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Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy.

ABSTRACT: Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated liposomes (Man-liposomes). The Man-liposomes had a mean diameter of 158.8 nm and zeta potential of -15.8 mV. In the HCT8/ADR cells that overexpress the mannose receptors, the Man-liposomes altered the intracellular distribution of Dox, resulting in a high accumulation of Dox in the nuclei and thus displaying the highest cytotoxicity (IC50=0.073 ?g/mL) among all the groups. In a subcutaneous HCT8/ADR tumor xenograft model, administration of the Man-liposomes resulted in a tumor inhibition rate of 88.59%, compared to that of 47.46% or 70.54%, respectively, for the treatment with free Dox or free Dox+DHA. The mechanisms underlying the anti-MDR effect of the Man-liposomes involved preferential nuclear accumulation of the therapeutic agents, enhanced cancer cell apoptosis, downregulation of Bcl-xl, and the induction of autophagy.

SUBMITTER: Kang XJ

PROVIDER: S-EPMC5520183 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy.

Kang Xue-Jia XJ Wang Hui-Yuan HY Peng Hui-Ge HG Chen Bin-Fan BF Zhang Wen-Yuan WY Wu Ai-Hua AH Xu Qin Q Huang Yong-Zhuo YZ

Acta pharmacologica Sinica 20170508 6

Multidrug resistance (MDR) is a major hurdle in cancer chemotherapy and makes the treatment benefits unsustainable. Combination therapy is a commonly used method for overcoming MDR. In this study we investigated the anti-MDR effect of dihydroartemisinin (DHA), a derivative of artemisinin, in combination with doxorubicin (Dox) in drug-resistant human colon tumor HCT8/ADR cells. We developed a tumor-targeting codelivery system, in which the two drugs were co-encapsulated into the mannosylated lipo ...[more]

PMID: 28479604

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Project description:BackgroundReactive oxygen species (ROS)-responsive drug delivery systems (DDSs) are potential tools to minimize the side effects and substantially enhance the therapeutic efficacy of chemotherapy. However, it is challenging to achieve spatially and temporally controllable and accurate drug release in tumor sites based on ROS-responsive DDSs. To solve this problem, we designed a nanosystem combined photodynamic therapy (PDT) and ROS-responsive chemotherapy.MethodsIndocyanine green (ICG), an ROS trigger and photosensitizer, and pB-DOX, a ROS-responsive prodrug of doxorubicin (DOX), were coencapsulated in polyethylene glycol modified liposomes (Lipo/pB-DOX/ICG) to construct a combination therapy nanosystem. The safety of nanosystem was assessed on normal HEK-293 cells, and the cellular uptake, intracellular ROS production capacity, target cell toxicity, and combined treatment effect were estimated on human breast cancer cells MDA-MB-231. In vivo biodistribution, biosafety assessment, and combination therapy effects were investigated based on MDA-MB-231 subcutaneous tumor model.ResultsCompared with DOX·HCl, Lipo/pB-DOX/ICG showed higher safety on normal cells. The toxicity of target cells of Lipo/pB-DOX/ICG was much higher than that of DOX·HCl, Lipo/pB-DOX, and Lipo/ICG. After endocytosis by MDA-MB-231 cells, Lipo/pB-DOX/ICG produced a large amount of ROS for PDT by laser irradiation, and pB-DOX was converted to DOX by ROS for chemotherapy. The cell inhibition rate of combination therapy reached up to 93.5 %. After the tail vein injection (DOX equivalent of 3.0 mg/kg, ICG of 3.5 mg/kg) in mice bearing MDA-MB-231 tumors, Lipo/pB-DOX/ICG continuously accumulated at the tumor site and reached the peak at 24 h post injection. Under irradiation at this time point, the tumors in Lipo/pB-DOX/ICG group almost disappeared with 94.9 % tumor growth inhibition, while those in the control groups were only partially inhibited. Negligible cardiotoxicity and no treatment-induced side effects were observed.ConclusionsLipo/pB-DOX/ICG is a novel tool for on-demand drug release at tumor site and also a promising candidate for controllable and accurate combinatorial tumor therapy.

Dataset Information

Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy.

Publications

Codelivery of dihydroartemisinin and doxorubicin in mannosylated liposomes for drug-resistant colon cancer therapy.

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