Biomimetic nanocarrier for direct cytosolic drug delivery.
نویسندگان
چکیده
The ability to transport a large quantity of drug molecules into cytosolic compartments of cancer cells has powerful implications in modern molecular therapeutics because the sites of action of the drugs are often cytosolic organelles. Furthermore, direct cytosolic delivery might offer a means to evade efflux transporters, such as multidrug-resistance proteins and P-glycoproteins. Nanoparticle carriers play a dominant role in this frontier field, at least in part because of their ability to carry a large payload of drug entities protected from extracellular degradation. However, cells often take up particles through endocytosis, macropinocytosis, or phagocytosis. Since these processes confine the internalized particles to closed vesicles (endosomes or phagosomes), subsequent fusion of these vesicles with lysosomes often leads to the rapid destruction of therapeutic molecules with little release into the cytosol. Thus, the sequestration of drug carriers within endosomes following endocytosis is one of the most critical bottlenecks for cytosolic drug delivery. Recent studies in this research area have focused on increasing the ability of nanocarriers to escape endolysosomes through controlled lysosomal destabilization (e.g., triggered by the lysosomal pH value or enzymes) and the incorporation of membrane-disruptive or fusogenic moieties (e.g., viral peptides). The engineering of a nanocarrier that can bypass the endosomal route entirely would open a new avenue for enhanced cytosolic drug delivery. The scavenger receptor class B type I (SR-BI) mediates the selective transport of cholesterol esters from high-density lipoprotein (HDL) to the cytosol of cells, presumably by forming a hydrophobic channel in the cell membrane. To exploit this unique non-endocytic uptake mechanism for the direct cytosolic delivery of cancer diagnostics and therapeutics, we created a peptide–phospholipid nanocarrier (denoted as NC). The NC was prepared by three simple steps (Figure 1A): 1) formation of a dry lipid film with 1,2dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol oleate, and DiR-BOA (1,1’-dioctadecyl-3,3,3’,3’-tetramethylindotricarbocyanine iodide bisoleate, a lipid-anchored near-infrared fluorophore to serve as the model drug cargo), 2) formation of a lipid emulsion, and 3) titration of the emulsion with an apoA-I-mimetic, amphipathic ahelical peptide (FAEKFKEAVKDYFAKFWD) to produce a core–shell NC that traps DiR-BOA in the core (denoted as DNC; see the Supporting Information for synthetic details). We hypothesized that the interaction between the selfassembled a-helical-peptide network and the lipid monolayer would provide the desired structural control over nanoparticle size, monodispersity, and stability, as well as functional control over its cellular uptake mechanism. The DNCs appeared spherical in shape on the basis of transmission electron microscopy (TEM; Figure 1B). However, when the payload was omitted, discoidal particles were observed by TEM, a result consistent with previous studies in which only DMPC was combined with HDL-mimetic peptides. The shapes observed by TEM are consistent with other reports of discoidal and spherical HDL. To distinguish the fate of cargo molecules from that of the nanoparticle components themselves, two additional fluorescein-labeled DNC particles were prepared. In the first, F(lipid)-DNC, a portion of the lipid component was replaced with a fluorescein-labeled lipid (DSPE-PEG-CF). In the second particle, F(peptide)-DNC, some lysine residues on the a-helical peptide were labeled with fluorescein. All three particles, DNC, F(lipid)-DNC, and F(peptide)-DNC (Figure 1C) were readily synthesized and purified by fast protein liquid chromatography (see Figure 1 in the Supporting Information) and were stable under physiological conditions (37 8C, pH 7.5) for 24 h without DiR-BOA leakage. The proposed mechanism for direct cytosolic cargo transport by the NC is depicted in Figure 1C. Upon recognition of [*] Dr. Z. H. Zhang, Dr. W. G. Cao, H. L. Jin, Dr. M. Yang, L. L. Ding, Dr. J. Chen, Dr. I. Corbin, Dr. G. Zheng Department of Medical Biophysics and Ontario Cancer Institute University of Toronto, Toronto, Ontario M5G 1L7 (Canada) E-mail: [email protected] Homepage: http://www.utoronto.ca/zhenglab
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ورودعنوان ژورنال:
- Angewandte Chemie
دوره 48 48 شماره
صفحات -
تاریخ انتشار 2009