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. 2019 Jan 11:14:543-556.
doi: 10.2147/IJN.S190027. eCollection 2019.

Idarubicin-loaded methoxy poly(ethylene glycol)- b-poly(l-lactide-co-glycolide) nanoparticles for enhancing cellular uptake and promoting antileukemia activity

Bin Liang  1 , Na Li  2 , Shuofei Zhang  3 , Aihua Qi  4 , Jianhua Feng  1 , Weiwei Jing  5 , Changcan Shi  2 , Zhaipu Ma  6 , Shenmeng Gao  7
Affiliations

Idarubicin-loaded methoxy poly(ethylene glycol)- b-poly(l-lactide-co-glycolide) nanoparticles for enhancing cellular uptake and promoting antileukemia activity

Bin Liang et al. Int J Nanomedicine. .

Abstract

Purpose: Nanoparticle (NP)-based drug delivery approaches have tremendous potential for enhancing treatment efficacy and decreasing doses of chemotherapeutics. Idarubicin (IDA) is one of the most common chemotherapeutic drugs used in the treatment of acute myeloid leukemia (AML). However, severe side effects and drug resistance markedly limit the application of IDA.

Methods: In this study, we encapsulated IDA in polymeric NPs and validated their antileukemia activity in vitro and in vivo.

Results: NPs with an average diameter of 84 nm was assembled from a methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide) (mPEG-PLGA). After loading of IDA, IDA-loaded mPEG-PLGA NPs (IDA/mPEG-PLGA NPs) were formed. The in vitro release data showed that the IDA/mPEG-PLGA NPs have excellent sustained release property. IDA/mPEG-PLGA NPs had exhibited the lower IC50 than pure IDA. Moreover, IDA/mPEG-PLGA NPs in the same concentration substantially induced apoptosis than did pure IDA. Most importantly, IDA/MPEG-PLGA NPs significantly decreased the infiltration of leukemia blasts and improved the overall survival of MLL-AF9-induced murine leukemia compared with free IDA. However, the blank NPs were nontoxic to normal cultured cells in vitro, suggesting that NPs were the safe carrier.

Conclusion: Our data suggest that IDA/mPEG-PLGA NPs might be a suitable carrier to encapsulate IDA. Low dose of IDA/mPEG-PLGA NPs can be used as a conventional dosage for antileukemia therapy to reduce side effect and improve survival.

Keywords: acute myeloid leukemia; idarubicin; mPEG-PLGA; nanoparticles.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
(A) Synthesis route of mPEG-PLGA diblock copolymer and schematic diagram of preparation of IDA/mPEG-PLGA NPs. (B) H NMR characterization of mPEG-PLGA diblock copolymers. (C) FTIR spectra of three kinds of mPEG-PLGA diblock copolymers. Abbreviations: GA, glycolide; IDA, idarubicin; LLA, l-lactide; mPEG, methoxy poly(ethylene glycol); mPEG-PLGA, mPEG-b-poly(LLA-co-GA); NPs, nanoparticles.
Figure 2
Figure 2
TEM images of mPEG-PLGA1 NPs (A) and IDA/mPEG-PLGA NPs (B). Abbreviations: IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles; TEM, transmission electron microscopy.
Figure 3
Figure 3
Standard curve of IDA and cumulative release of IDA/mPEG-PLGA NPs. Notes: (A) Standard curve of IDA; images of IDA and IDA/mPEG-PLGA NPs after centrifugation separation. (B) Cumulative release of IDA/mPEG-PLGA NPs. Abbreviations: IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles.
Figure 4
Figure 4
Cytotoxicity of mPEG-PLGA1 NPs, IDA/mPEG-PLGA NPs, and IDA in L929 cells and normal human CD34+ HSPCs. Notes: (A and B) The cell viability was measured in murine L929 cells and normal human CD34+ HSPCs treated with different concentrations of mPEG-PLGA1 NPs, IDA, and IDA/mPEG-PLGA1 NPs for 24 hours (**P<0.01 vs control group; NS, nonsignificant between control group and IDA/mPEG-PLGA NPs). Abbreviations: HSPCs, hematological stem and progenitor cells; IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles.
Figure 5
Figure 5
Pharmacokinetics and biodistribution analysis by ex vivo imaging system. Notes: (A) Six-week-old wild-type C57BL/6J mice were intraperitoneally injected with IDA/mPEG-PLGA NPs. Liver, spleen, heart, lung, kidney, and intestine were dissected out after administration for 6 hours. The 540Ex/620Em was used to analyze DsRed fluorescence by IDA and captured by ex vivo imaging system. (B) Six-week-old wild-type C57BL/6J mice were intraperitoneally injected with IDA/mPEG-PLGA NPs. Bone marrow was dissected out after administration for 6 hours for subsequent ex vivo imaging analysis. (C) Ex vivo imaging analysis for liver and spleen, which were dissected out after mice were injected with IDA (3 mg/kg) or IDA/mPEG-PLGA NPs (3 mg/kg) for 2, 24, 48, and 96 hours. Abbreviations: IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles.
Figure 6
Figure 6
mPEG-PLGA enhances the cellular uptake of IDA. Notes: PE fluorescence by IDA was measured by flow cytometry in HL-60, which were treated with 0.1 µM IDA or 0.1 µM IDA/mPEG-PLGA NPs for 6 hours. Shown is the representative plots (left) and summary of PE+ cells (right). Abbreviations: IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles; PE, phycoerythrin.
Figure 7
Figure 7
Antileukemia activity of IDA and IDA/mPEG-PLGA NPs in leukemia cells in vitro. Notes: (A) HL-60 and U937 cells were treated with different concentrations of IDA or IDA/mPEG-PLGA for 24 hours. Cell growth was measured by the MTT assay. IC50 was calculated for HL-60 and U937 cells. Apoptosis was measured by annexin V/PI staining in HL-60 (B) and U937 (C) cells, which were treated with 0.01 µM IDA/mPEG-PLGA NPs, 0.01 µM IDA, or mPEG-PLGA NPs for 4 days. *P<0.01. Abbreviations: IC50, half maximal inhibitory concentration; IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles; PI, propidium iodide.
Figure 8
Figure 8
Antileukemia activity of IDA and IDA/mPEG-PLGA in MLL-AF9-induced murine leukemia in vivo. Notes: (A) GFP+ cells were measured in BM from the MLL-AF9-induced murine leukemia treated with IDA/mPEG-PLGA NPs, IDA, mPEG-PLGA, or vehicle when vehicle mice developed full-blown leukemia (n=4). Shown is the representative plots (left) and summary of GFP+ cells (right). **P<0.01. (B) A representative image of blood, BM, and spleen smears in the MLL-AF9-induced leukemia treated with IDA/mPEG-PLGA NPs, IDA, mPEG-PLGA, or vehicle. (C) A representative image of spleen (left) and summary of spleen weight (right) from the MLL-AF9-induced leukemia treated with IDA/mPEG-PLGA NPs, IDA, mPEG-PLGA, or vehicle (n=4). **P<0.01. (D) Overall survival was analyzed in the MLL-AF9-induced leukemia treated with IDA/mPEG-PLGA NPs, IDA, mPEG-PLGA, or vehicle (n=6). **P<0.01. Abbreviations: BM, bone marrow; IDA, idarubicin; mPEG-PLGA, methoxy poly(ethylene glycol)-b-poly(l-lactide-co-glycolide); NPs, nanoparticles.
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