we synthesized two zinc(II) phthalocyanines (PcSA and PcOA) monosubstituted with a sulphonate group in the alpha position with "O bridge" and "S bridge" as bonds and prepared a liposomal nanophotosensitizer (PcSA@Lip) by thin-film hydration method to regulate the aggregation of PcSA in the aqueous solution and enhance its tumor targeting ability. PcSA@Lip exhibited highly efficient production of superoxide radical (O) and singlet oxygen (O) in water under light irradiation, which were 2.

A J-aggregated nanoporphyrin overcoming phototoxic side effects in superior phototherapy with two-pronged effects.

Phototherapy has been a promising therapeutic modality for pathological tissue due to its spatiotemporal selectivity and non-invasive characteristics. However, as a core component of phototherapy, a single photosensitizer (PS) nanoplatform integrating excellent therapeutic efficiency and minimal side effects remains an urgent but unmet need. Here, we construct a J-aggregated nano-porphyrin termed MTE based on the self-assembly of methyl-pheophorbide a derivative MPa-TEG (MT) and natural polyphenolic compound epigallocatechin gallate (EGCG).

Discovery of a potent EGFR and ALK dual mutation inhibitor containing N-(3-((4-((2-(cyclopropylsulfinyl)phenyl)amino)pyrimidin-2-yl)amino) phenyl)acrylamide scaffold.

A series of EGFR and ALK dual inhibitors containing sulfoxide and cyclopropyl groups were designed and synthesized. The lead compound 8a showed a significant activity against EGFR and ALK in both the enzymatic and cellular assays. The study of anti-tumor mechanism indicated that 8a could effectively block the phosphorylation of EGFR and ALK proteins, so as to effectively inhibiting the proliferation and inducing apoptosis of H1975 tumor cells, blocking the cell cycle and reducing the mitochondrial membrane potential inhibited the migration of H1975 cells.

Design, Synthesis, and Evaluation of New Mesenchymal-Epithelial Transition Factor (c-Met) Kinase Inhibitors with Dual Chiral Centers.

A series of tepotinib derivatives with two chiral centers was designed, synthesized, and evaluated as anticancer agents. The optimal compound strongly exhibited antiproliferative activity against MHCC97H cell lines with an IC value of 0.002 μM, compared to tepotinib (IC = 0.

Hexa-BODIPY-cyclotriphosphazene based nanoparticle for NIR fluorescence/photoacoustic dual-modal imaging and photothermal cancer therapy.

Theranostic, which integrates the diagnosis and tumor treatment in tandem, is an emerging strategy in cancer treatment. Here, we report a novel and unique theranostic nanoparticle, HBCP NP, based on hexa-BODIPY cyclophosphazene (HBCP). Due to the unique bulky molecular structure of HBCP, this nanoparticle can simultaneously perform near-infrared (NIR) fluorescence imaging and photoacoustic imaging (PAI).

Molecular and Supramolecular Approach to Highly Photocytotoxic Phthalocyanines with Dual Cell Uptake Pathways and Albumin-Enhanced Tumor Targeting.

Phototherapy for non-invasive cancer treatment has been extensively studied. An urgent challenge in phototherapy application is to fabricate appropriate targeted agents to achieve efficient therapeutic effect. Herein, a molecular and supramolecular approach for targeting phototherapy was reasonably designed and realized through the axial sulfonate modification of silicon(IV) phthalocyanines (Pcs), followed by supramolecular interaction with albumin.

Synthesis and evaluation of new pirfenidone derivatives as anti-fibrosis agents.

Two series of new pirfenidone derivatives, in which phenyl groups or benzyl groups are attached to the nitrogen atom of the pyridin-2(1)-one moiety were synthesized and evaluated as anti-fibrosis agents. Among them, compound 5d, with a ()-2-(dimethylamino) propanamido group in the R position (series 1) exhibited 10 times the anti-fibrosis activity (IC: 0.245 mM) of pirfenidone (IC: 2.

Acid-Responsive Nanoporphyrin Evolution for Near-Infrared Fluorescence-Guided Photo-Ablation of Biofilm.

Combating biofilm infections remains a challenge due to the shield and acidic conditions. Herein, an acid-responsive nanoporphyrin (PN3-NP) based on the self-assembly of a water-soluble porphyrin derivative (PN3) is constructed. Additional kinetic control sites formed by the conjugation of the spermine molecules to a porphyrin macrocycle make PN3 self-assemble into stable nanoparticles (PN3-NP) in the physiological environment.

Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer.

The critical T790M secondary mutation in epidermal growth-factor receptor (EGFR) mediates resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Herein, we identified 12 new 2,4-diaryl pyrimidine derivatives containing thiophene fragments as new selective third-generation EGFR inhibitors. Among them, Compound 6a showed good inhibitory activity against EGFR mutant cells with an IC value of 0.

Discovery of a Novel Stilbene Derivative as a Microtubule Targeting Agent Capable of Inducing Cell Ferroptosis.

Microtubule targeting agents (MTAs) are used as clinically effective chemotherapies for cancer treatment but might be limited by the acquired or intrinsic resistance of cancer cells to apoptosis. The vulnerability of therapy-resistant cancers to ferroptosis provides an alternative way to overcome drug resistance. In this study, on the basis of the MTAs obtained in our previous studies, a series of MTAs were synthesized, and detailed structure-activity relationships were obtained through extensive molecular dynamics studies.