Dendrimer advances for the central nervous system delivery of therapeutics

Abstract

The effectiveness of noninvasive treatment for central nervous system (CNS) diseases is generally limited by the poor access of therapeutic agents into the CNS. Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier (BBB), and overcoming this has become one of the most significant challenges in the development of CNS therapeutics. Rapid advances in nanotechnology have provided promising solutions to this challenge. This review discusses the latest applications of dendrimers in the treatment of CNS diseases with an emphasis on brain tumors. Dendrimer-mediated drug delivery, imaging, and diagnosis are also reviewed. The toxicity, biodistribution, and transport mechanisms in dendrimer-mediated delivery of CNS therapeutic agents bypassing or crossing the BBB are also discussed. Future directions and major challenges of dendrimer-mediated delivery of CNS therapeutic agents are included.

Figure 1

Schematic presentation of dendrimers as a nanoscaffold with a core, interior, and surface. Abbreviations: G, generation; Z, surface group for host–guest interactions and functionalization.

Figure 2

Mechanism of dendrimer intracellular delivery of therapeutics such as DOX and CPT. (1) Dendrimer nanomedicine is attracted to the cells by an electrostatic difference; (2) Ligand–receptor-mediated endocytosis occurs, and dendrimer nanomedicine is internalized into the cells; (3) reduction of the pH value from the endocytic vesicle to the lysosome triggers therapeutics to be cleaved from the dendrimer carrier and released into the cytoplasm; (5) released therapeutics diffuse into the nucleus, intercalate the DNA strand, and break the DNA chain to prevent its replication.

Figure 3

Dendrimer platform for CNS delivery of therapeutics and imaging reagents. (1) Full-generation PAMAM dendrimer is reacted with NHS-PEG-MAL to express MAL on the surface. (2) CNS ligands are specifically reacted with MAL of the dendrimer to form a PAMAM-PEG-ligand nanoparticle. (3) Hydrophobic or gene therapeutics can be entrapped inside of the dendrimer core via hydrophobicity or electrostatics. (4) Hydrophilic or hydrophobic therapeutics can also be covalent conjugated onto dendrimer surface. (5) Imaging reagents are reacted with MAL of the dendrimer to form a PAMAM-PEG-drug-ligands-imaging reagent nanoparticle. Abbreviation: NHS, N-hydroxysuccinimide; MAL, maleimide; PEG, poly(ethylene glycol); Tf, transferrin; EGF, epidermal growth factor; DOX, doxorubicin; FITC, fluorescein isothiocyanate; AAF, N-acetyl-2-aminofluorene; CPT, camptothecin.