Theranostics 2020; 10(1):109-122. doi:10.7150/thno.38388 This issue
1. National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou 510006, China.
2. Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou 510641, China.
3. Department of Chemistry and Biochemistry, University of Oklahoma, Stephenson Life Sciences Research Center Norman, OK, 73019, USA.
4. School of Biomedical Science and Engineering, South China University of Technology, Guangzhou 510006, China.
5. Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, China.
6. Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510006, China.
*These authors contributed equally to this work.
Background: Localized delivery of antimicrobial agents such as antimicrobial peptides (AMPs) by a biomaterial should be on-demand. Namely, AMPs should be latent and biocompatible in the absence of bacterial infection, but released in an amount enough to kill bacteria immediately in response to bacterial infection.
Methods: To achieve the unmet goal of such on-demand delivery, here we turned a titanium implant with titania nanotubes (Ti-NTs) into a Pandora's box. The box was loaded with AMPs (HHC36 peptides, with a sequence of KRWWKWWRR) inside the nanotubes and “closed” (surface-modified) with a pH-responsive molecular gate, poly(methacrylic acid) (PMAA), which swelled under normal physiological conditions (pH 7.4) but collapsed under bacterial infection (pH ≤ 6.0). Thus, the PMAA-gated Ti-NTs behaved just like a Pandora's box. The box retarded the burst release of AMPs under physiological conditions because the gate swelled to block the nanotubes opening. However, it was opened to release AMPs to kill bacteria immediately when bacterial infection occurred to lowering the pH (and thus made the gate collapse).
Results: We demonstrated such smart excellent bactericidal activity against a panel of four clinically important bacteria, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus. In addition, this box was biocompatible and could promote the osteogenic differentiation of human mesenchymal stem cells. Both in vitro and in vivo studies confirmed the smart “on-demand” bactericidal activity of the Pandora's box. The molecularly gated Pandora's box design represents a new strategy in smart drug delivery.
Keywords: Titania nanotubes, pH-Responsive molecular gate, On-demand delivery, Bactericidal activity, Peptides