Pharmacology of nanocarriers on the microscale: importance of uptake mechanisms and intracellular trafficking for efficient drug delivery

Nanocarrier-based systems hold a promise to become “Dr. Ehrlich’s Magic Bullet” capable of delivering drugs, proteins and genetic materials intact to a specific location in an organism down to subcellular level. The key question, however, how a nanocarrier is internalized by cells and how its intracellular trafficking and the fate in the cell can be controlled remains yet to be answered. In this review we survey drug delivery systems based on various polymeric nanocarriers, their uptake mechanisms, as well as the experimental techniques and common pathway inhibitors applied for internalization studies. While energy-dependent endocytosis is observed as the main uptake pathway, the integrity of a drug-loaded nanocarrier upon its internalization appears to be a seldomly addressed problem that can drastically affect the uptake kinetics and toxicity of the system in vitro and in vivo.

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Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2009.104 ◽

2009 ◽

Vol 29 (12) ◽

pp. 1914-1923 ◽

Cited By ~ 56

Author(s):

Rongqin Huang ◽

Weilun Ke ◽

Liang Han ◽

Yang Liu ◽

Kun Shao ◽

...

Keyword(s):

Drug Delivery ◽

Intracellular Trafficking ◽

Drug Delivery Systems ◽

Brain Targeting ◽

Brain Capillary ◽

Modified Dna ◽

Targeting Delivery ◽

Capillary Endothelial Cells ◽

First Time ◽

The Brain

Ligand-mediated brain-targeting drug delivery is one of the focuses at present. Elucidation of exact targeting mechanisms serves to efficiently design these drug delivery systems. In our previous studies, lactoferrin (Lf) was successfully exploited as a brain-targeting ligand to modify cationic dendrimer-based nanoparticles (NPs). The mechanisms of Lf-modified NPs to the brain were systematically investigated in this study for the first time. The uptake of Lf-modified vectors and NPs by brain capillary endothelial cells (BCECs) was related to clathrin-dependent endocytosis, caveolae-mediated endocytosis, and macropinocytosis. The intracellular trafficking results showed that Lf-modified NPs could rapidly enter the acidic endolysosomal compartments within 5 mins and then partly escape within 30 mins. Both Lf-modified vectors and NPs showed higher blood–brain barrier-crossing efficiency than unmodified counterparts. All the results suggest that both receptor- and adsorptive-mediated mechanisms contribute to the cellular uptake of Lf-modified vectors and NPs. Enhanced brain-targeting delivery could be achieved through the synergistic effect of the macromolecular polymers and the ligand.

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Characterization of phospholipid-encapsulated gold nanoparticles: a versatile platform to study drug delivery and cellular uptake mechanisms

Canadian Journal of Chemistry ◽

10.1139/cjc-2014-0280 ◽

2015 ◽

Vol 93 (2) ◽

pp. 265-271 ◽

Cited By ~ 5

Author(s):

Meijing Wang ◽

Nils O. Petersen

Keyword(s):

Drug Delivery ◽

Gold Nanoparticles ◽

Cellular Uptake ◽

Study Drug ◽

Cellular Systems ◽

Reaction Conditions ◽

Overall Stability ◽

Comprehensive Characterization ◽

Uptake Mechanisms

The data presented in this work aim to provide a comprehensive characterization of lipid-coated gold nanoparticles. We show that it is possible to envelop gold nanoparticles with a coating of lipids during the formation of the gold nanoparticles, that the gold in these lipid-coated gold nanoparticles is crystalline and the size and shape can be controlled by the reaction conditions (within limits), that the lipid coating corresponds to a thickness consistent with the formation of a bilayer, that the bilayer can include fluorescent probes that, while quenched, can be used to trace the fate of the gold nanoparticles in cellular systems, that their surface charge, and hence their overall stability in solution, is influenced by the lipid coating, and that while some lipid dyes may exchange among the particles, they are sufficiently stable to exchange to permit their use as tracers in cell studies. We believe this is the most comprehensive characterization of these systems to date.

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