Title:
Programmable cellular retention of nanoparticles by replacing the synergistic anion of transferrin.

Abstract:
The ability to program the intracellular retention of nanoparticles (NPs) would increase their applicability for imaging and therapeutic applications. To date, there has been no efficient method developed to control the fate of NPs once they enter cells. Existing approaches to manipulate the intracellular retention of NPs are mostly "passive" and particle size-dependent. Different sized particles hold distinct cellular responses. The adverse effect of particle size may limit the utility of nanodelivery systems. Therefore, the development of tunable/"active" NP intracellular retention systems with fixed particle sizes remains a considerable challenge. By replacing the synergistic anions of transferrin (Tf) immobilized on quantum dots (Tf-QDs, ca. 25 nm), we have examined the feasibility of this concept. Substitution of synergistic anions of Tf from carbonate (holo-Tf) to oxalate (oxa-Tf) significantly increased the intracellular accumulation of the oxa-Tf-QDs as a result of (i) a delay in cellular removal triggered by oxalate (oxa-Tf)-induced endosomal Tf iron-release retardation and (ii) enhanced recycling of Tf-QD/TfR (Tf receptor) complexes from early endosomes to the plasma membrane. This accumulation extended the intracellular NP retention interval. The half-maximum fluorescence intensity of the oxa-Tf-QDs in vivo was 4 times higher than that of the holo-Tf-QDs. Programming of the intracellular NP retention time was accomplished through manipulation of the ratio of holo- and oxa-Tfs on the surfaces of the QDs. Using this simple and efficient approach, it was possible to readily achieve a desirable intracellular retention interval for the NPs.