Self-Assembled pH-Responsive Polymeric Micelles for Highly Efficient, Noncytotoxic Delivery of Doxorubicin Chemotherapy To Inhibit Macrophage Activation: In Vitro Investigation.

Self-assembled pH-responsive polymeric micelles, a combination of hydrophilic poly(ethylene glycol) segments and hydrogen bonding interactions within a biocompatible polyurethane substrate, can spontaneously self-assemble into highly controlled, nanosized micelles in aqueous solution. These newly developed micelles exhibit excellent pH-responsive behavior and biocompatibility, highly controlled drug (doxorubicin; DOX) release behavior, and high drug encapsulation stability in different aqueous environments, making the micelles highly attractive potential candidates for safer, more effective drug delivery in applications such as cancer chemotherapy. In addition, in vitro cell studies revealed the drug-loaded micelles possessed excellent drug entrapment stability and low cytotoxicity toward macrophages under normal physiological conditions (pH 7.4, 37 °C). When the pH of the culture media was reduced to 6.0 to mimic the acidic tumor microenvironment, the drug-loaded micelles triggered rapid release of DOX within the cells, which induced potent antiproliferative and cytotoxic effects in vitro. Importantly, fluorescent imaging and flow cytometric analyses confirmed the DOX-loaded micelles were efficiently delivered into the cytoplasm of the cells via endocytosis and then subsequently gradually translocated into the nucleus. Therefore, these multifunctional micelles could serve as delivery vehicles for precise, effective, controlled drug release to prevent accumulation and activation of tumor-promoting tumor-associated macrophages in cancer tissues. Thus, this unique system may offer a potential route toward the practical realization of next-generation pH-responsive therapeutic delivery systems.

Nucleobase-Functionalized Supramolecular Micelles with Tunable Physical Properties for Efficient Controlled Drug Release.

Complementary nucleobase-functionalized polymeric micelles, a combination of adenine-thymine (A-U) base pairs and a blend of hydrophilic-hydrophobic polymer pairs, can be used to construct 3D supramolecular polymer networks; these micelles exhibit excellent self-assembly ability in aqueous solution, rapid pH-responsiveness, high drug loading capacity, and triggerable drug release. In this study, a multi-uracil functionalized poly(ε-caprolactone) (U-PCL) and adenine end-capped difunctional oligomeric poly(ethylene glycol) (BA-PEG) are successfully developed and show high affinity and specific recognition in solution owing to dynamically reversible A-U-induced formation of physical cross-links. The U-PCL/BA-PEG blend system produces supramolecular micelles that can be readily adjusted to provide the desired critical micellization concentration, particle size, and stability. Importantly, in vitro release studies show that doxorubicin (DOX)-loaded micelles exhibit excellent DOX-encapsulated stability under physiological conditions. When the pH value of the solution is reduced from 7.4 to 5.0, DOX-loaded micelles can be rapidly triggered to release encapsulated DOX, suggesting these polymeric micelles represent promising candidate pH-responsive nanocarriers for controlled-release drug delivery and pharmaceutical applications.