Abstract
(Arginine-alanine-aspartic acid-alanine)4 ((RADA)4) nanoscaffolds are excellent candidates for use as peptide delivery vehicles: they are relatively easy to synthesize with custom bio-functionality, and assemble in situ to allow a focal point of release. This enables (RADA)4 to be utilized in multiple release strategies by embedding a variety of bioactive molecules in an all-in-one “construct”. One novel strategy focuses on the local, on-demand release of peptides triggered via proteolysis of tethered peptide sequences. However, the spatial-temporal morphology of self-assembling nanoscaffolds may greatly influence the ability of enzymes to both diffuse into as well as actively cleave substrates. Fine structure and its impact on the overall effect on peptide release is poorly understood. In addition, fractal networks observed in nanoscaffolds are linked to the fractal nature of diffusion in these systems. Therefore, matrix morphology and fractal dimension of virgin (RADA)4 and mixtures of (RADA)4 and matrix metalloproteinase 2 (MMP-2) cleavable substrate modified (RADA)4 were characterized over time. Sites of high (glycine-proline-glutamine-glycine+isoleucine-alanine-serine-glutamine (GPQG+IASQ), CP1) and low (glycine-proline-glutamine-glycine+proline-alanine-glycine-glutamine (GPQG+PAGQ), CP2) cleavage activity were chosen. Fine structure was visualized using transmission electron microscopy. After 2 h of incubation, nanofiber networks showed an established fractal nature; however, nanofibers continued to bundle in all cases as incubation times increased. It was observed that despite extensive nanofiber bundling after 24 h of incubation time, the CP1 and CP2 nanoscaffolds were susceptible to MMP-2 cleavage. The properties of these engineered nanoscaffolds characterized herein illustrate that they are an excellent candidate as an enzymatically initiated peptide delivery platform.
Highlights
Peptides are the fastest growing segment of the pharmaceutical industry, and are generally considered the ideal therapeutic: specific, potent, small enough for diffusion, etc. [1]
In our study we addressed this concern by observing nanoscale architecture and fractal features during self-assembly, which have been linked to diffusion in similar scaffolds
The temporal growth morphology and fractal dimension for a (RADA)4 hydrogel were studied as a function of C-terminal tethered matrix metalloproteinase 2 (MMP-2) substrate (GPQG+IASQ (CP1), GPQG+PAGQ (CP2)), and overall substrate concentration within the matrix
Summary
Peptides are the fastest growing segment of the pharmaceutical industry, and are generally considered the ideal therapeutic: specific, potent, small enough for diffusion, etc. [1]. Peptide therapeutics suffer from a major drawback; they are cleaved by naturally circulating proteases, and are short lived To circumvent this problem, peptide therapeutics have been incorporated into delivery vehicles with “on-demand” release cues, such as specific proteolytic cleavage sites [2,3]. High throughput and systematic studies are imperative to drug discovery, requiring precisely timed drug release and cell response measurements, but are exceedingly complicated to perform on hydrogels [10,11]. With these limitations in mind, the ideal drug delivery hydrogel should incorporate accurate release cues, have reproducible gelation morphology, and be simple to synthesize. To these ends, controlled release peptide content can be precisely modulated and corresponding nanoscale morphology observed in a self-assembling peptides (SAPs)
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