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Methylene diphosphonate-conjugated adriamycin liposomes: preparation, characteristics, and targeted therapy for osteosarcomas in vitro and in vivo

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Abstract

Methylenediphosphonate (MDP)-conjugated adriamycin liposomes (MDP-LADMs) were prepared using mild dynamic dialysis equilibrium method, and their targeted therapeutic effects against osteosarcomas and metastatic SOSP-M lung nodules were evaluated in vivo. The drug loading and encapsulation efficiency of the MDP-LADMs were measured via high-performance liquid chromatography, and their size and morphology of the MDP-LADMs were determined using transmission electron microscopy and a particle size analyzer, respectively. Cells apoptosis were evaluated by flow cytometry and caspase-3 activity. The targeted therapeutic effects of MDP-LADMs against UMR106 and SOSP-M osteosarcoma cells were evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor growth and animal survival rates were evaluated after UMR106 osteosarcomas were established in Sprague-Dawley rats and SOSP-M pulmonary metastatic osteosarcoma model were established in nude mice, respectively. The results show that the average diameter of the MDP-LADMs was 152 ± 14 nm, and their ADM encapsulation efficiency was 91.7% with respect to a 250 μg/ml of loading efficiency. The conjugation efficiency between technetium-MDP and LADMs was 87.6%. Infrared spectra results of the samples dissolved in deuterated water confirmed that the methylenediphosphonate (MDP) was conjugated with LADMs through hydrogen bonding. The toxicity assay revealed a median lethal dose of 26.78 mg/kg for MDP-LADMs, which was significantly higher than doses observed for free ADM of 9.64 mg/kg (P < 0.05) and LADMs of 15.02 mg/kg(P < 0.05). Tumor growth and animal survival in the MDP-LADMs group were significantly higher than those in the ADM-only, MDP-only (P < 0.01) and LADMs groups (P < 0.05). These findings indicate that MDP-LADMs have higher therapeutic efficacy against osteosarcomas, demonstrate lower toxicity and their clearly targets osteosarcomas more clearly than the stand-alone systems, making them as a promising novel targeted therapy for the treatment of osteosarcoma.

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Acknowledgement

This study was supported in part by the grants of National Basic Research Program 973 of China (Nos. 2010CB732603) and the National Nature Science Foundation of China (Nos.30772658, and 30970712).

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Authors and Affiliations

  1. Key Laboratory of Biomedical Information Engineering of Education Ministry, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an, 710049, China

    Daocheng Wu & Mingxi Wan

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  1. Daocheng Wu
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  2. Mingxi Wan
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Correspondence to Daocheng Wu.

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SFigure 1

Caspase-8 activities and drug concentrations of UMR106 and SOSP-M osteosarcoma cells. Caspase-8 activity was evaluated using a FLICE/Caspase-8 Colorimetric Protease Assay Kit. Measurements were performed by using a microplate reader at OD 405 nm. Caspase-8 activities: (A) ADM; (B) LADMs and (C) MDP-LADMs. (D) ADM concentrations of UMR106 and SOSP-M osteosarcoma cells. Data represent means ±S.E. (n = 4). *P < 0.01; significantly different from control cells. (JPEG 146 kb)

High resolution image (TIFF 1903 kb)

SFigure 2

(A) Turbidity measurements (absorbance at 500 nm over a 4h period) results of serum-induced aggregation in vitro.(B) Turbidity measurements (absorbance at 500 nm over a 4h period) results of serum-induced aggregation in vivo. (n = 4). 0.3μmol of LADMs and MDP-LADMs were mixed with 0.3 mL of HEPESY glucose,then mixed with 0.7 ml of SD rats serum, then incubated at 37-C. Turbidity was evaluated by absorbance at 500 nm over a 4h period. Zero absorbance was set with HEPESYglucose alone. Control samples consisted of 0.7 ml serum plus 0.3 mL HEPESY glucose without liposomes. (JPEG 94 kb)

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Wu, D., Wan, M. Methylene diphosphonate-conjugated adriamycin liposomes: preparation, characteristics, and targeted therapy for osteosarcomas in vitro and in vivo . Biomed Microdevices 14, 497–510 (2012). https://doi.org/10.1007/s10544-011-9626-3

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