Journal
BIOMACROMOLECULES
Volume 14, Issue 10, Pages 3697-3705Publisher
AMER CHEMICAL SOC
DOI: 10.1021/bm4010518
Keywords
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Funding
- National Institutes of Health [1R21EB016947-01A1, NIHR01CA134659, NIHCA112356, NIHCA103828]
- Office of Basic Energy Sciences of the U.S. Department of Energy [DE-AC02-05CH11231]
- Office of Army of the U.S. Department of Defense [W91NF-09-1-0374]
- UniQure
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Designing stable drug nanocarriers, 10-30 nm in size, would have significant impact on their transport in circulation, tumor penetration, and therapeutic efficacy. In the. present study, biological properties of 3-helix micelles loaded with 8 wt % doxorubicin (DOX), similar to 15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-Helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics.
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