A Polyhydroxyalkanoates-Based Carrier Platform of Bioactive Substances for Therapeutic Applications

Abstract

Bioactive substances (BAS), such as small molecule drugs, proteins, RNA, cells, etc., play a vital role in many therapeutic applications, especially in tissue repair and regeneration. However, the therapeutic effect is still a challenge due to the uncontrollable release and instable physico-chemical properties of bioactive components. To address this, many biodegradable carrier systems of micro-nano structures have been rapidly developed based on different biocompatible polymers including polyhydroxyalkanoates (PHA), the microbial synthesized polyesters, to provide load protection and controlled-release of BAS. We herein highlight the developments of PHA-based carrier systems in recent therapeutic studies, and give an overview of its prospective applications in various disease treatments. Specifically, the biosynthesis and material properties of diverse PHA polymers, designs and fabrication of micro- and nano-structure PHA particles, as well as therapeutic studies based on PHA particles, are summarized to give a comprehensive landscape of PHA-based BAS carriers and applications thereof. Moreover, recent efforts focusing on novel-type BAS nano-carriers, the functionalized self-assembled PHA granules in vivo, was discussed in this review, proposing the underlying innovations of designs and fabrications of PHA-based BAS carriers powered by synthetic biology. This review outlines a promising and applicable BAS carrier platform of novelty based on PHA particles for different medical uses.

Keywords: bioactive substances; carrier platform; drug delivery; polyhydroxyalkanoates; self-assembled PHA granules; therapeutic applications.

FIGURE 1

Overview of polyhydroxyalkanoates (PHA) from biosynthesis to therapeutic applications.

FIGURE 2

Biosynthesis pathways of SCL- and M/LCL-PHA. Metabolic pathways of short-chain length (SCL) PHA, medium/long-chain length (M/LCL) PHA and their copolymers (SCL-M/LCL) PHA are summarized. Specifically, SCL PHA indicates monomers containing only 3-5 carbon atoms (C3-C5), and monomers with over 6 carbon atoms are termed M/LCL PHA. The enzymes and metabolites shown are: PhaA, β-ketothiolase; PhaB, acetoacetyl-CoA reductase; PhaC, PHA synthase; PhaG, 3-hydroxyacyl-ACP-CoA transacylase; PhaJ, enoyl-CoA hydratase; 3HPAld, 3-hydroxypropionaldehyde; 3HP, 3-hydroxyproiponate; 3HA-ACP, 3-hydroxyacyl-ACP; SSA, succinate semialdehyde; 4HB, 4-hydroxybutyrate; 3HB-CoA, 3-hydroxybutyrate-CoA; 3HV-CoA, 3-hydroxyvaleryl-CoA.

FIGURE 3

Fabrication and applications of PHA-based particles including micro-/nanoparticles and microspheres. (A) and (B) Fabrication methods of polymeric particles based on single and double emulsion-solvent extraction methods, respectively. (C) Therapeutic applications of PHA particles loaded with anti-cancer molecules ellipticine (EPT) and docetaxel (DTXL) for oncotherapy, as well as stem cells and growth factors like Bone Morphogenetic Protein 7 (BMP7) for tissue engineering. Abbreviations: PHBV, poly (3-hydroxybutyrate-co-3-hydroxyvalerate); PVA, polyvinyl alcohol; PHB, poly (3-hydroxyalkanoate); PEG, polyethylene glycol; ADSC, adipose-derived mesenchymal stem cell. Regenerated from (Di Mascolo et al., 2016), (Wei et al., 2018a) and (Chen et al., 2020) with permission.

FIGURE 4

Fabrication and applications of PHA-based BAS carriers. (A) Functionalization of self-assembled PHA granules using PhaC- (A₁) and phasins- (A₂) based fusion approach. (B) Structural schema of a natural synthesized PHA-protein complex. (C) Functionalized PHA particles coated with Spy-catcher tag to form immobilized biocatalysts scaffold. Regenerated from (Wong and Rehm, 2018) with permission. (D) TB antigens modified PHA particles as vaccine for skin test. Regenerated from (Parlane et al., 2017) with permission. (E) Schematic diagram of AL-PHA system (Advanced proteoLytic detector PolyHydroxyAlkanoates). Regenerated from (Kelwick et al., 2021) with permission.