TY - JOUR
T1 - Effect of an alkyl spacer on the morphology and internalization of MUC1 aptamer-naphthalimide amphiphiles for targeting and imaging triple negative breast cancer cells
AU - Kuang, Huihui
AU - Schneiderman, Zachary
AU - Shabana, Ahmed M.
AU - Russo, Gabriella C.
AU - Guo, Jun
AU - Wirtz, Denis
AU - Kokkoli, Efrosini
N1 - Funding Information:
The authors thank the Whiting School of Engineering of the Johns Hopkins University for funding and acknowledge use of the following facilities at the Johns Hopkins University: NMR Core Facility, Center for Molecular Biophysics, Integrated Imaging Center, Ross Flow Cytometry Core Facility. The authors would especially like to acknowledge Hanhvy Bui at the Integrated Imaging Center for her assistance with some of the flow cytometry studies.
Publisher Copyright:
© 2020 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of American Institute of Chemical Engineers.
PY - 2021/1
Y1 - 2021/1
N2 - Despite decades of research, there are few targeted treatment options available for triple negative breast cancer (TNBC), leaving chemotherapy, and radiation treatment regimes with poor response and high toxicity. Herein aptamer-amphiphiles were synthesized which selectively bind to the mucin-1 (MUC1) glycoprotein that is overexpressed in TNBC cells. These amphiphiles have a fluorescent tail (1,8-naphthalimide or 4-nitro-1,8-naphthalimide) which enables self-assembly of the amphiphiles and allows for easy visualization without the requirement for further conjugation of a fluorophore. Interestingly, the length of the alkyl spacer (C4 or C12) between the aptamer and tail was shown to influence the morphology of the self-assembled structure, and thus its ability to internalize into the TNBC cells. While both the MUC1 aptamer-C4-napthalimide spherical micelles and the MUC1 aptamer-C12-napthalimide long cylindrical micelles showed internalization into MDA-MB-468 TNBC cells but not the noncancerous MCF-10A breast cells, the cylindrical micelles showed greatly enhanced internalization into the MDA-MB-468 cells. Similar patterns of enhanced binding and internalization were observed between the MUC1 aptamer-C12-napthalimide cylindrical micelles and SUM159 and MDA-MB-231 TNBC cells. The MUC1 aptamer cylindrical micelles were not toxic to the cells, and when used to deliver doxorubicin to the TNBC cells, were shown to be as cytotoxic as free doxorubicin. Moreover, a pharmacokinetic study in mice showed a prolonged systemic circulation time of the MUC1 aptamer cylindrical micelles. There was a 4.6-fold increase in the elimination half-life of the aptamer cylindrical micelles, and their clearance decreased 10-fold compared to the MUC1 aptamer spherical micelles. Thus, the MUC1 aptamer-C12-napthalimide nanofibers represent a promising vehicle that could be used for easy visualization and targeted delivery of therapeutic loads to TNBC cells.
AB - Despite decades of research, there are few targeted treatment options available for triple negative breast cancer (TNBC), leaving chemotherapy, and radiation treatment regimes with poor response and high toxicity. Herein aptamer-amphiphiles were synthesized which selectively bind to the mucin-1 (MUC1) glycoprotein that is overexpressed in TNBC cells. These amphiphiles have a fluorescent tail (1,8-naphthalimide or 4-nitro-1,8-naphthalimide) which enables self-assembly of the amphiphiles and allows for easy visualization without the requirement for further conjugation of a fluorophore. Interestingly, the length of the alkyl spacer (C4 or C12) between the aptamer and tail was shown to influence the morphology of the self-assembled structure, and thus its ability to internalize into the TNBC cells. While both the MUC1 aptamer-C4-napthalimide spherical micelles and the MUC1 aptamer-C12-napthalimide long cylindrical micelles showed internalization into MDA-MB-468 TNBC cells but not the noncancerous MCF-10A breast cells, the cylindrical micelles showed greatly enhanced internalization into the MDA-MB-468 cells. Similar patterns of enhanced binding and internalization were observed between the MUC1 aptamer-C12-napthalimide cylindrical micelles and SUM159 and MDA-MB-231 TNBC cells. The MUC1 aptamer cylindrical micelles were not toxic to the cells, and when used to deliver doxorubicin to the TNBC cells, were shown to be as cytotoxic as free doxorubicin. Moreover, a pharmacokinetic study in mice showed a prolonged systemic circulation time of the MUC1 aptamer cylindrical micelles. There was a 4.6-fold increase in the elimination half-life of the aptamer cylindrical micelles, and their clearance decreased 10-fold compared to the MUC1 aptamer spherical micelles. Thus, the MUC1 aptamer-C12-napthalimide nanofibers represent a promising vehicle that could be used for easy visualization and targeted delivery of therapeutic loads to TNBC cells.
KW - aptamer nanofibers
KW - effect of spacer on self-assembly
KW - nanoparticles
KW - ssDNA aptamer-amphiphiles
KW - targeted drug delivery
KW - targeting MUC1
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U2 - 10.1002/btm2.10194
DO - 10.1002/btm2.10194
M3 - Article
C2 - 33532593
AN - SCOPUS:85096775103
SN - 2380-6761
VL - 6
JO - Bioengineering and Translational Medicine
JF - Bioengineering and Translational Medicine
IS - 1
M1 - e10194
ER -