Effect of an alkyl spacer on the morphology and internalization of MUC1 aptamer‐naphthalimide amphiphiles for targeting and imaging triple negative breast cancer cells

Abstract

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-1,8naphthalimide) 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 non-cancerous 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.

ssDNA nanotubes for selective targeting of glioblastoma and delivery of doxorubicin for enhanced survival

“…We examined the ability of the NT to deliver a therapeutic load, such as DOX. DOX has been shown to intercalate into the double-stranded region of ssDNA stem-loop or G-quadruplex structures, thus forming physical complexes with the ssDNA sequences through noncovalent intercalations ( 50 , 51 ). The retention of DOX by the NT was investigated by dialyzing a sample of the NT that intercalated DOX against PBS at 37°C for 6 weeks.…”

A Possible Inhibitory Role of Sialic Acid on MUC1 in Peritoneal Dissemination of Clear Cell-Type Ovarian Cancer Cells

“…However, involvement of other cell surface molecules, such as MUC1, in peritoneal dissemination has yet to be determined. Determination of the role of MUC1 with unique glycans during the process of cancer cell damage to the host is important because MUC1 has recently become an important target of advanced forms of diagnosis and therapy with antibodies and related molecules [ 4 , 5 , 6 , 7 , 8 ].…”

“…The association of overexpressed or aberrantly glycosylated Mucin 1 (MUC1) with poor prognosis and malignant behaviors in many types of cancers has been reported [ 3 ]. For this reason, MUC1 with unique glycosylation has long been considered as a therapeutic target, and a number of therapeutic chemicals and antibodies have been developed [ 4 , 5 , 6 , 7 , 8 ]. Some of these reagents have been shown to attenuate the putative functions of MUC1.…”

Multivalent Aptamer Approach: Designs, Strategies, and Applications

“…With properly selected lengths and materials, spacers can increase the avidities of multivalent constructs by overcoming steric hindrances due to adjacent aptamers. The most common spacers are PEG [ 77 , 78 ]; alkyl [ 78 , 79 ]; ssDNAs, such as oligo-T and oligo-A [ 78 , 80 , 81 ]; and dsDNA [ 82 ]. Among these different types of spacers, oligo-T spacers are perhaps the most commonly used [ 75 ]; therefore, in this section, we focus on oligo-T spacers.…”