Surface modified Genistein phytosome for Breast Cancer Treatment: In-vitro Appraisal, Pharmacokinetics, and In-vivo Antitumor Efficacy

Based on phytosomes advantages over liposomes, hyaluronic acid (HA) with/out pegylated phospholipid was used to develop surface-modified genistein (Gen) phytosome as Gen pegylated hyaluophytosomes (G-PHA) and Gen hyaluophytosomes (G-HA) as novel delivery systems for breast cancer treatment. In this study, in-vitro characterization of G-HA and G-PHA shows PS 144.2 ±1.266 nm and 220.3 ±2.51 nm, ZP -30.9 ±0.75 and -32.06 ±0.305 respectively. Morphological elucidation shows HA covers the surface of G-HA and the presence of a transparent layer of PEG surrounding G-PHA. In-vitro release shows a significant slow Gen release from G- HA, and G-PHA compared to Gen solution and Gen phytosomes. In-vivo bioavailability data shows improvement in bioavailability for G-HA and G-PHA compared to Gen suspension (AUC0-t :3.563 ±0.067, 2.092 ±0.058, 0.374 ±0.085 μg/ml*h respectively). Therapeutic evaluation of the prepared targeted formulations was carried out by subcutaneous injection in an EAC-induced breast cancer model in mice. G-HA and G-PHA show a promising chemotherapeutic effect in terms of lowering the tumor size and tumor biomarkers (CEA: -34.6, -44.7 & CA15.3: -77.8, -81.6 respectively). This reduction in their values compared to Gen phytosomes, Gen suspension, and the control group is attributed to high Gen accumulation at the target organ owing to targeting properties of HA that are used in phytosomal surface modification in G-HA. Additionally, the presence of MPEG2000-DSPE in G-PHA tends to improve interstitium lymphatic drainage following SC administration, resulting in maximizing the therapeutic benefits of breast cancer despite the difference in pharmacokinetics behavior compared to G-HA. These formulations can be further studied for metastatic breast cancer.

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Materials

Genistein (Gen) powder was purchased from Shanghai-Soyoung Biotech. Inc (Shanghai, China). Lipoid® S100 (∼98% pure soy phosphatidylcholine SPC) and 2-dioleoyloxy-3-Trimethylammoniumpropanchloride (DOTAP) and Lipoid PE 18:0/18:0-PEG 2000 (N-(Carbonyl-methoxy polyethylene glycol-2000)-1, 2 distearoyl-sn-glycero-3 phosphoethanolamine, sodium salt) MPEG2000-DSPE were gift samples from Lipoid Co., Ludwigshafen (Germany). Low molecular weight Hyaluronic acid [Mwt = 0.8-1.17×104 Da] was a sample gift from Shiseido (Japan). Propylparaben base was a sample gift from Medizen Pharmaceutical Industries, Egypt. Methanol and Acetonitrile HPLC were purchased from J.T.Baker (USA). 0.85% Phosphoric acid, acetic anhydride, glacial acetic acid, ammonium acetate, and Diethyl ether were purchased from Loba Chemie (India).

Ibrahim A. Komeil, Ossama Y. Abdallah, Wessam M. El-Refaie, Surface modified Genistein phytosome for Breast Cancer Treatment: In-vitro Appraisal, Pharmacokinetics, and In-vivo Antitumor Efficacy, European Journal of Pharmaceutical Sciences, 2022, 106297, ISSN 0928-0987, https://doi.org/10.1016/j.ejps.2022.106297

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