Targeted Quantum Dot Conjugates for siRNA Delivery.

@article{citeulike:1610087, abstract = {Treatment of human diseases such as cancer generally involves the sequential use of diagnostic tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging functions in a single vehicle promise to change this paradigm. in particular, nanoparticle-based multifunctional platforms offer the potential to improve the pharmacokinetics of drug formulations, while providing attachment sites for diagnostic imaging and disease targeting features. We have applied these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered by rapid excretion and nontargeted tissue distribution. Using a PEGlyated quantum dot (QD) core as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle's surface. We found that the homing peptide was required for targeted internalization by tumor cells, and that siRNA cargo could be coattached without affecting the function of the peptide. Using an EGFP model system, the role of conjugation chemistry was investigated, with siRNA attached to the particle by disulfide cross-linkers showing greater silencing efficiency than when attached by a nonreducible thioether linkage. Since each particle contains a limited number of attachment sites, we further explored the tradeoff between number of F3 peptides and the number of siRNA per particle, leading to an optimized formulation. Delivery of these F3/siRNA-QDs to EGFP-transfected HeLa cells and release from their endosomal entrapment led to significant knockdown of EGFP signal. By designing the siRNA sequence against a therapeutic target (e.g., oncogene) instead of EGFP, this technology may be ultimately adapted to simultaneously treat and image metastatic cancer.}, address = {Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, Burnham Institute for Medical Research, La Jolla, California 92037, Health Sciences and Technology/Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138.}, author = {Derfus, Austin M. and Chen, Alice A. and Min, Dal-Hee H. and Ruoslahti, Erkki and Bhatia, Sangeeta N. }, citeulike-article-id = {1610087}, doi = {10.1021/bc060367e}, issn = {1043-1802}, journal = {Bioconjug Chem}, keywords = {ccne, drug\_design, nanotech, nucleic\_acids}, month = {July}, posted-at = {2008-05-15 11:51:36}, priority = {2}, title = {Targeted Quantum Dot Conjugates for siRNA Delivery.}, url = {http://dx.doi.org/10.1021/bc060367e}, year = {2007} }

TY - JOUR ID - citeulike:1610087 L3 - citeulike-article-id:1610087 TI - Targeted Quantum Dot Conjugates for siRNA Delivery. JF - Bioconjug Chem AD - Department of Bioengineering, University of California at San Diego, La Jolla, California 92093, Burnham Institute for Medical Research, La Jolla, California 92037, Health Sciences and Technology/Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, and School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138. SN - 1043-1802 N2 - Treatment of human diseases such as cancer generally involves the sequential use of diagnostic tools and therapeutic modalities. Multifunctional platforms combining therapeutic and diagnostic imaging functions in a single vehicle promise to change this paradigm. in particular, nanoparticle-based multifunctional platforms offer the potential to improve the pharmacokinetics of drug formulations, while providing attachment sites for diagnostic imaging and disease targeting features. We have applied these principles to the delivery of small interfering RNA (siRNA) therapeutics, where systemic delivery is hampered by rapid excretion and nontargeted tissue distribution. Using a PEGlyated quantum dot (QD) core as a scaffold, siRNA and tumor-homing peptides (F3) were conjugated to functional groups on the particle's surface. We found that the homing peptide was required for targeted internalization by tumor cells, and that siRNA cargo could be coattached without affecting the function of the peptide. Using an EGFP model system, the role of conjugation chemistry was investigated, with siRNA attached to the particle by disulfide cross-linkers showing greater silencing efficiency than when attached by a nonreducible thioether linkage. Since each particle contains a limited number of attachment sites, we further explored the tradeoff between number of F3 peptides and the number of siRNA per particle, leading to an optimized formulation. Delivery of these F3/siRNA-QDs to EGFP-transfected HeLa cells and release from their endosomal entrapment led to significant knockdown of EGFP signal. By designing the siRNA sequence against a therapeutic target (e.g., oncogene) instead of EGFP, this technology may be ultimately adapted to simultaneously treat and image metastatic cancer. KW - ccne KW - drug_design KW - nanotech KW - nucleic_acids AU - Derfus, Austin AU - Chen, Alice AU - Min, Dal-Hee AU - Ruoslahti, Erkki AU - Bhatia, Sangeeta PY - 2007/07/14/ UR - http://dx.doi.org/10.1021/bc060367e ER -