Targeted intracellular delivery of resveratrol to glioblastoma cells using apolipoprotein E-containing reconstituted HDL as a nanovehicle

• Published in: PloS one 2015-08, Vol.10 (8), p.e0135130
• Main Authors: Kim, Sea H, Adhikari, Birendra Babu, Cruz, Siobanth, Schramm, Michael P, Vinson, Joe A, Narayanaswami, Vasanthy
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Antineoplastic Agents, Phytogenic - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Apolipoprotein E; Apolipoprotein E3 - chemistry; Apolipoprotein E3 - metabolism; Apolipoproteins; Azoles; Binding; Bioavailability; Biochemistry; Brain cancer; Cancer; Cell Line, Tumor; Cobalt; Drug delivery systems; Drug Delivery Systems - methods; Endocytosis; Endosomes; Endosomes - drug effects; Endosomes - metabolism; Fluorescence; Fluorescent Dyes; Glioblastoma; Glioblastoma cells; Glioblastomas; High density lipoprotein; Humans; Hydrophobic and Hydrophilic Interactions; Hydrophobicity; Immunoprecipitation; Intracellular; Lipids; Lipoproteins, HDL - chemistry; Lipoproteins, HDL - metabolism; Localization; Low density lipoprotein receptors; Low density lipoproteins; Lysosomes; Nanoparticles; Neuroglia - drug effects; Neuroglia - metabolism; Neuroglia - pathology; Nitrobenzenes; Particle Size; Phospholipids; Plasma; Protein Structure, Tertiary; Proteins; Receptor density; Receptors, LDL - chemistry; Receptors, LDL - metabolism; Resveratrol; Staining and Labeling - methods; Stilbenes - metabolism; Stilbenes - pharmacology; Studies; Transport
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135130

The objective of this study is to transport and deliver resveratrol to intracellular sites using apolipoprotein E3 (apoE3). Reconstituted high-density lipoprotein (rHDL) bearing resveratrol (rHDL/res) was prepared using phospholipids and the low-density lipoprotein receptor (LDLr)-binding domain of apoE3. Biophysical characterization revealed that resveratrol was partitioned into the phospholipid bilayer of discoidal rHDL/res particles (~19 nm diameter). Co-immunoprecipitation studies indicated that the LDLr-binding ability of apoE3 was retained. Cellular uptake of resveratrol to intracellular sites was evaluated in glioblastoma A-172 cells by direct fluorescence using chemically synthesized NBD-labeled resveratrol (res/NBD) embedded in rHDL/res. Competition and inhibition studies indicate that the uptake is by receptor mediated endocytosis via the LDLr, with co-localization of apoE3 and res/NBD in late endosomes/lysosomes. We propose that rHDL provides an ideal hydrophobic milieu to sequester resveratrol and that rHDL containing apoE3 serves as an effective "nanovehicle" to transport and deliver resveratrol to targeted intracellular sites.