Delivery of hydrophilic drug doxorubicin hydrochloride-targeted liver using apoAI as carrier

Abstract

High-density lipoprotein (HDL) particles can deliver cholesterol from peripheral tissues to the liver through apolipoprotein A1 (Apo A1), which specifically binds to the scavenger receptor class B type 1 (SR-B1) receptor on the surface of hepatocytes. Therefore, ApoA1 can be potentially used to target drugs to the liver. In this study, we successfully loaded doxorubicin hydrochloride (Dox or Dox-HCl), which is a hydrophilic drug used in a wide variety of clinical applications, into the core of reconstituted HDL (rHDL prepared by apoAI and egg phospholipids) to form a doxorubicin-HDL complex (rHDL-Dox). The MTT assays showed that rHDL-Dox particles also had higher cytotoxicity against several cells lines compared to free drug or Dox encapsulated into liposomes. A cellular uptake assay demonstrated that rHDL-Dox had higher absorption in SR-BI receptor positive liver cells. Importantly, in vivo experiments showed that rHDL-Dox can reduce tumor growth more effectively than liposomes. In addition, an in vitro hemolysis assay showed that rHDL-Dox caused only limited hemolysis in the case of high doses. Taken together, our findings indicate that rHDL is a safe and effective drug delivery system for targeting liver.

Synthetic High-Density Lipoprotein-Like Nanoparticles as Cancer Therapy

“…Compared to the free drug, cytotoxicity in the malignant cell lines was significantly increased, while cytotoxicity in retinal pigment epithelial cells, a control cell line for off-target fenretinide toxicity, was reduced [62, 78]. Feng and coworkers used a similar strategy of drug encapsulation to target the chemotherapeutic doxorubicin to hepatocellular carcinoma and hepatoma cells lines [73, 77]. In this work, HDL-like NPs were composed of egg phospholipids, apoA-I, and doxorubicin and showed increased cytotoxicity, apoptosis induction, and conjugate accumulation in target cells compared with the free or liposome encapsulated drug [73].…”

“…In this work, HDL-like NPs were composed of egg phospholipids, apoA-I, and doxorubicin and showed increased cytotoxicity, apoptosis induction, and conjugate accumulation in target cells compared with the free or liposome encapsulated drug [73]. The drug-loaded HDL-like NPs also decreased tumor growth in a metastatic model of human hepatocellular carcinoma (HCC) in nude mice and reduced hemolysis-related side effects [77]. …”

Lipoproteins and lipoprotein mimetics for imaging and drug delivery

“…Similar work has been reported, with HDL loaded with fenretinide,[165] a retinoid derivative, and doxorubicin. [166, 167] In both cases, encapsulation of the drug in HDL enhanced cytotoxicity of neuroblastoma and hepatocellular carcinoma cells, respectively, while reducing off-target effects in healthy, normal cells.…”

Lipoprotein-Related and Apolipoprotein-Mediated Delivery Systems for Drug Targeting and Imaging

“…Equally good results were obtained for rHDL loaded with doxorubicin. The particles showed high absorption to SR-B1 positive hepatocytes in vitro and when applied in vivo tumor growth was more effectively reduced than by liposomal doxorubicin [116]. In another example, HDL was pre-incubated with cholesterol-modified siRNA and the HDL-bound cholesterol-siRNA was injected into Styrian hamster [52].…”