Challenges in delivering therapeutic peptides and proteins: A silk-based solution

Abstract

Peptide- and protein-based therapeutics have drawn significant attention over the past few decades for the treatment of infectious diseases, genetic disorders, oncology, and many other clinical needs. Yet, protecting peptide- and protein-based drugs from degradation and denaturation during processing, storage and delivery remain significant challenges. In this review, we introduce the properties of peptide- and protein-based drugs and the challenges associated with their stability and delivery. Then, we discuss delivery strategies using synthetic polymers and their advantages and limitations. This is followed by a focus on silk protein-based materials for peptide/protein drug processing, storage, and delivery, as a path to overcome stability and delivery challenges with current systems.

Keywords: Biomaterials; Drug delivery; Drug release; Peptide/protein drugs; Silk.

Figure 1.

Current percentage distribution of routes of administration for therapeutic peptides and proteins. Adapted from THPdb. (https://webs.iiitd.edu.in/raghava/thpdb/index.html)

Figure 2.

The delivery challenge of peptide/protein-based drugs in various routes. A. Mucus barrier, biochemical barrier, and cellular barrier in oral drug delivery. B. Mucus barrier, biochemical barrier, immunological barrier, and cellular barrier in pulmonary drug delivery. C. Mucus barrier, mechanical barrier, and cellular barrier in nasal drug delivery. D. Cellular barrier in transdermal drug delivery. E. three types of parenteral drug delivery.

Figure 3.

Peptide/protein-based drug encapsulation methods using synthetic polymers. A. preparation of synthetic polymers in organic solvent that are used as drug delivery carriers. B. methods to prepare polymeric microsphere to encapsulate peptide/protein-based drugs. C. methods to make polymeric nanoparticles- for encapsulating peptide/protein drugs. D. methods to prepare drug loaded polymeric hydrogels. E. methods to prepare polymeric microneedles. (adapted from DeMuth et al. (76), reproduced with permission, Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim )

Figure 4.

Peptide/protein-based drug encapsulation methods using silk. A. Preparation of silk aqueous solutions for peptide/protein-based drug loading. B. Methods to prepare drug encapsulated silk microspheres. C. List of methods to prepare drug loaded silk nanoparticles. D. Methods for using silk hydrogels to encapsulate peptide/protein drugs. E. Method to prepare silk microneedles for encapsulating peptide/protein drugs. (adapted from Tsioris et al. (182), reproduced with permission, copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim))

Figure 5.

Silk-based stabilization materials and stabilization mechanisms. (adapted from Li et al.(187), reproduced with permission, copyright © 2015 Elsevier B.V. All rights reserved.) A. Silk and peptide/protein drug molecules. B. Silk-based materials stabilize drug molecules in the water phase. C. Silk-based materials stabilize drug molecules in the solid phase. D. Silk-based materials stabilize drug molecules in vivo from the harsh GI environment.

Figure 6.

Mechanisms of drug release. A. Drug release from polymeric matrices through dissolution controlled, chemical hydrolysis and diffusion-controlled mechanisms. B. Drug release from silk encapsulation through enzymatic degradation and diffusion-controlled mechanisms.

Figure 7.

Comparison of bioavailability of the peptides/protein drugs without protection, with common synthetic polymer strategies, and with a silk protection strategy. A. The bioavailability of naked peptide/protein drugs affected by factors during encapsulation, delivery, and release. B. The bioavailability of peptide/protein drugs protected using common polymer strategies affected by factors during encapsulation, delivery, and release. C. The bioavailability of peptide/protein drugs protected using silk fibroin strategy affected by factors during encapsulation, delivery, and release. The decrease of the bioavailability in the figure is a qualitative analysis, to provide a visual comparison of the differences between the polymeric and silk strategies.