Lisaftoclax (APG-2575) Is a Novel BCL-2 Inhibitor with Robust Antitumor Activity in Preclinical Models of Hematologic Malignancy.

Purpose: Development of B-cell lymphoma 2 (BCL-2)-specific inhibitors poses unique challenges in drug design because of BCL-2 homology domain 3 (BH3) shared homology between BCL-2 family members and the shallow surface of their protein-protein interactions. We report herein discovery and extensive preclinical investigation of lisaftoclax (APG-2575).

Experimental Design: Computational modeling was used to design "lead" compounds.

Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors.

Background: Imatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored.

Methods: The binding activities of HQP1351 with native or mutant KIT were first analyzed.

Ranking Itraconazole Formulations Based on the Flux through Artificial Lipophilic Membrane.

Purpose: The goal of the study was to evaluate a miniaturized dissolution-permeation apparatus (μFLUX™ apparatus) for its ability to benchmark several itraconazole (ITZ) formulations for which in vivo PK data was available in the literature.

Method: Untreated and micronized powders of ITZ and various enabling formulations of ITZ (commercial Sporanox® solid dispersion, a Soluplus®-based solid dispersion and a nanosuspension) were introduced to the donor compartment of μFLUX™ apparatus. Donor and acceptor chambers were divided from each other by a lipophilic membrane.

Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids To Improve Solubility and Enable Parenteral Delivery.

Solubilization of parenteral drugs is a high unmet need in both preclinical and clinical drug development. Recently, co-amorphous drug formulation has emerged as a new strategy to solubilize orally dosed drugs. The aim of the present study is to explore the feasibility of using the co-amorphous strategy to enable the dosing of parenteral zwitterionic drugs at a high concentration.

Efficient synthesis of eriodictyol from L-tyrosine in Escherichia coli.

The health benefits of flavonoids for humans are increasingly attracting attention. Because the extraction of high-purity flavonoids from plants presents a major obstacle, interest has emerged in biosynthesizing them using microbial hosts. Eriodictyol is a flavonoid with anti-inflammatory and antioxidant activities.

Targeting of tumor-associated macrophages made possible by PEG-sheddable, mannose-modified nanoparticles.

It is increasingly evident that tumor-associated macrophages (TAMs) play an important role in tumor invasion, proliferation, and metastasis. While delivery of drugs, imaging agents, and vaccines to TAMs was achieved by exploiting membrane receptors on TAMs, the uptake by normal macrophages remains an issue. In this communication, we report a PEG-sheddable, mannose-modified nanoparticle platform that can efficiently target TAMs via mannose-mannose receptor recognition after acid-sensitive PEG shedding in the acidic tumor microenvironment, while their uptake by normal macrophages in the mononuclear phagocyte system (MPS) organs was significantly reduced due to effective PEG shielding at neutral pH.

Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression.

Gemcitabine is a deoxycytidine analog that is widely used in the chemotherapy of many solid tumors. However, acquired tumor cell resistance often limits its use. Previously, we discovered that 4-(N)-stearoyl gemcitabine solid lipid nanoparticles (4-(N)-GemC18-SLNs) can overcome multiple acquired gemcitabine resistance mechanisms, including RRM1 overexpression.

A nanoparticle depot formulation of 4-(N)-stearoyl gemcitabine shows a strong anti-tumour activity.

Objectives: Depot formulation as a carrier for cytotoxic chemotherapeutic drugs is not well studied. The objective of this study is to test the feasibility of using a subcutaneous depot formulation to administer a cytotoxic anti-cancer drug for systemic therapy.

Methods: A fatty-acid amide prodrug of the nucleoside analogue gemcitabine (4-(N)-stearoyl gemcitabine (GemC18)) was incorporated into poly(lactic-co-glycolic acid) (PLGA) nanoparticles or microspheres.

The effect of the acid-sensitivity of 4-(N)-stearoyl gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression.

Chemoresistance is a major issue for most gemcitabine-related chemotherapies. The overexpression of ribonucleotide reductase subunit M1 (RRM1) plays a key role in gemcitabine resistance. In this study, we synthesized a new highly acid-sensitive amphiphilic micelle material by conjugating hydrophilic polyethylene glycol with a hydrophobic stearic acid derivative (C18) using a hydrazone bond, which was named as PHC-2.

Microneedle-mediated transcutaneous immunization with plasmid DNA coated on cationic PLGA nanoparticles.

