Evaluation of gender differences in the pharmacokinetics of oral zileuton nanocrystalline formulation using a rat model.

Zileuton is a leukotriene inhibitor used to treat asthma. As a BCS class II drug it exhibits challenges with solubility which likely impact its absorption. As patient gender significantly impacts the pharmacokinetics of many drugs, this study aimed to investigate potential gender-based pharmacokinetic differences after oral zileuton administration in rats. Male and female Sprague Dawley rats received single oral gavage doses of pure zileuton as an active pharmaceutical ingredient (30 mg/kg body weight (bw)), physical mixture (PM; at 30 mg/kg bw of the formulation contains zileuton, kollidon VA64 fine, dowfax2A1 and trehalose), and nanocrystalline formulation of zileuton (NfZ; at 30 mg/kg bw of the formulation). Plasma, tissue, and urine concentrations were quantified using high performance liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis showed higher zileuton levels in the plasma of female versus male rats across all evaluated forms of zileuton (API, PM, and NfZ). Female rats demonstrated higher peak plasma concentrations (Cmax) and increased area under the plasma concentration-time curve (AUC) relative to males, regardless of formulation. These findings reveal substantial gender disparities in the pharmacokinetics of zileuton in the rat model. This study emphasizes the critical need to evaluate gender differences during preclinical drug development to enable gender-based precision dosing strategies for equivalent efficacy/safety outcomes in male and female patients. Additional studies are warranted to investigate underlying mechanisms of such pharmacokinetic gender divergences.

Lyophilized liposomal formulation of a peptidomimetic-Dox conjugate for HER2 positive breast and lung cancer.

Nanocarrier-mediated administration of chemotherapeutic drugs can increase the therapeutic index of drugs by reducing off-target site toxicity. Ligand-targeted drug delivery can be utilized to deliver chemotherapeutic drugs to cancer cells selectively and specifically. Here we report the evaluation of a lyophilized formulation of a liposome containing a peptidomimetic-doxorubicin conjugate for targeted delivery of doxorubicin to HER2-positive cancer cells. The lyophilized liposomal formulation exhibited improved release of peptidomimetic-doxorubicin conjugate at pH 6.5 compared to 7.4 and improved cellular uptake in cancer cells at pH 6.5. In vivo studies indicated that pH-sensitive formulation exhibited site-specific formulation delivery and improved anticancer efficacy than free doxorubicin. The findings suggested that combining a lyophilized pH-sensitive liposomal formulation containing trehalose as lyoprotectant with a targeting ligand coupled cytotoxic agent is a potential method for cancer chemotherapy while maintaining long-term stability at 4 °C of the liposome formulation.

A pH-sensitive liposome formulation of a peptidomimetic-Dox conjugate for targeting HER2 + cancer.

Cancer treatment faces the challenge of selective delivery of the cytotoxic drug to the desired site of action to minimize undesired side effects. The liposomal formulation containing targeting ligand conjugated cytotoxic drug can be an effective approach to specifically deliver chemotherapeutic drugs to cancer cells that overexpress a particular cell surface receptor. This research focuses on the in vitro and in vivo studies of a peptidomimetic ligand attached doxorubicin for the HER2 positive lung and breast cancer cells transported by a pH-dependent liposomal formulation system for the enhancement of targeted anticancer treatment. The selected pH-sensitive liposome formulation showed effective pH-dependent delivery of peptidomimetic-doxorubicin conjugate at lower pH conditions mimicking tumor microenvironment (pH-6.5) compared to normal physiological conditions (pH 7.4), leading to the improvement of cell uptake. In vivo results revealed the site-specific delivery of the formulation and enhanced antitumor activity with reduced toxicity compared to the free doxorubicin (Free Dox). The results suggested that the targeting ligand conjugated cytotoxic drug with the pH-sensitive liposomal formulation is a promising approach to chemotherapy.

Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis.

Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Similar to other cancer cells, a fundamental characteristic of LC cells is unregulated proliferation and cell division. Inhibition of proliferation by halting cell cycle progression has been shown to be a promising approach for cancer treatment, including LC. miRNA therapeutics have emerged as important post-transcriptional gene regulators and are increasingly being studied for use in cancer treatment. In recent work, we utilized two miRNAs, miR-143 and miR-506, to regulate cell cycle progression. A549 non-small cell lung cancer (NSCLC) cells were transfected, gene expression alterations were analyzed, and apoptotic activity due to the treatment was finally analyzed. Downregulation of cyclin-dependent kinases (CDKs) were detected (i.e., CDK1, CDK4 and CDK6), and cell cycle halted at the G1/S and G2/M phase transitions. Pathway analysis indicated potential antiangiogenic activity of the treatment, which endows the approach with multifaceted activity. Here, described are the methodologies used to identify miRNA activity regarding cell cycle inhibition, induction of apoptosis, and effects of treatment on endothelial cells by inhibition of angiogenesis. It is hoped that the methods presented here will support future research on miRNA therapeutics and corresponding activity and that the representative data will guide other researchers during experimental analyses.