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. 2016 Aug 9;7(32):51535-51552.
doi: 10.18632/oncotarget.10493.

Synthetic low-density lipoprotein (sLDL) selectively delivers paclitaxel to tumor with low systemic toxicity

Hai-Tao Su  1 , Xin Li  1 , De-Sheng Liang  1 , Xian-Rong Qi  1   2
Affiliations

Synthetic low-density lipoprotein (sLDL) selectively delivers paclitaxel to tumor with low systemic toxicity

Hai-Tao Su et al. Oncotarget. .

Abstract

Low density lipoprotein (LDL), which is a principal carrier for the delivery of cholesterol, has been used as a great candidate for the delivery of drugs to tumor based on the great requirements for cholesterol of many cancer cells. Mimicking the structure and composition of LDL, we designed a synthetic low-density lipoprotein (sLDL) to encapsulate paclitaxel-alpha linolenic acid (PALA) for tumor therapy. The PALA loaded sLDL (PALA-sLDL) and PALA-loaded microemulsion (PALA-ME, without the binding domain for LDLR) displayed uniform sizes with high drug loading efficiency (> 90%). In vitro studies demonstrated PALA-sLDL exhibited enhanced cellular uptake capacity and better cytotoxicity to LDLR over-expressed U87 MG cells as compared to PALA-ME. The uptake mechanisms of PALA-sLDL were involved in a receptor mediated endocytosis and macropinocytosis. Furthermore, the in vivo biodistribution and tumor growth inhibition studies of PALA-sLDL were investigated in xenograft U87 MG tumor-bearing mice. The results showed that PALA-sLDL exhibited higher tumor accumulation than PALA-ME and superior tumor inhibition efficiency (72.1%) compared to Taxol® (51.2%) and PALA-ME (58.8%) but with lower toxicity. These studies suggested that sLDL is potential to be used as a valuable carrier for the selective delivery of anticancer drugs to tumor with low systemic toxicity.

Keywords: PTX-alpha linolenic acid (PALA); anti-tumor efficacy; biomimetic; low systemic toxicity; synthetic low-density lipoprotein (sLDL).

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Conflict of interest statement

All the authors declare no conflicts of interests.

Figures

Figure 1
Figure 1. Synthesis schemes of DSPE-PEG2000-Peptide (A) and its MALDI-TOF MS (B)
Figure 2
Figure 2. Synthesis schemes of PALA (A) and its MALDI-TOF MS (B) and 1H NMR (C)
Figure 3
Figure 3. Preparation of PALA-sLDL
(A). PALA-ME was prepared by an identical procedure but did not contain DSPE-PEG2000-peptide. The loading efficiency of PTX-ME and PALA-ME (n = 3) (B). Size distribution of PALA-ME (C) and PALA-sLDL (D) by dynamic light scattering. Transmission electron micrograph of PALA-ME (E) and PALA-sLDL (F).
Figure 4
Figure 4. The LDLR count of a single cell
The results are present as mean ± SD (n = 3).
Figure 5
Figure 5. Uptake of COU by U87 MG cells determined by flow cytometric analysis (A) and by confocal (B)
The results are present as mean ± SD (n = 3).
Figure 6
Figure 6. Uptake of COU by HepG2 cells determined by flow cytometric analysis (A) and by confocal (B)
The results are present as mean ± SD (n = 3).
Figure 7
Figure 7. Cytotoxicity of different formulations on HepG2 (A) and U87 MG (B)
The results are present as mean ± SD (n = 4).
Figure 8
Figure 8. Receptor block experiment (A) and the uptake mechanism (B) of U87 MG cells
The results are present as mean ± SD (n = 3).
Figure 9
Figure 9. In vivo NIR fluorescence imaging of U87 MG tumor-bearing mice at 1, 3, 6, 12, 24, 36, 48, 60 and 72 h after iv injection of free DiR, DiR-ME and DiR-sLDL
Tumor site is marked by dashed circle.
Figure 10
Figure 10. Tumor volume-time profile (A) and body weight-time profiles (B) of U87 MG tumor-bearing BALB/c nude mice after injected with 0.9% NaCl (control), Taxol®, PALA, PALA-ME and PALA-sLDL
Photograph (C) and weight (D) of the solid tumors removed from different treatment groups at the study termination. The results are present as mean ± SD (n = 6).
Figure 11
Figure 11. Histological (H&E) analysis of tumor samples from different treatment groups
Figure 12
Figure 12. Therapeutic effect on apoptosis by TUNEL staining of the dissected tumor tissue (A)
Apoptotic indexes of tumors in each group (B). The results are present as mean ± SD (n = 6).
See this image and copyright information in PMC

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