Controlled release of dexamethasone from peptide nanofiber gels to modulate inflammatory response

Abstract

New biomaterials that have the ability to locally suppress an immune response could have broad therapeutic use in the treatment of diseases characterized by acute or chronic inflammation or as a strategy to facilitate improved efficacy in cell or tissue transplantation. We report here on the preparation of a modular peptide amphiphile (PA) capable of releasing an anti-inflammatory drug, dexamethasone (Dex), by conjugation via a labile hydrazone linkage. This molecule self-assembled in water into long supramolecular nanofibers when mixed with a similar PA lacking the drug conjugate, and the addition of calcium salt to screen electrostatic repulsion between nanofibers promoted gel formation. These nanofiber gels demonstrated sustained release of soluble Dex for over one month in physiologic media. The Dex released from these gels maintained its anti-inflammatory activity when evaluated in vitro using a human inflammatory reporter cell line and furthermore preserved cardiomyocytes viability upon induced oxidative stress. The ability of this gel to mitigate the inflammatory response in cell transplantation strategies was evaluated using cell-surrogate polystyrene microparticles suspended in the nanofiber gel that were then subcutaneously injected in a mouse. Live animal luminescence imaging using the chemiluminescent reporter molecule luminol showed a significant reduction in inflammation at the site where particles were injected with Dex-PA compared to the site of injection for particles within a control PA in the same animal. Histological evidence suggested a marked reduction in the number of infiltrating inflammatory cells when particles were delivered within Dex-PA nanofiber gels and very little inflammation was observed at either 3 days or 21 days post-implantation. The use of Dex-PA could facilitate localized anti-inflammatory activity as a component of biomaterials designed for various applications in regenerative medicine and could specifically be a useful module for PA-based therapies. More broadly, these studies define a versatile strategy for facile synthesis of self-assembling peptide-based materials with the ability to control drug release.

Assessment of the drug loading, in vitro and in vivo release behavior of novel pH-sensitive hydrogel

“…For example, it could achieve good results in the treatment of ulcerative colitis (Fedorak et al, 1995;Buritova et al, 1996;Van Meeteren et al, 2000;Keely et al, 2009;Webber et al, 2012). However, due to the hydrophobicity, its in vivo release behavior and function were limited.…”

Self-assembled peptide nanomaterials for biomedical applications: promises and pitfalls

“…[58][59][60][61] For advanced functions, the self-assembled systems should have domains specific for targeting or sensory capability to be utilized for the intended application. 56,62 As an example of the aforementioned application, Webber et al 63 conjugated the anti-inflammatory drug dexamethasone with the peptide amphiphile (C 16 -V 2 A 2 E 2 ) via a hydrazine linkage to achieve long-term drug release in both in vitro and in vivo tests. In vitro studies showed that dexamethasone could be released over several weeks at physiological pH and temperature.…”

“…The results demonstrated that the localized drug-loaded nanofiber gel could promote immune suppression. 63 Zhang et al 64 utilized the self-assembling Tat peptide to encapsulate the hydrophobic drug paclitaxel to facilitate drug delivery and efficacy. First, four sequences with different numbers of hydrophobic tails were tested, and only the four-tailed sequence qC 8 -Tat self-assembled into nanotubes under aqueous solutions at a pH of 7.4 ( Figure 6).…”

Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part II: Challenges on the Evolution from Single to Multiple Bioactive Factor Delivery

“…Patterning, 330,331 surface immobilization, 332,333 creation of gradients, 334,335 self-assembly, 336,337 and layer-by-layer deposition 338,339 are among the techniques that are currently being further improved and explored due to advances in nanotechnology. This significant list of contributions highlights the decisive role of nanotechnology on the development of multifunctional biomaterials for bone, cartilage, and osteochondral engineering.…”