Polypeptoid-Assisted Formation of Supramolecular Architectures from Folic Acid for Targeted Cancer Therapy with Enhanced Efficacy

In recent years, much research has focused on assemblies formed by charged polyelectrolytes via electrostatic interactions in aqueous solutions as they have the potential to be used in a variety of biomedical applications. In this study, we analyzed supramolecular architectures fabricated from poly(N-allyl glycine) modified with cysteamine (PNAG-NH2) and folic acid (FA) via electrostatic interactions. The PNAG-NH2/FA complex exhibits a reversible pH-responsive morphological transformation from vesicles (pH = 7.0) to nanofibers (pH = 5.0). Besides, we demonstrated that homopolypeptoids electrostatically interact with FA, thereby facilitating ribbon-and disk-like H-bonded FA patterns and inducing the formation of vesicle nanostructures and fiber arrays, respectively. Additionally, we systematically studied the influence of the degree of polymerization of the polymers, concentration, charge mixing ratio, and type of the polymer and the small-molecule acid on the assemblies. We show the superior stability of the polypeptoid/FA complex as compared to those based on other polymers. We established that the polypeptoid/FA complex exhibits a superior stability than those based on other polymers. By applying these beneficial properties, we encapsulated the anticancer drug doxorubicin (DOX) in the complex vesicle to obtain a pH-induced drug carrier. Cytotoxicity studies and internalization assays revealed that the DOX-loaded PNAG-NH2/FA complex vesicles display an enhanced therapeutic efficacy via typical FA-folate receptor-mediated endocytosis in vitro.

Automated summary

This study analyzes the assemblies formed by charged polyelectrolytes via electrostatic interactions and demonstrates the superior stability of the polypeptoid/folic acid complex as compared to other polymers. By encapsulating the anticancer drug in the complex vesicles, enhanced therapeutic efficacy is achieved through receptor-mediated endocytosis. pH-responsive morphological transformations were also observed.