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A Quantitative Description of Absolute Endocytosis and Exocytosis Rates for Nanoparticles

Hong Jin, Chemical Engineering, Massachusettes Institute of Technology, Building 66-580, 25 Ames St., Cambridge, MA 02139, Daniel A. Heller, Department of Chemistry, University of Illinois at Urbana-Champaign, 104 RAL, Box 93-5, MC-712, 600 S. Mathews Ave., Urbana, IL 61801, Richa Sharma, Chemical Engineering, MIT, 66-565, 25 Ames St., Cambridge, MA 02139, and Michael S. Strano, 66-566 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139.

The endocytosis of nanoparticles is important to drug delivery, bioimaging and toxicology. However, there is no quantitative model linking internalization rate with nanoparticle geometry. Current theory suggests that the rate is bracketed by elastic energy release as the cell membrane wraps the nanoparticle and an entropic penalty as additional cell surface receptors are recruited to continue the process. While successful in predicting a maximum uptake at a given radius, the approach requires this value be a threshold below which endocytosis is impossible and this is in direct contradiction to experiment. To address this, we develop a deterministic kinetic model and assert that nanoparticles smaller than the predicted cutoff can cluster on the cell surface after diffusion, thereby gaining the free energy necessary to surmount the entropic barrier for uptake. We focus on d(GT)15 wrapped SWNT1, and use its intrinsic band gap fluorescence to track interactions with 3T3 cells using a 2D InGaAs imaging array coupled to an inverted microscope with a perfusion stage2.

The model accurately describes uptake rates from single particle tracking for single walled carbon nanotubes(SWNT)2 of lengths from 130±18 to 660±40 nm and literature data for Au nanoparticles of diameters from 14 to 100 nm. Remarkably, both have a maximum rate near 25 nm when scaled using an interaction radius for membrane diffusion. The endocytosis rate constant of SWNT (10-3 min-1) is nearly 1000 times that of Au nanoparticles (10-6 min-1). The recycling (exocytosis) rate constants are similar in magnitude (10-4 to 10-3 min-1) for poly(D,L-lactide-co-glycolide), SWNT and Au nanoparticles and across cell lines and generally decrease with increasing size. The ability to understand and predict the cellular uptake of nanoparticles quantitatively should find utility in designing nano-systems with controlled toxicity, efficacy and functionality.

(1) Jin, H.; Jeng, E. S.; Heller, D. A.; Jena, P. V.; Kirmse, R.; Langowski, J.; Strano, M. S. Macromolecules 2007, 40, 6731-6739.

(2) Jin, H.; Heller, D. A.; Strano, M. S. Nano Lett. 2008, ASAP.