Abstract
In the human endocrine system many protein hormones including urotensin, glucagon, obestatin, bombesin and secretin, among others, are supplied from amyloidal secretory granules. These granules form part of the so called functional amyloids, which within the whole aggregome appear to be more abundant than formerly believed. Bacterial inclusion bodies (IBs) are non-toxic, nanostructured functional amyloids whose biological fabrication can be tailored to render materials with defined biophysical properties. Since under physiological conditions they steadily release their building block protein in a soluble and functional form, IBs are considered as mimetics of endocrine secretory granules. We have explored here if the in vivo implantation of functional IBs in a given tissue would represent a stable local source of functional protein. Upon intratumoral injection of bacterial IBs formed by a potent protein ligand of CXCR4 we have observed high stability and prevalence of the material in absence of toxicity, accompanied by apoptosis of CXCR4+ cells and tumor ablation. Then, the local immobilization of bacterial amyloids formed by therapeutic proteins in tumors or other tissues might represent a promising strategy for a sustained local delivery of protein drugs by mimicking the functional amyloidal architecture of the mammals’ endocrine system.
Highlights
In the human endocrine system many protein hormones including urotensin, glucagon, obestatin, bombesin and secretin, among others, are supplied from amyloidal secretory granules
Any therapeutically valuable protein produced in bacteria can be packaged as IBs27, and in addition, bacterial inclusion bodies (IBs) show a high intrinsic and spontaneous penetrability into mammalian cells where they deliver, assisted by molecular chaperones, the functional protein fraction embedded into the amyloidal scaffold[28]
Bacterial IBs are regular shaped soft materials that show a moderate polydispersion in size (Fig. 1)[29,30]
Summary
Bacterial IBs are regular shaped soft materials that show a moderate polydispersion in size (Fig. 1)[29,30]. In addition to the releasable nature of a fraction of IB protein, the high inherent membrane-activity of bacterial IBs allows efficient adhesion and cell penetration in absence of cytotoxicity, properties that justified the exploration of IBs as both functional topographies in tissue engineering and as protein delivery agents in replacement therapies[24]. In this context, the absence of intrinsic toxicity of bacterial IBs has been widely demonstrated by conventional procedures on IBs formed by diverse proteins with potential biomedical interest, in therapeutic/ prophylactic setting ups. The recent identification of IB formation in food-grade bacteria[57], the development of endotoxin-free E. coli strains[58] and their adaptation to the production of endotoxin-free IBs59 further expand the opportunities for the in vivo uses of IBs, supporting again the added values of biofabrication versus chemical synthesis in the production of functional materials
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