Abstract 804: Cancer nanotechnology: drug encapsulated nanoparticle-aptamer bioconjugates for targeted delivery to prostate cancer cells
Citation: European Journal of Cancer Supplements Volume 3, No. 2, October 2005, Page 229
O.C. Farokhzad12, J. Cheng2, B. Teply2, A. Khademhosseini2, S. Jon3, E. Levy-Nissenbaum12, R. Langer2
1Brigham and Women's Hospital, Harvard Med School, Department of Anesthesiology, Boston, Massachusetts, USA
2Massachusetts Institute of Technology, Division of Health Sciences and Technology, Cambridge, Massachusetts, USA
3Gwangju Institute of Science & Technology, Department of Life Science, Gwangju, South Korea
Introduction: Nucleic acid ligands (aptamers) are potentially well suited for the therapeutic targeting of drug encapsulated controlled release polymer nanoparticles in a cell- or tissue-specific manner. We used Prostate Cancer (PCa) cells as a model to test this hypothesis.
Methods: We synthesized poly(lactic acid)-block-poly(ethylene glycol) controlled release copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH), and encapsulated rhodamine-labeled dextran (as a model drug) within PLA-PEG-COOH nanoparticles using the double emulsion method. We generated nanoparticle-aptamer bioconjugates using nuclease stabilized RNA aptamers that bind to the Prostate Specific Membrane Antigen (PSMA), a well known PCa tumor-marker which is over-expressed on prostate acinar epithelial cells. These bioconjugates were examined for targeted delivery and uptake by LNCaP (PSMA+) and PC3 (PSMA-) model PCa cells under a range of physiologic shear stress conditions using microfluidic channels.
Results: Nanoparticles had the following desirable characteristics: 1) negative surface charge (-50 mV ± 3 mV, Mean ± SD, N = 3), which may minimize non-specific interaction with the negatively charged nucleic acid aptamers, 2) carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers, 3) presence of PEG on particle surface which enhances circulating half-life while contributing to decreased uptake in non-targeted cells. Nanoparticles were conjugated to PSMA aptamers to develop the first example of a nanoparticle-aptamer bioconjugate.
Nanoparticle-aptamer bioconjugates selectively adhered to LNCaP but not PC3 cells at static and low shear (<1 dyne/cm2) but not higher shear (~4.5 dynes/cm2) conditions. Using z-axis fluorescent microscopy and 3-D image reconstruction (figure 1), we studied the localization of the nanoparticle-aptamer bioconjugates (red dots) after incubation with LNCaP cells, and confirmed that even at 2 hrs, the particles were largely internalized into cells. In contrast to LNCaP cells, the uptake of these particles is not enhanced in PC3 cells which do not express the PSMA protein.
Fig. 1
Discussion: This represents the first example of targeted drug delivery using nanoparticle-aptamer bioconjugates. Through modification of the controlled release polymer system or the aptamer targeting group, similar vehicles can be made to target a myriad of important human cancers.
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