Graft copolymers with tunable amphiphilicity tailored for efficient dual drug delivery via encapsulation and pH-sensitive drug conjugation

• Published in: Polymer chemistry 2020-07, Vol.11 (27), p.4438-4453
• Main Authors: Bláhová, Markéta, Randárová, Eva, Konefał, Rafal, Nottelet, Benjamin, Etrych, Tomáš
• Format: Article
• Language: English
• Subjects: Addition polymerization; Blood circulation; Buffers (chemistry); Cancer; Chemical Sciences; Chemical synthesis; Conjugation; Doxorubicin; Drug delivery systems; Encapsulation; Galenic pharmacology; Graft copolymers; Life Sciences; Lipase; Lysosomes; Methacrylamide; Micelles; Pharmaceutical sciences; Physical properties; Polymer chemistry; Polymers; Self-assembly
• ISSN: 1759-9954; 1759-9962
• DOI: 10.1039/D0PY00609B

Polymer-based drug delivery systems may significantly improve cancer therapy. We developed amphiphilic poly(ε-caprolactone)- graft -(poly- N -(2-hydroxypropyl) methacrylamide) copolymers (PCL- graft -pHPMA) with tunable amphiphilicity intended for efficient dual delivery via simultaneous encapsulation of hydrophobic drug, Bcl-2 inhibitor ABT-199, and pH-sensitive conjugation of other chemotherapeutics, doxorubicin, to desired sites, e.g. tumors. Using controlled RAFT polymerization and click chemistry well-defined PCL- graft -pHPMA of diverse M w and physical properties were prepared. By simple dissolution they self-assembled into highly stable micelles with D h ≈ 25 nm and low critical micelle concentration (around 5 μg mL −1 ). The total drug payload reached 17 wt% while maintaining system solubility. The micelles exhibited long-term stability in buffers, while they were cleaved in the presence of lipase, thus proving degradation and drug release after uptake to lysosomes of cancer cells with minimal drug leakage during blood circulation. PCL- graft -pHPMA micelles may serve as a long-circulating drug depo for effective dual therapy of diverse malignancies.