Lipid rafts-mediated endocytosis and physiology-based cell membrane traffic models of doxorubicin liposomes

Abstract

The clathrin-mediated endocytosis is likely a major mechanism of liposomes' internalization. A kinetic approach was used to assess the internalization mechanism of doxorubicin (Dox) loaded cationic liposomes and to establish physiology-based cell membrane traffic mathematic models. Lipid rafts-mediated endocytosis, including dynamin-dependent or -independent endocytosis of noncaveolar structure, was a dominant process. The mathematic models divided Dox loaded liposomes binding lipid rafts (B) into saturable binding (SB) and nonsaturable binding (NSB) followed by energy-driven endocytosis. The intracellular trafficking demonstrated early endosome-late endosome-lysosome or early/late endosome-cytoplasm-nucleus pathways. The three properties of liposome structures, i.e., cationic lipid, fusogenic lipid, and pegylation, were investigated to compare their contributions to cell membrane and intracellular traffic. The results revealed great contribution of cationic lipid DOTAP and fusogenic lipid DOPE to cell membrane binding and internalization. The valid Dox in the nuclei of HepG2 and A375 cells treated with cationic liposomes containing 40mol% of DOPE were 1.2-fold and 1.5-fold higher than that in the nuclei of HepG2 and A375 cells treated with liposomes containing 20mol% of DOPE, respectively, suggesting the dependence of cell type. This tendency was proportional to the increase of cell-associated total liposomal Dox. The mathematic models would be useful to predict intracellular trafficking of liposomal Dox.

Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell

“…Thus, liposomes modified with octaarginines and cholesterol enter into mouse colon carcinoma C26 cells by both CME and macropinocytosis, which is also the case in A549 human lung carcinoma cells, with a main role for CME and the intervention of CVME as well [61]. Furthermore, liposomes decorated with fusogenic peptides and lipids such as the zwitterionic lipid dioleoylphosphatidylethanolamine can follow lipid-rafts mediated endocytosis related to CVME as described for human hepatocyte carcinoma Hep G2 and human malignant melanoma A375 cells [62]. However, other modifications do not seem to change the CME pathway that liposomes usually follow, as it happens with GALA peptide (WEAALAEALAEALAEHLAEALAEALEALAA)-modified liposomes in human lung microvascular endothelial cells (HMVEC-L) [63] or liposomes containing a malachite green derivative in the lipid membrane [64] in mouse colon adenocarcinoma Colon 26 cells.…”

<p>D-&alpha;-tocopherol polyethylene glycol 1000 succinate-modified liposomes with an siRNA corona confer enhanced cellular uptake and targeted delivery of doxorubicin via tumor priming</p>

“…The cationic LPs were prepared using the film dispersion method. 15 DOTAP, DPPC, and CHOL were dissolved in chloroform and mixed at a molar ratio of 40:40:20 in a roundbottom flask. After evaporation of the organic solvent using a rotary evaporator, the formed lipid film was immediately hydrated with 120 mM ammonium sulfate solution and further extruded through a polycarbonate membrane (100 nm pore size) using a mini-extruder (Avanti Polar Lipids, Inc.) to obtain bare LPs.…”

Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems

“…Lysosomal degradation of the nanoparticles and the payload following receptor mediated endocytosis may be one of the reasons targeted nanomedicines have not shown the dramatic improvements in therapeutic index that was expected from these tumor homing constructs [ 147 ]. The development of novel targeting ligands (for e.g., peptides and aptamers) that can selectively trigger endosomal escape of the nanoparticles prior to lysosomal degradation may prove to be a promising strategy towards improving the therapeutic indices of targeted nanomedicines [ 42 , 139 , 148 , 149 , 150 , 151 , 152 , 153 , 154 ]. Overcoming intracellular and extracellular barriers is one of the major challenges in siRNA delivery.…”