Aptamer-functionalized hybrid nanoparticle for the treatment of breast cancer

Schematic diagram showing the organization of the nanoparticles. [Display omitted] Resistance to chemotherapeutic agents such as doxorubicin is a major reason for cancer treatment failure. At present the treatment option for metastatic breast cancer is very poor. Therefore, development of an effecti...

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Published in:European journal of pharmaceutics and biopharmaceutics 2017-05, Vol.114, p.108-118
Main Authors: Powell, David, Chandra, Sruti, Dodson, Kyra, Shaheen, Farhana, Wiltz, Kylar, Ireland, Shubha, Syed, Muniruzzaman, Dash, Srikanta, Wiese, Thomas, Mandal, Tarun, Kundu, Anup
Format: Article
Language:English
Subjects:
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - therapeutic use
Aptamer
Aptamers, Nucleotide - chemistry
Breast Neoplasms - drug therapy
Cell Line, Tumor
Drug Delivery Systems
Excipients
Female
Gene Silencing
Her-2
Humans
Liposomes
MCF-7 Cells
Nanoparticle
Nanoparticles - chemistry
P-glycoprotein
Particle Size
Receptor, ErbB-2 - metabolism
RNA, Small Interfering - administration & dosage
RNA, Small Interfering - therapeutic use
siRNA
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Summary:Schematic diagram showing the organization of the nanoparticles. [Display omitted] Resistance to chemotherapeutic agents such as doxorubicin is a major reason for cancer treatment failure. At present the treatment option for metastatic breast cancer is very poor. Therefore, development of an effective therapeutic strategy to circumvent MDR of metastatic breast cancer is highly anticipated. The MDR of metastatic breast cancer cells was accompanied with the overexpression of P-gp transporter. Even though the overexpression of P-gp could be minimized by silencing with siRNA, the question is how they can be selectively targeted to the cancer cells. We propose that aptamer surface labeling of the nanoparticles could enhance the selectively delivery of p-gp siRNA into the metastatic breast cancer cells. Our hypothesis is that conjugating nanoparticles with a cancer cell specific aptamer should allow selective delivery of therapeutic drugs to tumor cells leading to enhanced cellular toxicity and antitumor effect as compared to unconjugated nanoparticles. The primary objective of this study is to develop a targeted nanocarrier delivery system for siRNA into breast cancer cells. For targeted delivery, Aptamer A6 has been used which can bind to Her-2 receptors on breast cancer cells. For aptamer binding to particle surface, maleimide-terminated PEG-DSPE (Mal-PEG) was incorporated into the nanoparticles. Initially, three blank hybrid nanoparticles (i.e. F21, F31, and F40) out of nine different formulations prepared by high pressure homogenization (HPH) using different amount of DOTAP, cholesterol, PLGA or PLGA-PEG and Mal-PEG were chosen. Then protamine sulfate-condensed GAPDH siRNA (TRITC conjugated; red) or P-gp siRNA was encapsulated into those nanoparticles. Finally, the particles were incubated with aptamer A6 (FITC conjugated; green) for surface labeling. Aptamer labeled-nanoparticles having PLGA are smaller in size than those having PLGA-PEG. Surface charge was reduced when the particles were labeled with aptamer. Cell transfection was increased significantly in Her-2 (+) SKBR-3 and 4T1-R cells but not in Her-2 poorly expressed MDA MB-231 and MCF-7 cells. The knockdown of P-gp was increased significantly when the particles were labeled with aptamer. No significant cellular toxicity was observed for any of these formulations. This preliminary study concludes that aptamer-functionalized hybrid nanoparticles could be used to deliver P-gp targeted siRNA into the b
ISSN:0939-6411
1873-3441
DOI:10.1016/j.ejpb.2017.01.011