Co-administration of protein drugs with gold nanoparticles to enable percutaneous delivery
Introduction
Skin is regarded as an ideal entry route for non-invasive drug delivery because of its easy accessibility. Yet, the stratum corneum (SC), a composite structure responsible for the skin’s barrier function [1], [2], normally precludes percutaneous absorption of protein drugs owing to their large size and hydrophilic nature. The lipid-filled extracellular space between corneocytes provides the essential pathway for percutaneous absorption. The skin barrier can be weakened typically by use of chemical permeation enhancers, which interact with the skin lipids and chemically or physically alter the SC structure [3].
Growing understanding of the biological effects of nanoparticles on the body has led to numerous drug delivery systems meant to improve drug therapy. Rigid metal-based nanoparticles exhibit many distinct biological properties due to their non-deformable shape and much smaller size (e.g. <10 nm), compared to the lipid or polymeric counterparts. For instance, the potential skin penetration of such rigid nanoparticles has recently received much attention [4]. Known for their nano-biological interactions with membrane lipids [5], [6], the nanoparticles have shown to modulate membrane lipid phase transitions [7], [8] and induce gelled areas on the membrane [9], thereby increasing the lipid fluidity. Since the skin barrier is actually governed by the physical state and structural organization of SC extracellular lipids [10], the lipid-fluidizing functions of nanoparticles play an important role in their ability to alter skin permeability. Metal-based nanoparticles of less than 10 nm in size, including quantum dots [11] and iron oxide nanoparticles [12], [13], were revealed to be capable of penetrating through intact skin, due largely to the interaction with the lipid in extracellular space. Hence, the altered condition of skin accompanied by percutaneous penetration of nanoparticles leads to the breach of skin barrier.
Beyond these facts, there is an intriguing yet almost ignored potential that the altered state of skin barrier caused by nanoparticles could benefit percutaneous delivery of drugs. We hypothesized that the skin penetration may occur not only with the nanoparticles themselves but also with the co-administered compounds that will go through with nanoparticles because of the changed skin permeability. If this co-delivery effect does exist, it may provide a strategy for percutaneous drug delivery. Considering their wide applications in drug delivery and the advantages of biocompatibility and fine-tunable sizes, Au-NPs would be an ideal material in this study. In this study, we co-administered various protein drugs with Au-NPs on the skin of mice to investigate the percutaneous co-delivery effect.
Section snippets
Synthesis and characterization of Au-NPs
Two hundred and fifty microliters of 10 mm HAuCl4 aqueous solution was added to 10 ml of 20 mm polyvinylpyrrolidone (average MW 40 k, Sigma–Aldrich), followed by addition of 250 μl of 10 mm NaBH4 solution under vigorous stirring. Reaction mixture was stirred for additional 15 min at room temperature. The resulting Au-NPs were then purified by ultrafiltration (50 k NMWL, Millipore) with water to remove the free agents.
High-resolution transmission electron microscopy (HRTEM) was operated at an
Results and discussion
The synthesized Au-NPs were morphologically homogeneous and with a mean size of about 5 nm measured by HRTEM (Fig. 1). The hydrodynamic diameter was 11.6 nm, and the zeta potential was −18.3 mV. Over a course of 4 weeks, the nanoparticles remained stable without aggregation.
The skin permeability of these nanoparticles was examined on mice. Au-NPs were found to cross the SC layer of the skin and spread widely over the epidermis layer, and a limited amount of the nanoparticles was also detected
Conclusion
Interaction between the Au-NPs and skin barrier leads to the increase of skin permeability and effectively prompts percutaneous absorption of the co-administered proteins. The advantage of this co-delivery method is that it does not required to “load” drugs into the nanoparticulate system, but simply in a physical mixture instead. Therefore, compromise in activity can be minimized for both protein drugs and nanoparticles because of the exclusion of complicated drug-loading processes. Such
Acknowledgments
This work was supported in part by NIH R01 Grants CA114612 and NS066945. This work was also partially sponsored by Grant R31-2008-000-10103-01 from the WCU project of South Korea. Victor C. Yang is currently a Participating Faculty in the Department of Molecular Medicine and Biopharmaceutical Sciences, Seoul National University, South Korea. Dr. Yongzhuo Huang is the recipient of the Hundred-talent Program of the Chinese Academy of Sciences.
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2023, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :However, the authors did not explore the formation of clusters from Ag+ ions in presence of gloves or other clothes. Regarding Au NPs, Huang et al. [61] studied the in vivo percutaneous absorption of Au NPs through mice skin using a 200 µM solution of Au NPs of 5 nm, which was applied for 3 h to the previously clipped mice dorsal skin in a dose of 50 µL cm−2. The results showed that the NPs penetrate through stratum corneum extracellular lipid regions and did not get into the circulatory system (see Fig. 2).