Previously, it was shown that microneedle-mediated transcutaneous immunization with plasmid DNA can potentially induce a stronger immune response than intramuscular injection of the same plasmid DNA. In the present study, we showed that the immune responses induced by transcutaneous immunization by applying plasmid DNA onto a skin area pretreated with solid microneedles were significantly enhanced by coating the plasmid DNA on the surface of cationic nanoparticles. In addition, the net surface charge of the DNA-coated nanoparticles significantly affected their in vitro skin permeation and their ability to induce immune responses in vivo.

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells.

Gemcitabine is a deoxycytidine analog used for the treatment of a wide range of solid tumors. Its efficacy is however often reduced due to the development of resistance. Ribonucleotide reductase M1 subunit (RRM1) is a key determinant of gemcitabine resistance, and tumor cells that overexpress RRM1 are resistant to the cytotoxicity of gemcitabine.

Lysosomal delivery of a lipophilic gemcitabine prodrug using novel acid-sensitive micelles improved its antitumor activity.

Stimulus-sensitive micelles are attractive anticancer drug delivery systems. Herein, we reported a novel strategy to engineer acid-sensitive micelles using a amphiphilic material synthesized by directly conjugating the hydrophilic poly(ethylene glycol) (PEG) with a hydrophobic stearic acid derivative (C18) using an acid-sensitive hydrazone bond (PHC). An acid-insensitive PEG-amide-C18 (PAC) compound was also synthesized as a control.

RGD-modified PEG-PAMAM-DOX conjugates: in vitro and in vivo studies for glioma.

This work was based on our recent studies that a promising conjugate, RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive cis-aconityl linkage (RGD-PPCD), could increase tumor targeting by binding with the integrin receptors overexpressed on tumor cells and control release of free DOX in weakly acidic lysosomes. To explore the application of RGD-PPCD to glioma therapy, the effects of the conjugate were further evaluated in glioma model. For comparative studies, DOX was also conjugated to PEG-PAMAM by acid-insensitive succinic linkage to produce the PPSD conjugates, which was further modified by RGD to form RGD-PPSD.

PEGylated PAMAM dendrimers as a potential drug delivery carrier: in vitro and in vivo comparative evaluation of covalently conjugated drug and noncovalent drug inclusion complex.

To understand more about the influence of the types of interaction between drug and PEGylated PAMAM dendrimers on the in vitro and in vivo behavior of drug, methotrexate (MTX) was coupled to PEGylated or non-PEGylated generation 4 PAMAM (G4) through complexing drug within the dendritic architecture and covalently conjugated onto the surface of the dendrimer, respectively. PAMAM was first modified with PEG(5000) chains at three different degrees of substitution. The ability of PEGylated G4 complexing MTX was higher than that of non-PEGylated one.

Partly PEGylated polyamidoamine dendrimer for tumor-selective targeting of doxorubicin: the effects of PEGylation degree and drug conjugation style.

Partly PEGylated polyamidoamine (PAMAM) dendrimers were used as the carrier for tumor-selective targeting of the anticancer drug doxorubicin (DOX). Acid-sensitive cis-aconityl linkage or acid-insensitive succinic linkage was introduced between DOX and polymeric carriers to produce PPCD or PPSD conjugates, respectively. DOX release from PPCD conjugates followed an acid-triggered manner and increased with increasing PEGylation degree.

Application of Box-Behnken design in understanding the quality of genistein self-nanoemulsified drug delivery systems and optimizing its formulation.

The purpose of the present study was to understand the effect of formulation variables of self- nanoemulsified drug delivery systems (SNEDDS) on the rapid dissolution of a model drug, genistein (GN). A three-factor, three-level Box-Behnken design was used to explore the main and interaction effect of several independent formulation variables including the amount of Maisine 35-1 and Labrafac Lipophile WL 1349 (1:1, w/w) (X1), Cremophor EL and Labrasol (3:1, w/w) (X2), and Transcutol P (X3). Droplet size (Y1), turbidity (Y2), and dissolution percentage of GN after 5 (Y3) and 30 (Y4) min were the dependent variables.

PEGylated PAMAM dendrimer-doxorubicin conjugates: in vitro evaluation and in vivo tumor accumulation.

Purpose: To investigate the effects of PEGylation degree and drug conjugation style on the in vitro and in vivo behavior of PEGylated polyamidoamine (PAMAM) dendrimers-based drug delivery system.

