Terpolymer Micelles for the Delivery of Arsenic to Breast Cancer Cells: The Effect of Chain Sequence on Polymeric Micellar Characteristics and Cancer Cell Uptake.

Abstract

In this study, we developed a micellar platform composed of terpolymers for the encapsulation of inorganic arsenite or arsenous acid (AsIII). For this purpose, a series of terpolymers composed of poly(ethylene oxide) (PEO, block A), poly(α-carboxylate-ε-carprolactone) (PCCL, block B), and poly(ε-caprolactone) (PCL, block C) with either a blocked, i.e., BC or CB, or random, i.e., (B/C)ran block copolymer sequence in the polyester segment was synthesized. The COOH groups on block B were further modified with mercaptohexylamine for AsIII encapsulation. We then investigated how sequence of terpolymers can affect the stability and surface charge of micelles as well as the cellular uptake of their cargo, i.e., AsIII, by MDA-MB-435 cancer cells. 1H NMR spectroscopy in D2O and CDCl3 was also used to study the structure of different terpolymer micelles. Our results showed micelles with ABC sequence to have better stability over those of ACB and A(B/C)ran as reflected by a lower critical micellar concentration. The AsIII-loaded ABC micelles were less negatively charged on the surface than the other two types of terpolymer micelles. In line with this observation, ABC micelles showed a substantially enhanced uptake of AsIII by MDA-MB-435 cancer cells. Stability and surface charge are key parameters that can influence the performance of polymeric micelles as nanodrug carriers. Based on these results, we suggest ABC micelles to have improved characteristics for AsIII delivery compared to ACB and A(B/C)ran micelles.