Quercetin-loaded poly (lactic-<i>co</i>-glycolic acid)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles for the targeted treatment of liver cancer

<p>Utilization of quercetin (QT) in clinics is limited by its instability and poor solubility. To overcome these disadvantages, we prepared QT as QT-loaded PLGA-TPGS nanoparticles (QPTN) and examined its properties and therapeutic efficacy for liver cancer. QT-loaded PLGA nanoparticles (QPN) and QT/coumarin-6-loaded PLGA-TPGS nanoparticles (QCPTN) with coumarin-6 as a fluorescent marker were also prepared to investigate the cellular uptake by HepG2 and HCa-F cells using a confocal laser scanning microscope (CLSM), and their effects on apoptosis of HepG2 cells were assessed with flow cytometry. The results measured using transmission electron microscopy, scanning electron microscopy and size analyses indicated that QPTN were stably dispersed sphere with diameter in the range of 100-200 nm. It indicated that the QT loading and encapsulation efficiency in QPTN reached 21.63% and 93.74%, respectively, and the accumulative drug release of QPTN was 85.8%, the QCPTN uptake in HCa-F and HepG2 cells were 50.87% and 61.09% using HPLC analysis, respectively. The results determined using an Annexin-PI flow cytometry indicated that QPTN could induce HepG2 cell apoptosis in a dose dependent manner. The results of histological examination and HPLC analysis confirmed that QPTN was targeted to liver cells. <i>In vivo</i> analysis using solid tumor-bearing mouse model indicated that QPTN could suppress tumor growth by 59.07%. Moreover, all the studied properties of QPTN were more desirable than those of QT-loaded PLGA nanoparticles (QPN). In conclusion, QPTN could be used as a potential intravenous dosage form for the treatment of liver cancer owing to the enhanced pharmacological effects of QT with increased liver targeting.</p

Immolation of <i>p</i>‑Aminobenzyl Ether Linker and Payload Potency and Stability Determine the Cell-Killing Activity of Antibody–Drug Conjugates with Phenol-Containing Payloads

The valine-citrulline (Val-Cit) dipeptide and <i>p</i>-aminobenzyl (PAB) spacer have been commonly used as a cleavable self-immolating linker in ADC design including in the clinically approved ADC, brentuximab vedotin (Adcetris). When the same linker was used to connect to the phenol of the cyclopropabenzindolone (CBI) (<b>P1</b>), the resulting <b>ADC1</b> showed loss of potency in CD22 target-expressing cancer cell lines (e.g., BJAB, WSU-DLCL2). In comparison, the conjugate (<b>ADC2</b>) of a cyclopropapyrroloindolone (CPI) (<b>P2</b>) was potent despite the two corresponding free drugs having similar picomolar cell-killing activity. Although the corresponding spirocyclization products of <b>P1</b> and <b>P2</b>, responsible for DNA alkylation, are a prominent component in buffer, the linker immolation was slow when the PAB was connected as an ether (PABE) to the phenol in <b>P1</b> compared to that in <b>P2</b>. Additional immolation studies with two other PABE-linked substituted phenol compounds showed that electron-withdrawing groups accelerated the immolation to release an acidic phenol-containing payload (to delocalize the negative charge on the anticipated anionic phenol oxygen during immolation). In contrast, efficient immolation of <b>LD4</b> did not result in an active <b>ADC4</b> because the payload (<b>P4</b>) had a low potency to kill cells. In addition, nonimmolation of <b>LD5</b> did not affect the cell-killing potency of its <b>ADC5</b> since immolation is not required for DNA alkylation by the center-linked pyrrolobenzodiazepine. Therefore, careful evaluation needs to be conducted when the Val-Cit-PAB linker is used to connect antibodies to a phenol-containing drug as the linker immolation, as well as payload potency and stability, affects the cell-killing activity of an ADC

Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

PI3Kδ is a lipid kinase and a member of a larger family of enzymes, PI3K class IA­(α, β, δ) and IB (γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3Kδ inhibitors and describe a structural hypothesis for isoform (α, β, γ) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization