Polypeptide-Based Systems: From Synthesis to Application in Drug Delivery

Abstract

Synthetic polypeptides are biocompatible and biodegradable macromolecules whose composition and architecture can vary over a wide range. Their unique ability to form secondary structures, as well as different pathways of modification and biofunctionalization due to the diversity of amino acids, provide variation in the physicochemical and biological properties of polypeptide-containing materials. In this review article, we summarize the advances in the synthesis of polypeptides and their copolymers and the application of these systems for drug delivery in the form of (nano)particles or hydrogels. The issues, such as the diversity of polypeptide-containing (nano)particle types, the methods for their preparation and drug loading, as well as the influence of physicochemical characteristics on stability, degradability, cellular uptake, cytotoxicity, hemolysis, and immunogenicity of polypeptide-containing nanoparticles and their drug formulations, are comprehensively discussed. Finally, recent advances in the development of certain drug nanoformulations for peptides, proteins, gene delivery, cancer therapy, and antimicrobial and anti-inflammatory systems are summarized.

Keywords: drug delivery systems; hydrogels; polypeptide copolymers; polypeptide particles; polypeptides; self-assembly.

Figure 24

Scheme for miniemulsion polymerization. Reproduced with permission of John Wiley and Sons, Inc. from [299].

Figure 1

Normal amine mechanism of NCA polymerization.

Figure 2

Activated monomer mechanism of NCA polymerization.

Figure 3

Synthesis of polypeptides using amine-hydrochlorides as initiators in NCA ROP.

Figure 4

Proposed mechanism for polypeptide synthesis using HMDS initiator.

Figure 5

Ring-opening polymerization of NCA using transition metals zero-valence cyclooctadiene complexes.

Figure 6

Simplified scheme for the synthesis of copolypeptides by copolymerization of different NCAs.

Figure 7

Scheme for the preparation of block-polypeptides by sequential polymerization of different NCAs.

Figure 8

Synthesis of dextran-block-poly(γ-benzyl-L-glutamate) by “click chemistry”: (A) Synthesis of azido-terminated PGlu(OBzl) by ROP using 1-azido-3-aminopropane as initiator, (B) Functionalization of dextran by reductive amination with propargylamine to produce a terminal alkyne group, (C) Block coupling of PGlu(OBzl) and modified dextran by “click chemistry” to produce dextran-b-PGlu(OBzl). Reproduced without changes with permission of John Wiley and Sons, Inc. from [90].

Figure 9

A typical anatomical structure of a dendrimer and dendrons. G1, G2, and G3 represent the first, second, and third generations, respectively. Reproduced without changes with permission from [115], Copyright© 2019, American Chemical Society.

Figure 10

Schematic representation of the different PLys analogues: (A) linear PLys; (B) hyperbranched PLys; (C) third-generation dendritic PLys. Reproduced without changes with permission from [116], Copyright© 2012, American Chemical Society.

Figure 11

Scheme for “one pot” UV-triggered ROP of Lys(oNB) NCA at room temperature. Reproduced without changes with permission from [122], Copyright© 2017, American Chemical Society.

Figure 12

Scheme for Lys tetrafluoroborate NCA ROP catalyzed by Et₃N at 15 °C. Reproduced with permission of Elsevier from [124].

Figure 13

Synthesis of PLys-g-PEG using «grafting through» approach. Reproduced with adaptations with permission from [131], Copyright© 1999, American Chemical Society.

Figure 14

Various types of nanoparticles that can be obtained from polypeptides and polypeptide-containing copolymers.

Figure 15

Structures formed due to self-assembly of amphiphilic block copolymers depend on composition and properties of the amphiphile. Reproduced with permission of John Wiley and Sons, Inc. from [198] and completed with information from [199].

Figure 16

Schematic representation for preparation of nanoparticles by nanoprecipitation.

Figure 17

Scheme for producing nanoparticles by phase inversion method (dialysis) on the example of formation of polymersomes. Self-assembled NPs of other morphologies, e.g., micelles, vesicles, or nanogels, can also be obtained by this method. Figure reproduced with adaptation from [252] under the terms of the Creative Commons CC BY license.

Figure 18

Schematic representation of polypeptide polymersome production by film rehydration. Reproduced as a part of original figure with permission of John Wiley and Sons, Inc. from [200].

Figure 19

Scheme for production of nanoparticles by single emulsion method. Reproduced from [269] under the terms of the Creative Commons CC BY license.

Figure 20

Emulsion phase transfer technique to prepare nanoparticles (given example for the formation of polymersomes). Reproduced as a part of original figure with permission of John Wiley and Sons, Inc. from [200].

Figure 21

Schematic representation of the production of nanoparticles by electrospraying. Reproduced and adapted with permission from [273], Copyright© 2009, American Chemical Society.

Figure 22

Scheme for the preparation of the enzyme-loaded polypeptide-based PICsomes. Reproduced with permission of John Wiley & Sons, Inc. from [283].

Figure 23

Production of polypeptide-containing vesicles by ring-opening polymerization-induced self-assembly (ROPISA) method. Reproduced with permission from [293], Copyright© 2019, American Chemical Society.

Figure 25

Schematic representation of ROS-responsive hydrogels based on mPEG-b-PMet as an oxidation-triggered drug delivery (a) and as a protection for cells under oxidative stress system (b). Reproduced and adapted with permission of John Willey and Sons, Inc. from [406].

Figure 26

Schematic representation of pH-responsive QPABA/PVA hydrogel with encapsulated NIR-responsive MP196@PDA NPs as a wound treatment material for antibacterial therapy. Reproduced with permission of Elsevier from [411].