Journal
NANOSCALE
Volume 9, Issue 29, Pages 10447-10464Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c7nr03362a
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Funding
- NIH [P41 RR-01081]
- European Union Seventh Framework Program (FP7) under Marie Curie Actions grant [254897, 2013-BP-B-00109]
- Secretary of Universities and Research of the Economy and Knowledge Department of the Government of Catalonia
- Australian Research Council [DE150100784]
- Australian Research Council [DE150100784] Funding Source: Australian Research Council
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Significant efforts are being undertaken to optimize the cargo carrying capacity and especially the cellular delivery efficiency of functionalized nanoparticles for applications in biological research and pharmacological delivery. One approach to increasing nanoparticle surface cargo display capacity is to decrease the number of moieties required for mediating cellular delivery by improving their efficiency. We describe a series of multivalent cell penetrating peptide (CPP) dendrimers that facilitate rapid cellular delivery of prototypical nanoparticle-semiconductor quantum dots (QDs). The modular CPP dendrimers were assembled through an innovative convergent oxime ligation strategy between (Arg(9))(n) motifs and a dendritic QD-coordination scaffold. Dendrimeric peptides sequentially incorporate a terminal (His)(6) motif for metal-affinity QD coordination, a Pro(9) spacer, a branching poly-lysine scaffold, and wedged display of (Arg(9))(n) binding motifs with n = 1x, 2x, 4x, 8x, 16x multivalency. QD dendrimer display capacity was estimated using structural simulations and QD-(Arg(9))(1-16) conjugates characterized by dynamic light scattering along with surface plasmon resonance-based binding assays to heparan sulfate proteoglycan surfaces. Cellular uptake via endocytosis was confirmed and peptide delivery kinetics investigated as a function of QD-(Arg(9))(1-16) conjugate exposure time and QD assembly ratio where cellular viability assays reflected no overt cytotoxicity. The ability of single dendrimer conjugates to facilitate cellular uptake was confirmed for QD-(Arg(9))(2-16) repeats along with the ability to deliver >850 kDa of protein cargo per QD. Minimizing the number of CPPs required for cellular uptake is critical for expanding nanoparticle cargo carrying capacity and can allow for inclusion of additional sensors, therapeutics and contrast agents on their surface.
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