Cytocompatibility and P‑glycoprotein Inhibition of Block Copolymers: Structure–Activity Relationship

Amphiphilic polymeric micelles greatly improve the solubilization and sustained release of hydrophobic drugs and provide a protective environment for the cargo molecules in aqueous media, which favors lower drug administration doses, reduces adverse side effects, and increases blood circulation times and passive targeting to specific cells. These capabilities depend, among other variables, on the structure and composition of the polymer chains. Composition and, in particular, block length have been shown to play an important role in the modification of cellular responses such as drug internalization processes or transduction pathways when polymeric unimer/micelles are in close contact with cells. Here we present a detailed study about the role copolymer structure and composition play on cell viability and cellular response of several cell lines. To do that, more than 30 structurally related copolymers with diblock and triblock architectures containing different hydrophobic blocks and poly­(ethylene oxide) as the common hydrophilic unit have been analyzed regarding cytocompatibility and potential as “active” cell response modifiers by testing their influence on the P-gp pump efflux mechanism responsible of multidrug resistance in cancerous cells. An empirical threshold for cell viability could be established at a copolymer EO/PO_effective value above ca. 1.5 for copolymers with triblock structure, whereas no empirical rule could be observed for diblocks. Moreover, some of the tested copolymers (e.g., BO₁₂EO₂₂₇BO₁₂ and EO₅₇PO₄₆EO₅₇ that notably increased and C₁₆EO₄₅₅C₁₆ that decreased the P-gp ATPase activity) were observed to act as efficient inhibitors of the P-gp efflux pump promoting an enhanced doxorubicin (DOXO) accumulation inside multidrug resistant (MDR) NCI-ADR-RES cells