Bile Acid-Based Drug Delivery Systems for Enhanced Doxorubicin Encapsulation: Comparing Hydrophobic and Ionic Interactions in Drug Loading and Release

• Published in: Molecular pharmaceutics 2018-03, Vol.15 (3), p.1266-1276
• Main Authors: Cunningham, Alexander J, Robinson, Mattieu, Banquy, Xavier, Leblond, Jeanne, Zhu, X. X
• Format: Article
• Language: English
• Subjects: Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - pharmacokinetics; Breast Neoplasms - drug therapy; Chemical Sciences; Cholic Acid - chemistry; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Drug Carriers - chemistry; Drug Compounding - methods; Drug Liberation; Epoxy Compounds - chemistry; Female; Galenic pharmacology; HeLa Cells; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; Life Sciences; Medication; Micelles; Nanoparticles - chemistry; Pharmaceutical sciences; Polyethylene Glycols - chemistry; Polymers
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b01091

Doxorubicin (Dox) is a drug of choice in the design of drug delivery systems directed toward breast cancers, but is often limited by loading and control over its release from polymer micelles. Bile acid-based block copolymers present certain advantages over traditional polymer-based systems for drug delivery purposes, since they can enable a higher drug loading via the formation of a reservoir through their aggregation process. In this study, hydrophobic and electrostatic interactions are compared for their influence on Dox loading inside cholic acid based block copolymers. Poly­(allyl glycidyl ether) (PAGE) and poly­(ethylene glycol) (PEG) were grafted from the cholic acid (CA) core yielding a star-shaped block copolymer with 4 arms (CA-(PAGE-b-PEG)4) and then loaded with Dox via a nanoprecipitation technique. A high Dox loading of 14 wt % was achieved via electrostatic as opposed to hydrophobic interactions with or without oleic acid as a cosurfactant. The electrostatic interactions confer a pH responsiveness to the system. 50% of the loaded Dox was released at pH 5 in comparison to 12% at pH 7.4. The nanoparticles with Dox loaded via hydrophobic interactions did not show such a pH responsiveness. The systems with Dox loaded via electrostatic interactions showed the lowest IC50 and highest cellular internalization, indicating the pre-eminence of this interaction in Dox loading. The blank formulations are biocompatible and did not show cytotoxicity up to 0.17 mg/mL. The new functionalized star block copolymers based on cholic acid show great potential as drug delivery carriers.