Engineering of targeted nanoparticles for cancer therapy using internalizing aptamers isolated by cell-uptake selection.
One of the major challenges in the development of targeted nanoparticles (NPs) for cancer therapy is to discover targeting ligands that allow for differential binding and uptake by the target cancer cells. Using prostate cancer (PCa) as a model disease, we developed a cell-uptake selection strategy to isolate PCa-specific internalizing 2'-O-methyl RNA aptamers (Apts) for NP incorporation. Twelve cycles of selection and counter-selection were done to obtain a panel of internalizing Apts, which can distinguish PCa cells from nonprostate and normal prostate cells. After Apt characterization, size minimization, and conjugation of the Apts with fluorescently labeled polymeric NPs, the NP-Apt conjugates exhibit PCa specificity and enhancement in cellular uptake when compared to nontargeted NPs lacking the internalizing Apts. Furthermore, when docetaxel, a chemotherapeutic agent used for the treatment of PCa, was encapsulated within the NP-Apt, a significant improvement in cytotoxicity was achieved in targeted PCa cells. Rather than isolating high-affinity Apts as reported in previous selection processes, our selection strategy was designed to enrich cancer cell-specific internalizing Apts. A similar cell-uptake selection strategy may be used to develop specific internalizing ligands for a myriad of other diseases and can potentially facilitate delivering various molecules, including drugs and siRNAs, into target cells.
Laboratory of Nanomedicine and Biomaterials, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Zeyu
Z
Xiao
Etgar
E
Levy-Nissenbaum
Frank
F
Alexis
Andrej
A
Lupták
Benjamin A
BA
Teply
Juliana M
JM
Chan
Jinjun
J
Shi
Elise
E
Digga
Judy
J
Cheng
Robert
R
Langer
Omid C
OC
Farokhzad
D052157:Aptamers, Nucleotide / Q000737:chemistry* / Q000235:genetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D053769:Nanocapsules / Q000737:chemistry* / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000188:drug therapy* / Q000235:genetics; D016896:Treatment Outcome
D052157:Aptamers, Nucleotide; D053769:Nanocapsules