Long-Circulating 15 nm Micelles Based on Amphiphilic 3-Helix Peptide–PEG Conjugates

• Published in: ACS nano Vol. 6; no. 6; pp. 5320 - 5329
• Main Authors: Dong, He, Dube, Nikhil, Shu, Jessica Y, Seo, Jai W, Mahakian, Lisa M, Ferrara, Katherine W, Xu, Ting
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26-06-2012
• Subjects: Animals; Bundling; Circulation; Colloids - chemistry; Conjugates; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Drugs; Half life; Hydrophobic and Hydrophilic Interactions; Metabolites; Mice; Micelles; Nanocapsules - chemistry; Nanoparticles; Nanostructure; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Peptides - chemistry; Polyethylene Glycols - chemistry; Tissue Distribution; helix bundle; peptide−polymer conjugate; 3-helix micelle; stability; nanocarriers
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/nn301142r

Generating stable, multifunctional organic nanocarriers will have a significant impact on drug formulation. However, it remains a significant challenge to generate organic nanocarriers with a long circulation half-life, effective tumor penetration, and efficient clearance of metabolites. We have advanced this goal by designing a new family of amphiphiles based on coiled-coil 3-helix bundle forming peptide–poly(ethylene glycol) conjugates. The amphiphiles self-assemble into monodisperse micellar nanoparticles, 15 nm in diameter. Using the 3-helix micelles, a drug loading of ∼8 wt % was obtained using doxorubicin and the micelles showed minimal cargo leakage after 12 h of incubation with serum proteins at 37 °C. In vivo pharmacokinetics studies using positron emission tomography showed a circulation half-life of 29.5 h and minimal accumulation in the liver and spleen. The demonstrated strategy, by incorporating unique protein tertiary structure in the headgroup of an amphiphile, opens new avenues to generate organic nanoparticles with tunable stability, ligand clustering, and controlled disassembly to meet current demands in nanomedicine.