title: In vitro evaluation of dendrimer-polymer hybrid nanoparticles on their controlled cellular targeting kinetics.
abstract: Although polymeric nanoparticles (NPs) and dendrimers represent some of the most promising cancer-targeting nanocarriers, each of them has drawbacks such as limited tissue diffusivity/tumor penetration and rapid in vivo elimination, respectively. To address these issues, we have designed a multiscale hybrid NP system (nanohybrid) that combines folate (FA)-targeted poly(amidoamine) dendrimers and poly(ethylene glycol)-b-poly(d,l-lactide) NPs. The nanohybrids (∼100 nm NPs encapsulating ∼5 nm targeted dendrimers) were extensively characterized through a series of in vitro experiments that validate the design rationale of the system, in an aim to simulate their in vivo behaviors. Cellular uptake studies using FA receptor (FR)-overexpressing KB cells (KB FR(+)) revealed that the nanohybrids maintained high FR selectivity resembling the selectivity of free dendrimers, while displaying temporally controlled cellular interactions due to the presence of the polymeric NP shells. The cellular interactions of the nanohybrids were clathrin-dependent (characteristic of polymer NPs) at early incubation time points (4 h), which were partially converted to caveolae-mediated internalization (characteristic of FA-targeted dendrimers) at longer incubation hours (24 h). Simulated penetration assays using multicellular tumor spheroids of KB FR(+) cells also revealed that the targeted dendrimers penetrated deep into the spheroids upon their release from the nanohybrids, whereas the NP shell did not. Additionally, methotrexate-containing systems showed the selective, controlled cytotoxicity kinetics of the nanohybrids. These results all demonstrate that our nanohybrids successfully integrate the unique characteristics of dendrimers (effective targeting and penetration) and polymeric NPs (controlled release and suitable size for long circulation) in a kinetically controlled manner.
authors.affiliation: Department of Biopharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Suhair
authors.initials: S
authors.lastname: Sunoqrot
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Dong-Hwan
authors.initials: DH
authors.lastname: Kim
authors.forename: Seungpyo
authors.initials: S
authors.lastname: Hong
mesh_terms: D002460:Cell Line; D050091:Dendrimers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*
chemical_list: D050091:Dendrimers; D011108:Polymers; D005492:Folic Acid