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

Yun Zhou,Ke Li,Yonghua Zhan,Yang Wang,Fan Li,Shuang Han,Xueping Li

doi:10.1155/2019/5274598

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.

Highlights

Hepatocellular carcinoma (HCC) is the most primary liver cancer and the second most common cause of cancerrelated deaths in the world [1]
The results indicated that Dual-drug synergistic nanoparticles (DDS NPs) have great potential in HCC chemotherapy
ABT-737 and chemotherapeutic agents had the synergistic effect during HCC treatment [32, 33]

Summary

Introduction

Hepatocellular carcinoma (HCC) is the most primary liver cancer and the second most common cause of cancerrelated deaths in the world [1]. DOX was the most common first-line drug in treatment of advanced HCC. It demonstrated objective response rates ranging from 0% to 79% in an initial phase II study [7]. Severe side effects such as cardiotoxicity and neutropenia occurred due to poor targeting efficacy of DOX, which has caused very serious complications in clinical cancer treatment [8]. The cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) is a chemotherapeutic combination for treatment of HCC. It is an effective option for HCC patients who have normal liver function.

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Results

Conclusion