Synthesis of Apolipoprotein B Lipoparticles to Deliver Hydrophobic/Amphiphilic Materials

Abstract

To develop a drug delivery system (DDS), it is critical to address challenging tasks such as the delivery of hydrophobic and amphiphilic compounds, cell uptake, and the metabolic fate of the drug delivery carrier. Low-density lipoprotein (LDL) has been acknowledged as the human serum transporter of natively abundant lipoparticles such as cholesterol, triacylglycerides, and lipids. Apolipoprotein B (apo B) is the only protein contained in LDL, and possesses a binding moiety for the LDL receptor that can be internalized and degraded naturally by the cell. Therefore, synthetic/reconstituting apoB lipoparticle (rABL) could be an excellent delivery carrier for hydrophobic or amphiphilic materials. Here, we synthesized rABL in vitro, using full-length apoB through a five-step solvent exchange method, and addressed its potential as a DDS. Our rABL exhibited good biocompatibility when evaluated with cytotoxicity and cell metabolic response assays, and was stable during storage in phosphate-buffered saline at 4 °C for several months. Furthermore, hydrophobic superparamagnetic iron oxide nanoparticles (SPIONPs) and the anticancer drug M4N (tetra-O-methyl nordihydroguaiaretic acid), used as an imaging enhancer and lipophilic drug model, respectively, were incorporated into the rABL, leading to the formation of SPIONPs- and M4N- containing rABL (SPIO@rABL and M4N@rABL, respectively). Fourier transform infrared spectroscopy suggested that rABL has a similar composition to that of LDL, and successfully incorporated SPIONPs or M4N. SPIO@rABL presented significant hepatic contrast enhancement in T2-weighted magnetic resonance imaging in BALB/c mice, suggesting its potential application as a medical imaging contrast agent. M4N@rABL could reduce the viability of the cancer cell line A549. Interestingly, we developed solution-phase high-resolution transmission electron microscopy to observe both LDL and SPIO@rABL in the liquid state. In summary, our LDL-based DDS, rABL, has significant potential as a novel DDS for hydrophobic and amphiphilic materials, with good cell internalization properties and metabolicity.

Correlation between pretreatment serum LDL-cholesterol levels and prognosis in nasopharyngeal carcinoma patients

“… 17 Increasing evidence supports the idea that tumor cell growth is partly dependent on exogenous LDL. 18 , 19 Low-density lipoprotein receptors (LDLRs) are overexpressed in cancer cells, 20 – 22 and this has been attributed to the large quantities of cholesterol and fatty acids that are required for supporting the rapid proliferation that occurs during tumorigenesis in a variety of tumor cells. 21 , 23 LDL exposure induces cell proliferation, migration, and loss of adhesion, and is a hallmark of epithelial-to-mesenchymal transition.…”

Low density lipoprotein bionanoparticles: From cholesterol transport to delivery of anti-cancer drugs

“…This pathway could be useful for drug delivery, and may then be directed toward tumors expressing LDLR. Any drugs incorporated into the LDL particle accumulate within the targeted cell, providing a very effective mechanism for drug delivery (Chu et al, 2013). Accordingly, LDL-based hydrophobic/amphiphilic drug delivery systems (DDS) can be internalized and degraded by regular cell metabolism, and these properties can be used in targeted therapies for cancer (Chu et al, 2013).…”

“…The reconstituted apoB-100 lipoparticle may be an ideal carrier for transporting hydrophobic and amphiphilic compounds. Consequently, synthetic nanopaticles with a small fragment of apoB-100 or LDL-dextran mixture were developed (Chu et al, 2013).…”

“…Glioblastoma multiforme (GBM) is a highly aggressive tumor that accounts for approximately 85% of primary brain tumors in adults. A study on seven GBM cell lines showed that these cells have high LDLR expression (Chu et al, 2013). However, studies on the distribution of LDLRs in normal rat and monkey brain tissue suggest that normal brain tissue, particularly the gray matter of the cortex, has relatively low LDLRs (Chu et al, 2013).…”

Development of a Growth‐Hormone‐Conjugated Nanodiamond Complex for Cancer Therapy

“…Nanomaterials such as carbon nanotubes,18 nanoliposomes,19 and nanodiamonds (NDs)3 have been successfully conjugated with anticancer drugs. In particular, apolipoprotein B lipoparticles20 and NDs have been applied as nanovehicles for the delivery of therapeutic agents 17. These nanodelivery systems could enhance the therapeutic efficiency and targeting ability of drugs.…”