Doxorubicin and ABT-199 Coencapsulated Nanocarriers for Targeted Delivery and Synergistic Treatment against Hepatocellular Carcinoma

Abstract

For the patients with hepatocellular carcinoma (HCC), conventional chemotherapy is insufficient or has no benefit. Although combination chemotherapy has been proven as an efficient strategy to enhance anti-HCC efficacy, some barriers, such as low bioavailability and side effects, are limiting clinical development. In order to overcome disadvantages of combination chemotherapy in HCC, targeted nanoparticles (NPs) simultaneously loaded with doxorubicin (DOX) and ABT-199 in an optimal synergistic ratio were developed. First, the most synergistic combination with DOX was screened from ABT-199, ABT-263, and ABT-737. Among them, ABT-199 showed optimal synergy with DOX in a ratio of 10 : 1. Then, cationic amphipathic starch (CSaSt) and hyaluronic acid (HA) were used in coencapsulations of those two drugs. Dual-drug synergistic nanoparticles (DDS NPs) were constructed by absorption of DOX NPs around ABT-199 micelles with an optimal ratio via electrostatic interaction. The shape of DDS NPs was similar to a raspberry, and the size was 112 6 ± 13 4 nm. The encapsulation efficiencies of DOX and ABT-199 in DDS NPs were 90 2 ± 4 3% and 94 7 ± 2 8%, respectively; meanwhile, the drug loadings were 1 5 ± 0 4% and 14 1 ± 1 1%, respectively. After 72 h of dialysis, 95% of ABT-199 remained and less than 50% of DOX was released. In vitro investigation showed that the drugs in DDS NPs maintained the treated effect in three HCC cell lines; moreover, DDS NPs could perform intracellular delivery of dual drugs and exhibited continuous release of the drugs into different targets. Low in vivo toxicity was found after the acute toxicity test. In vivo fluorescent imaging revealed that DDS NPs could efficiently target and accumulate in the tumor tissues and be maintained more than 72 h after intravenous injection. Compared with free drugs, DDS NPs with the same dosages exhibited a more significant antitumor effect in the HCC xenograft mouse model. The results indicated that DDS NPs have great potential in HCC chemotherapy.Tables S1 and S2: CI and dose reduction values for inhibition of BEL-7402, SMMC-7721, and Huh-7 by combining DOX with ABT-263 or ABT-737. The synergistic effects of these two combinations were less than combined DOX with . Especially in ABT-263 combined with DOX, it showed few synergy in three HCC cell lines. Figure S1: WST assay results of BEL-7402, SMMC-7721, and Huh-7 cells treated with dual drugs and DDS NPs. As the result show, the toxicity of empty NPs was almost none, and DDS NPs and free dual drugs have equal antiproliferating effect against three HCC cell lines in vitro. The result indicated that the DDS NPs could perform the synergistic anti-HCC effect of ABT-199 combined with DOX. (Supplementary Materials)

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