Development of a Lysine-Based Poly(ester amide) Library with High Biosafety and a Finely Tunable Structure for Spatiotemporal-Controlled Protein Delivery

Abstract

With the fast growth of protein therapeutics, efficient, precise, and universal delivery platforms are highly required. However, very few reports have discussed the progress of precisely spatiotemporal-controlled protein delivery. Therefore, a mini library of well-designed amino acid-based poly(ester amide)s derived from lysine (Lys-aaPEAs) has been developed. Lys-aaPEAs can interact with and encapsulate proteins into nanocomplexes via electrostatic interactions. The chemical structure of Lys-aaPEAs can be finely tuned by changing the type and molar ratio of the monomers. Studies of structure–function relationships reveal that the carbon chain length of diacid/diol segments, hydrophilicity, and electrical properties affect the polymer–protein interaction, cell–material interaction, and, therefore, the outcome of protein delivery. By modulating the structures of Lys-aaPEAs, the delivery systems could present customized physiochemical and biological properties and perform time- and space-specific protein release and delivery without causing any systematic toxicity. The screened systems exhibited prolonged hypoglycemic activity and superior biosafety in vivo, using insulin as a model protein and a mouse model bearing type 1 diabetes mellitus (T1DM). This work establishes a novel lysine-based polymer platform for spatiotemporal-controlled protein delivery and offers a paradigm of precise structure–function controllability for designing the next generation of polymers.

Sorafenib Encapsulated Poly(ester amide) Nanoparticles for Efficient and Biosafe Prostate Cancer Therapy

“…26,27 Among them, polyesters with ester bond linkages have been discovered to possess remarkable flexibility, exceptional elasticity, and excellent biodegradability. 28 Polyamides exhibit exceptional thermal resistance and mechanical strength. 29 By combining them, poly(ester amide) polymers based on amino acids have the potential to serve as nanocarriers for drug delivery due to their high biosafety and biodegradability.…”

Recent advances in the development of poly(ester amide)s-based carriers for drug delivery

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Fig. 2 Solution polycondensation for AA-PEA synthesis (reproduced with permission from Han and Wu, 2022 ).

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Impact of Poly(Ester Amide) Structure on Properties and Drug Delivery for Prostate Cancer Therapy

“…By adjusting the types and ratios of these monomers, the physicochemical properties of PEAs can be finely regulated. Specifically, the choice of amino acid monomers can affect the overall hydrophilicity/hydrophobicity and electrical properties of the resulting PEAs, while the types of diacid and diol monomers can alter the molecular weight and thermodynamic properties, and collectively influence the interactions between the polymers and drugs, as well as the interactions between the materials and cells, ultimately affecting the overall performance of PEAs as drug delivery systems [ 31 – 34 ]. Therefore, the ability to tailor the physicochemical properties of PEAs by modifying the monomer structure enables the development of highly customized polymers that can meet specific therapeutic needs, such as drug delivery systems for prostate cancer therapy.…”