Investigating the Receptor Interactions and Mechanisms of a Folic Acid-Conjugated Nanoparticle in the Treatment of Breast Cancer

Abstract

An area of intense research focus is the development of a highly specific drug delivery system (DDS) for anti-cancer agents. Chemical engineering of a “smart” DDS to specifically target tumor cells has gained interest in cancer research, designed for safer, more efficient, and effective use of chemotherapeutics for the treatment of cancer. However, the selective targeting and choosing the right cancer surface biomarker are critical for targeted treatments to work. The folic acid receptor alpha (FRα) has gained popularity as a potential target in triple-negative breast cancer (TNBC). We have previously reported on a functionalized folic acid (FA)-conjugated amphiphilic alternating copolymer poly(styrene-alt-maleic anhydride) (FA-DABA-SMA) via a biodegradable linker 2,4-diaminobutyric acid (DABA) that has the requisite features for efficient drug delivery. This biocompatible NP self-assembles in a pH-dependent manner, providing stimuli-responsive, active targeting, and extended-release of hydrophobic chemotherapeutic agents. We have demonstrated that this NP effectively penetrates the inner core of 3-dimensional cancer spheroid models to deliver anti-cancer agents. Interestingly, NPs not loaded with chemotherapeutics also decreased spheroid volume, revealing a previously unknown mechanism of action. The present study investigates the interactions, toxicities, and mechanisms of FA-DABA-SMA in TNBC. Results indicate a size-and-shape dependent interaction of the NP with FRα in which regular receptor functions are disrupted. Treatment with FA-DABA-SMA reduces expression of key proteins, including p53, the product of the highly mutated TP53 gene, and additional oncogenic proteins c-Myc, STAT3, HES1, and Notch1, which are all directly or indirectly influenced by FRα. Treatment with FA-DABA-SMA induces apoptosis and further causes a change in morphology in MDA MB-231 cells, as well as significantly reduces their ability to migrate. Collectively, the results of this study provide a novel insight into the FA functionalized NP that is attributed to a novel dual mechanism of action of targeting FRα and disrupting its regulation of several protein expression levels. This dual mechanism of FA-DABA-SMA demonstrates its effective therapeutic potential for the treatment of TNBC.