Recent Advances in Epsilon-Poly-L-Lysine and L-Lysine-Based Dendrimer Synthesis, Modification, and Biomedical Applications

Abstract

With the advantages in biocompatibility, antimicrobial ability, and comparative facile synthesis technology, poly-L-lysine (PLL) has received considerable attention in recent years. Different arrangement forms and structures of the backbone endow lysine-based polymers with versatile applications, especially for ε-poly-L-lysine (EPL) and lysine-based dendrimer (LBD) compounds. This review summarized the advanced development of the synthesis and modification strategies of EPL and LBD, focus on the modification of bio-synthesis and artificial synthesis, respectively. Meanwhile, biomedical fields, where EPL and LBD are mainly utilized, such as agents, adjuvants, or carriers to anti-pathogen or used in tumor or gene therapies, are also introduced. With the deeper of knowledge of pharmacodynamics and pharmacokinetics of the drug system, the design and synthesis of these drugs can be further optimized. Furthermore, the performances of combination with other advanced methodologies and technologies demonstrated that challenges, such as scale production and high expenses, will not hinder the prospective future of lysine-based polymers.

Keywords: amphiphilic coploymer; lysine-based dendrimers; polypeptide; therapeutic application; ε-poly-L-lysine.

Graphical Abstract

Synthesis, modification, and biomedical applications of EPL and LBD.

Figure 1

Structures of PLL-related polymers with different morphologies. (A) The molecular structure of PLL (Ge et al., 2019); (B) The structure of EPL, one of the linear PLL forms; (C) Different molecular structure polylysine derivatives (Shi et al., 2015): (a) graft, (b) brush, (c) star architectures, (d) dendrimer, (e) hyperbranched, and (f) dendrigraft; (D) Self-assembled nanoparticles of PLL derivatives (Li Y. et al., 2020).

Figure 2

The physiological and transcriptional response mechanisms of S. albulus to spontaneous acid stress in the commercial biosynthesis of EPL (Wang C. Y. et al., 2020).

Figure 3

Illustrations to modification of lysine-based dendrimers: (A) Interior block [PLLD-G4, (Zhou et al., 2016)]; (B) Incorporation [G3KL-Fluo, (Gan et al., 2019)]; (C) Exterior modification [⁶⁸Ga-NOVA-DGL-PEG-RGDyC, (Fang et al., 2020)]; (D) Combination [DGL-coated MNP, (Shen et al., 2017)].

Figure 4

(A) Chemical structure of G3KL (Siriwardena et al., 2018a); (B) Snapshot of G4 polylysine dendrimer in molecular dynamic simulation (Francoia et al., 2017).

Figure 5

Illustrations of two types of LBD conjugates for drug delivery system. (A) Non-covalent capsid-like nanocarriers (Li et al., 2016); (B) Drug delivery system with multistage stimuli responses (Agazzi et al., 2020).

Figure 6

Overview of the affected metabolic pathways in the A549 and H1299 cells after treatment with the DNA conjugating LBD polyplexes (Alazzo et al., 2019).