Polyanhydride Chemistry

Abstract

Polyanhydrides (PAs) are a class of synthetic biodegradable polymers employed as controlled drug delivery vehicles. They can be synthesized and scaled up from low-cost starting materials. The structure of PAs can be manipulated synthetically to meet desirable characteristics. PAs are biocompatible, biodegradable, and generate nontoxic metabolites upon degradation, which are easily eliminated from the body. The rate of water penetrating into the polyanhydride (PA) matrix is slower than the anhydride bond cleavage. This phenomenon sets PAs as "surface-eroding drug delivery carriers." Consequently, a variety of PA-based drug delivery carriers in the form of solid implants, pasty injectable formulations, microspheres, nanoparticles, etc. have been developed for the sustained release of small molecule drugs, and vaccines, peptide drugs, and nucleic acid-based active agents. The rate of drug delivery is often controlled by the polymer erosion rate, which is influenced by the polymer structure and composition, crystallinity, hydrophobicity, pH of the release medium, device size, configuration, etc. Owing to the above-mentioned interesting physicochemical and mechanical properties of PAs, the present review focuses on the advancements made in the domain of synthetic biodegradable biomedical PAs for therapeutic delivery applications. Various classes of PAs, their structures, their unique characteristics, their physicochemical and mechanical properties, and factors influencing surface erosion are discussed in detail. The review also summarizes various methods involved in the synthesis of PAs and their utility in the biomedical domain as drug, vaccine, and peptide delivery carriers in different formulations are reviewed.

Scheme 1. Hydrolytic Cleavage of the Anhydride Bond into Carboxylic Acids

Figure 1

Schematic illustration of the current review focusing on the different classes of PAs and synthetic methods, factors affecting their hydrolytic degradation rates, and their applications in the biomedical field.

Scheme 2. Synthesis of Poly(isophthalic anhydride) and Poly(terephthalic anhydride) through Melt-Condensation Polymerization

Scheme 3. Synthetic Route of Poly(DBB), Poly(DBB-PEG), and Poly(DBB-SA) from the Melt-Condensation Polymerization of Disuccinate Betulin (DBB) and Sebacic Acid (or) Polyethylene Glycol (PEG)

Used with permission of Royal Society of Chemistry, from Novel Polymeric Derivatives of Betulin with Anticancer activity, Niewolik, D.; Krukiewicz, K.; Bednarczyk-Cwynar, B.; Ruszkowskic, P.; Jaszcz, K., Vol. 9, 2019; permission conveyed through Copyright Clearance Center, Inc.

Figure 2

Chemical structure of the poly(CPP-SA).

Scheme 4. Synthetic Route for Poly(p-carboxyphenoxy)alkanoic Anhydrides

Reproduced with permission from ref (104), Copyright 1989 American Chemical Society.

Scheme 5. Synthetic Route for Nonlinear Fatty-Acids Terminated Poly(sebacic anhydrides)

Reproduced with permission from ref (106). Copyright 2001 American Chemical Society.

Figure 3

Chemical structures of various poly(ester-anhydrides) synthesized through melt-condensation polymerization of activated ester diacid monomers.

Scheme 6. Difference between the Synthetic Routes for Random and Alternating Poly(SA-RA)

Reprinted from Stable Polyanhydride Synthesized from Sebacic acid and Ricinoleicacid, Vol. 257, Zada, M. H.; Basu, A.; Hagigit, T.; Schlinger, R.; Grishko, M.; Kraminsky, A.; Hanuka, E.; Domb, A. J., pp. 156–162, Copyright 2017, with permission from Elsevier.

Scheme 7. General Synthesis Protocol for the Synthesis of Poly(ester-anhydrides) from Dicarboxylic Acids (AA/SA/SUA/DA) and Hydroxyalkanoic Acids (RA/HSA)

Reprinted with permission from ref (49), Copyright 2022 John Wiley & Sons Ltd.

Scheme 8. General Synthetic Methods for PAs

Scheme 9. Synthesis of Cross-Linked PAs: (a) Synthetic Scheme for Dimethacrylated Anhydride Monomers and Their Radical-Mediated Photopolymerization; (b) Synthesis of Thioether Based Cross-Linked PA Based on Thio-ene Photopolymerization of PETMP and PNA

Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature Nature Biotechnology Photopolymerizable Degradable Polyanhydrides With Osteocompatibility, Anseth, K. S.; Shastri, V. R.; Langer, R. Copyright 1999. Used with permission of Royal Society of Chemistry, from Elastomeric and Degradable Polyanhydride Network Polymers by Step-growth Thiol–ene Photopolymerization, Shipp, D. A.; Mc Quinn, C. W.; Rutherglen, B. G.; Mc Bath, R. A., 2009; permission conveyed through Copyright Clearance Center, Inc.

Scheme 10. Synthetic Route for Itaconic Anhydrides and the Chemical Structures of Tetrafunctional Thiols (PETMP)/ Hexafunctional Thiols (DPEHMP) Used for the Synthesis of Cross-Linked PA-Networks through Thio-enechemistry

Used with permission of Royal Society of Chemistry, from Degradable Polyanhydride Networks Derived from Itaconic Acid, Sajjad, H.; Lillie, L. M.; Lau, C. M.; Ellison, C. J.; Tolman, W. B.; Reineke, T. M., Vol. 12, 2021; permission conveyed through Copyright Clearance Center, Inc.

Scheme 11. Hydrolysis of (a) Polyanhydrides and (b) Polyesters

Reproduced with permission from ref (20), Copyright 2012 Elsevier. Reprinted from Biodegradation of Polymers, Vol. 9, Murthy, N.; Wilson, S.; Sy, J. C., pp. 547-560, Copyright 2012, with permission from Elsevier.