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. 2005 Feb 21;11(7):954-9.
doi: 10.3748/wjg.v11.i7.954.

High-density lipoprotein as a potential carrier for delivery of a lipophilic antitumoral drug into hepatoma cells

Bin Lou  1 , Xue-Ling Liao, Man-Ping Wu, Pei-Fang Cheng, Chun-Yan Yin, Zheng Fei
Affiliations

High-density lipoprotein as a potential carrier for delivery of a lipophilic antitumoral drug into hepatoma cells

Bin Lou et al. World J Gastroenterol. .

Abstract

Aim: To investigate the possibility of recombinant high-density lipoprotein (rHDL) being a carrier for delivering antitumoral drug to hepatoma cells.

Methods: Recombinant complex of HDL and aclacinomycin (rHDL-ACM) was prepared by cosonication of apoproteins from HDL (Apo HDL) and ACM as well as phosphatidylcholine. Characteristics of the rHDL-ACM were elucidated by electrophoretic mobility, including the size of particles, morphology and entrapment efficiency. Binding activity of rHDL-ACM to human hepatoma cells was determined by competition assay in the presence of excess native HDL. The cytotoxicity of rHDL-ACM was assessed by MTT method.

Results: The density range of rHDL-ACM was 1.063-1.210 g/mL, and the same as that of native HDL. The purity of all rHDL-ACM preparations was more than 92%. Encapsulated efficiencies of rHDL-ACM were more than 90%. rHDL-ACM particles were typical sphere model of lipoproteins and heterogeneous in particle size. The average diameter was 31.26+/-5.62 nm by measure of 110 rHDL-ACM particles in the range of diameter of lipoproteins. rHDL-ACM could bind on SMMC-7721 cells, and such binding could be competed against in the presence of excess native HDL. rHDL-ACM had same binding capacity as native HDL. The cellular uptake of rHDL-ACM by SMMC-7721 hepatoma cells was significantly higher than that of free ACM at the concentration range of 0.5-10 microg/mL (P<0.01). Cytotoxicity of rHDL-ACM to SMMC-7721 cells was significantly higher than that of free ACM at concentration range of less than 5 microg/mL (P<0.01) and IC50 of rHDL-ACM was lower than IC50 of free ACM (1.68 nmol/L vs 3 nmol/L). Compared to L02 hepatocytes, a normal liver cell line, the cellular uptake of rHDL-ACM by SMMC-7721 cells was significantly higher (P<0.01) and in a dose-dependent manner at the concentration range of 0.5-10 microg/mL. Cytotoxicity of the rHDL-ACM to SMMC-7721 cells was significantly higher than that to L02 cells at concentration range of 1-7.5 microg/mL (P<0.01). IC50 for SMMC-7721 cells (1.68 nmol/L) was lower than that for L02 cells (5.68 nmol/L), showing a preferential cytotoxicity of rHDL-ACM for SMMC-7721 cells.

Conclusion: rHDL-ACM complex keeps the basic physical and biological binding properties of native HDL and shows a preferential cytotoxicity for SMMC-7721 hepatoma to normal L02 hepatocytes. HDL is a potential carrier for delivering lipophilic antitumoral drug to hepatoma cells.

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Figures

Figure 1
Figure 1
Elution profile of rHDL-ACM on SephadexG-25. Flow rate, 30 mL/h. Elution solution:0.15 mol/L NaCl, 1 mmol/L EDTA, 0.02% NaN3, pH 6.5. A: rHDL-ACM before dialysis against 0.15 mol/L NaCl, 1 mmol/L EDTA, 0.02% NaN3, pH 6.5 Peak 1: rHDL-ACM, Peak 2: fACM; B: rHDL-ACM after dialysis against 0.15 mol/L NaCl, 1 mmol/L EDTA, 0.02% NaN3, pH 6.5.
Figure 2
Figure 2
Electron micrograph of rHDL-ACM. rHDL-ACM preparation was negatively stained with 1% sodium phosphotungstate pH 7.4. Bar marker represents 200 nm. (×52 K).
Figure 3
Figure 3
Competitive binding of rHDL-ACM to SMMC-7721 cells in the presence of excess native HDL. Incubation was carried out at 37 °C for 3 h, at native human plasma HDL concentrations ranging from 0 to 2000 µg/2×105 cell.
Figure 4
Figure 4
Cellular-uptake of rHDL-ACM and free ACM (fACM) by SMMC-7721 cells (n = 3). Incubation was carried out at 37 °C for 24 h. Drug concentration indicates ACM concentration in the medium.
Figure 5
Figure 5
Cytotoxicity of rHDL-ACM and fACM against SMMC-7721 cells (n = 3). Drug concentration indicates ACM concentration in the medium.
Figure 6
Figure 6
Cellular-uptake of rHDL-ACM by SMMC-7721 cells and L02 cells (n = 3) Incubation was carried out at 37 °C for 24 h. Drug concentration indicates ACM concentration in the medium.
Figure 7
Figure 7
Cytotoxicity of rHDL-ACM against SMMC-7721 and L02 cells (n = 3). Drug concentration indicates ACM concentration in the medium.
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