Degradable Polyphosphoester-Protein Conjugates: “PPEylation” of Proteins

Abstract

Pharmacokinetic properties determine the efficacy of protein therapeutics. The covalent attachment of poly(ethylene glycol) (PEG) extends the half-life of such biologicals to maintain a therapeutically effective concentration over a prolonged period of time and improves administration and compliance. A major obstacle of these polymer-protein conjugates is the chemical stability of the PEG preventing its metabolism and leading to side effects. Instead, we propose the PPEylation, that is, the conjugation of degradable poly(phosphoester)s (PPE) to proteins, in order to generate fully biodegradable polymer-protein conjugates. The structure of the PPEylated protein conjugates was verified with mass spectrometry and size exclusion chromatography. They were compared to structural analogues, except classical, PEGylated proteins, and exhibit comparable bioactivity, but avoiding any nondegradable polymer in the conjugate. We proved the degradation of the protective polymer shell surrounding the conjugate in aqueous environments at physiological conditions by online triple detection size exclusion chromatography and gel electrophoresis. We believe that this research will provide an attractive alternative for future drug design with implications for the clinical use of biologicals.

Molecular self‐assembly and morphology induction in high‐performance aromatic phosphonated block copolymers

“…[5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] In this regard block copolymers with an ability to phase separate due to their dissimilar chemical contents can resolve the issue of having a controlled morphology. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] In these materials, a strong repulsion between two unlike segments of block copolymer may usually result in microphase separation leading to columnar, lamellar, bicontinuous, and gyroid types of morphologies. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] In the bulk, the phase separation between different chemically immiscible blocks and the chemical bonds constraints govern the formation of ordered domains.…”

Insights on the Structure, Molecular Weight and Activity of an Antibacterial Protein–Polymer Hybrid

“…For example, upon attachment of neutral polymers, the host protein often shows enhanced stability in the biological environment . This is especially useful for protein delivery wherein the protein often experiences varied (and often harsh) biochemical environments . When placing a “smart” polymer close to the active site of a protein, it becomes possible to control protein function via controlling the polymer function .…”

“…[7][8][9][10] This is especially useful for protein delivery wherein the protein often experiences varied (and often harsh) biochemical environments. [11][12][13][14][15] When placing a" smart" polymer close to the actives ite of ap rotein, it becomes possible to control protein functionv ia controlling the polymer function. [16][17][18] On the other hand, introducing proteins into polymeric materials provides enhanced biocompatibility and biological functions.…”

Controllable Synthesis of Multiarm Star‐Shaped Copolymers Composed of Phosphoester Chains and Their Application on Drug Delivery

“…Results showed that PPEs can reduce protein adsorption and prevent nonspecific cellular uptake as well as PEG. To make up the defects of non‐biodegradable PEG, PPEs can be used as novel stealth polymers for efficient drug delivery . As a consequence, PPEs are one of the most promising polymers as biomimetic building blocks applied to the biomedical field …”

“…To make up the defects of non-biodegradable PEG, PPEs can be used as novel stealth polymers for efficient drug delivery. [30,31] As a consequence, PPEs are one of the most promising polymers as biomimetic building blocks applied to the biomedical field. [32][33][34][35][36][37][38] To combine the above advantages of dendrimers and PPEs for drug delivery system, in this work, we constructed a high-capacity and scalable nanocarrier based on a multiarm star-shaped copolymer, which consisted of dendritic poly(amido amine) (PAMAM) and biodegradable polyphosphoesters.…”