Simvastatin (SV) repurposing has emerged as an alternative approach for the treatment of cancer. In this study, SV chitosan nanoparticles co-crosslinked with tripolyphosphate and chondroitin sulfate (SVCSChSNPs) were developed in order to maximize SV therapeutic efficiency. The hepatic targeting was realized using N-acetylgalactosamine (GalNAc) residues of ChS, which can be identified by the ASGPR receptors specifically expressed in hepatocytes. SV was repurposed as an anticancer agent against hepatocellular carcinoma (HCC). NPs were fabricated by the ionic gelation method, and the formulation variables (CS concentration, CS:ChS ratio, and CS solution pH) were optimized using a three-factor, three-level Box-Behnken design. The optimized NPs were investigated for particle size, size distribution, zeta potential, morphology, in vitro cytotoxicity, apoptotic effects against human hepatocellular carcinoma HepG2 cells, and detection of intracellular localization. The NPs were further evaluated for in vitro release behavior of SV and pharmacokinetics using Wister albino rats. Transmission electron microscopy (TEM) imaging showed a spherical shape with regular surface NPs of < 100 nm diameter. In vitro cytotoxicity testing showed that the SVCSChSNPs exhibited greater inhibition of proliferation in HepG2 cells and high cellular uptake through ASGPR-mediated endocytosis. The in vitro dissolution profile was 2.1-fold greater than that of pure SV suspension. Furthermore, in vivo oral pharmacokinetics revealed that the obtained NPs enhanced the bioavailability of SV by up to 2- and 1.6-fold for SV and SVA, respectively, compared to the pure SV suspension. These findings demonstrated that hepatic-targeted CSChSNPs delivering SV could potentially serve as a promising platform for HCC and other liver-related diseases.

辛伐他汀（SV）的替代治疗已经成为治疗癌症的替代方法。在这项研究中，开发了与三聚磷酸盐和硫酸软骨素（SVCSChSNPs）共交联的SV壳聚糖纳米颗粒，以最大限度地提高SV的治疗效率。使用ChS的N-乙酰半乳糖胺（GalNAc）残基可以实现肝靶向，这可以通过在肝细胞中特异性表达的ASGPR受体进行鉴定。SV被重新用作抗肝细胞癌（HCC）的抗癌药。通过离子凝胶法制备NP，并使用三因素三级Box-Behnken设计优化配方变量（CS浓度，CS：ChS比和CS溶液pH）。研究了优化的NP的粒径，尺寸分布，ζ电位，形态，体外细胞毒性，对人肝癌HepG2细胞的凋亡作用以及细胞内定位的检测。使用Wister白化病大鼠进一步评估NP的SV体外释放行为和药代动力学。透射电子显微镜（TEM）成像显示球形，规则表面NP的直径小于100 nm。体外细胞毒性测试表明，SVCSChSNPs表现出更大的HepG2细胞增殖抑制作用，并且通过ASGPR介导的内吞作用具有较高的细胞摄取率。该体外溶出曲线为2.1倍大于纯SV悬浮液。此外，体内口服药代动力学显示，与纯SV悬浮液相比，获得的NP对SV和SVA的SV的生物利用度分别提高了2倍和1.6倍。这些发现表明，以肝靶向的CSChSNPs传递SV可能成为肝癌和其他肝相关疾病的有前途的平台。