Methods: Doxorubicin (DOX) was conjugated to differently PEGylated PAMAM dendrimers by acid-sensitive cis-aconityl linkage and acid-insensitive succinic linkage to produce the products of PPCD and PPSD conjugates, respectively. In vitro evaluations including pH-dependent DOX release, cytotoxicity, cellular uptake, cell internalization mechanism, and intracellular localization were performed.

Novel anti-tumor strategy: PEG-hydroxycamptothecin conjugate loaded transferrin-PEG-nanoparticles.

The aim of the study was to prepare transferrin modified stealth nanoparticles (Tf-PEG-NP) encapsulating poly(ethylene) glycol-hydroxycamptothecin conjugate (PEG-HCPT) and exploit the possiblility of combination of the functions of passive and active targeting by Tf-PEG-NP, as well as sustained drug release in tumor by PEGylated drug for most efficient tumor targeting and anti-tumor effects enhancement. PEG was covalently linked to the 10-hydroxyl group of HCPT to produce PEG-HCPT conjugate. The conjugate was stable, highly water soluable with the cytotoxicity similar to the parent drug.

Effects of polyoxyethylene (40) stearate on the activity of P-glycoprotein and cytochrome P450.

The present study was aimed to investigate the effects of polyoxyethylene (40) stearate (PS), a non-ionic surfactant, on the activity of P-glycoprotein (P-gp) and six major cytochrome P450 (CYP) isoforms. An in vitro diffusion chamber system was utilized to estimate the effects of PS concentration on the transport characteristics of Rhodamine 123 (R123) and Rhodamine 110 (R110), a standard P-gp substrate and nonsubstrate, respectively, across the excised intestinal segments of rat. Caco-2 cells were cultured to investigate the mechanisms by estimating the effects of PS on intracellular ATP levels, P-gp ATPase activity and membrane fluidity.

Efficient tumor targeting of hydroxycamptothecin loaded PEGylated niosomes modified with transferrin.

The aim of the present report was to exploit the possibility of combination of the stealth action by polyethylene glycol cyanoacrylate-co-hexadecyl cyanoacrylate (PEG-PHDCA) modified niosomes and active targeting function of transferrin (Tf) by transferrin receptor-mediated endocytosis to promote drug delivery to solid tumor following intravenous administration with hydroxycamptothecin (HCPT) as model drug. HCPT-loaded PEG-niosomes (PEG-NS) were prepared by thin-film hydration and ultrasound method; the periodate-oxidated Tf was coupled to terminal amino group of PEG to produce the active targeting vesicles with average diameters of 116 nm. The uptake of Tf-PEG-NS into KB cells was concentration and time dependent, which could be inhibited by low temperature and free Tf, indicating that the endocytosis process was energy-driven and receptor specific.

In situ intestinal absorption of cyclosporine A solid dispersion in rats.

Effects of concentration of Polyoxyethylene (40) stearate, Na(+) and P-gp inhibitor on cyclosporin A (CyA-SD) absorption were investigated by in situ circulation method. The results showed that the absorption of CyA increased linearly with its concentration, indicating a passive diffusion process was dominated. CyA absorption decreased with the carrier concentration.

Active tumor-targeted delivery of PEG-protein via transferrin-transferrin-receptor system.

Transferrin (Tf) holds promise as a drug carrier because of overexpress transferring receptors (TfRs) on the surface of tumor cells. The purpose of this work was to conjugate Tf to PEGylated protein (Tf-PEG-protein) to improve tumor-targeted delivery of PEG-protein. After a model protein, beta-lactoglobulin B (LG), was modified by the heterobifunctional polyethyleneglycol (PEG), Tf was covalently linked to the distal end of the PEG chains on the PEG-LG (PL) conjugate.

Tumor cell targeting of transferrin-PEG-TNF-alpha conjugate via a receptor-mediated delivery system: design, synthesis, and biological evaluation.

PEGylation is a procedure of growing interest for enhancing the therapeutic and biotechnological potential of peptides and proteins. Transferrin (Tf) has been proposed to be useful for targeting cancer cells. The aim of this study was to modify PEGylated recombinant human tumor necrosis factor alpha (PEG-TNF-alpha) with Tf to form Tf-PEG-TNF-alpha conjugates, which would maintain the advantages of PEGylation and also achieve the function of active targeting to tumor cells.