Novel PEGylated cholephytosomes for targeting fisetin to breast cancer: in vitro appraisal and in vivo antitumoral studies.

Fisetin (FIS) is a multifunctional bioactive flavanol that has been recently exploited as anticancer drug against various cancers including breast cancer. However, its poor aqueous solubility has constrained its clinical application. In the current work, fisetin is complexed for the first time with soy phosphatidylcholine in the presence of cholesterol to form a novel biocompatible phytosomal system entitled "cholephytosomes." To improve fisetin antitumor activity against breast cancer, stearylamine bearing cationic cholephytosomes (mPHY) were prepared and furtherly modified with hyaluronic acid (HPHY) to allow their orientation to cancer cells through their surface exposed phosphatidylserine and CD-44 receptors, respectively. In vitro characterization studies revealed promising physicochemical properties of both modified vesicles (mPHY and HPHY) including excellent FIS complexation efficiency (Ë·100%), improved octanol/water solubility along with a sustained drug release over 24 h. In vitro cell line studies against MDA-MB-231 cell line showed about 10- and 3.5-fold inhibition in IC50 of modified vesicles compared with free drug and conventional drug-phospholipid complex, respectively. Preclinical studies revealed that both modified cholephytosomes (mPHY and HPHY) had comparable cytotoxicity that is significantly surpassing free drug cytotoxicity. TGF-ß1and its non-canonical related signaling pathway; ERK1/2, NF-κB, and MMP-9 were involved in halting tumorigenesis. Thus, tailoring novel phytosomal nanosystems for FIS could open opportunity for its clinical utility against cancer.

Self-assembled fisetin-phospholipid complex: Fisetin-integrated phytosomes for effective delivery to breast cancer.

Nowadays, fisetin (FIS) is extensively studied as potent anticancer surrogate with a multitarget actions against various types of cancers including breast cancer. However, its poor aqueous solubility handicapped its clinical utility. The current work endeavored, for the first time, to develop FIS phytosomes (FIS-PHY) for improving its physicochemical properties and subsequently its anticancer activity. Optimization of FIS- phytosomes involved different preparation techniques (Thin film hydration and ethanol injection) and different FIS: phospholipid molar ratios (1:1, 1:2, and 1:3). Complex formation was confirmed by complexation efficiency, infrared spectroscopy (IR), solubility studies and transmission electron microscope. The optimized FIS-PHY of 1:1 M ratio (PHY1) exhibited a nanometric particle size of 233.01 ± 9.46 nm with homogenous distribution (PDI = 0.27), negative zeta potential of - 29.41 mV, 100% complexation efficiency and controlled drug release over 24 h. In-vitro cytotoxicity study showed 2.5-fold decrease in IC50 of PHY1 compared with free FIS. Also, pharmacodynamic studies confirmed the promoted cytotoxicity of PHY1 against breast cancer through modulating TGF-ß1/MMP-9 molecular pathways of tumorigenesis. Overall, overcoming FIS drawbacks were successfully achieved through development of innovative biocompatible phytosomal system.

Lecithin Microemulsion Lipogels Versus Conventional Gels for Skin Targeting of Terconazole: In Vitro, Ex Vivo, and In Vivo Investigation.

Topical treatment of fungal infections has several superiorities over oral treatment. However, the greatest challenge for dermal delivery is the stratum corneum which is considered an effective barrier for penetration of most antifungal drugs into deeper skin layers. Terconazole (Tr), which is the first marketed triazole antifungal, was reported to be one of the most active azoles against vaginal candidiasis. Nevertheless, our work group is the first to investigate the potential of Tr in the treatment of skin mycosis via integration into lecithin microemulsion-based lipogels (LMBGs). The microemulsion regions of the investigated systems were detected through ternary phase diagrams. The in vitro characterization studies revealed promising physicochemical merits for the selected LMBGs as well as satisfactory in vitro antifungal activity. The current research work was endeavored to investigate the potential of such novel Tr-loaded LMBGs in comparison with conventional gels. Ex vivo permeation and retention studies in addition to in vivo deposition study showed a significant improvement in the permeability of Tr through animal skin from LMBGs compared to other conventional gels. Furthermore, the optimized microemulsion lipogel proved to be safe and a nonirritant to experimental animals through the acute sensitivity study and histological skin examination. Overall, lecithin-based microemulsion lipogels of different composition confirmed their potential as interesting nanocarriers for skin delivery of terconazole compared to current therapy.

Novel lecithin-integrated liquid crystalline nanogels for enhanced cutaneous targeting of terconazole: development, in vitro and in vivo studies.

Terconazole (Tr) is the first marketed, most active triazole for vaginal candidiasis. Owing to poor skin permeation and challenging physicochemical properties, Tr was not employed for the treatment of cutaneous candidiasis. This is the first study to investigate the relevance of novel lecithin-integrated liquid crystalline nano-organogels (LCGs) to improve physicochemical characteristics of Tr in order to enable its dermal application in skin candidiasis. Ternary phase diagram was constructed using lecithin/capryol 90/water to identify the region of liquid crystalline organogel. The selected organogel possessed promising physicochemical characteristics based on particle size, rheological behavior, pH, loading efficiency, and in vitro antifungal activity. Microstructure of the selected organogel was confirmed by polarized light microscopy and transmission electron microscopy. Ex vivo and in vivo skin permeation studies revealed a significant 4.7- and 2.7-fold increase in the permeability of Tr-loaded LCG when compared to conventional hydrogel. Moreover, acute irritation study indicated safety and compatibility of liquid crystalline organogel to the skin. The in vivo antifungal activity confirmed the superiority of LCG over the conventional hydrogel for the eradication of Candida infection. Overall, lecithin-based liquid crystalline organogel confirmed its potential as an interesting dermal nanocarrier for skin targeting purpose.