Development of Arteannuin B Sustained-Release Microspheres for Anti-Tumor Therapy by Integrated Experimental and Molecular Modeling Approaches

Abstract

Arteannuin B (AB) has been found to demonstrate obvious anti-tumor activity. However, AB is not available for clinical use due to its very low solubility and very short half-life. This study aimed to develop AB long sustained-release microspheres (ABMs) to improve the feasibility of clinical applications. Firstly, AB-polylactic-co-glycolic acid (PLGA) microspheres were prepared by a single emulsification method. In vitro characterization studies showed that ABMs had a low burst release and stable in vitro release for up to one week. The particle size of microspheres was 69.10 μm (D50). The drug loading is 37.8%, and the encapsulation rate is 85%. Moreover, molecular dynamics modeling was firstly used to simulate the preparation process of microspheres, which clearly indicated the molecular image of microspheres and provided in-depth insights for understanding several key preparation parameters. Next, in vivo pharmacokinetics (PK) study was carried out to evaluate its sustained release effect in Sprague-Dawley (SD) rats. Subsequently, the methyl thiazolyl tetrazolium (MTT) method with human lung cancer cells (A549) was used to evaluate the in vitro efficacy of ABMs, which showed the IC50 of ABMs (3.82 μM) to be lower than that of AB (16.03 μM) at day four. Finally, in vivo anti-tumor activity and basic toxicity studies were performed on BALB/c nude mice by subcutaneous injection once a week, four times in total. The relative tumor proliferation rate T/C of AMBs was lower than 40% and lasted for 21 days after administration. The organ index, organ staining, and tumor cell staining indicated the excellent safety of ABMs than Cis-platinum. In summary, the ABMs were successfully developed and evaluated with a low burst release and a stable release within a week. Molecular dynamics modeling was firstly applied to investigate the molecular mechanism of the microsphere preparation. Moreover, the ABMs possess excellent in vitro and in vivo anti-tumor activity and low toxicity, showing great potential for clinical applications.

Application of biodegradable microsphere injections: an anticancer perspective

“…The PLGA microspheres loaded with arteannuin B can effectively inhibit the growth of the tumor. 35 The relative tumor proliferation rate is less than 40%, and only weekly subcutaneous injection achieved the continuous release of API for 21 days. Furthermore, the index of organ, organ staining, and staining of tumor cells indicated that this microsphere formulation was safer than cis -platinum diamine–dichloride injection; thus, it might be the first microsphere to deliver small molecule antitumor drugs.…”

Integrating Network Pharmacology and Experimental Validation to Explore the Effects and Mechanisms of Qinghao Biejia Decoction and Its Active Compound Artemisinin B Against Non-Small-Cell Lung Cancer

“… 13 It was also reported that ART B could inhibit the proliferation of HT-29, HepG2, SGC-7901, A549, K562, B16-F10, and Du145 cells, while having no obvious toxicity to normal human embryonic liver cells L-02. 14 However, the anti-cancer effect and mechanism of both QBD and ART B on NSCLC are unknown, and the chemical basis of QBD action is also unclear.…”