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

Objective: We aim to develop a polymer library consisting of phenylalanine-based poly(ester amide)s (Phe-PEAs) for cancer therapy and investigate the structure–property relationship of these polymers to understand their impact on the drug delivery efficiency of corresponding nanoparticles (NPs). Impact Statement: Our study provides insights into the structure–property relationship of polymers in NP-based drug delivery applications and offers a potential polymer library and NP platform for enhancing cancer therapy. Introduction: Polymer NP-based drug delivery systems have demonstrated substantial potential in cancer therapy by improving drug efficacy and minimizing systemic toxicity. However, successful design and optimization of these systems require a comprehensive understanding of the relationship between polymer structure and physicochemical properties, which directly influence the drug delivery efficiency of the corresponding NPs. Methods: A series of Phe-PEAs with tunable structures was synthesized by varying the length of the methylene group in the diol part of the polymers. Subsequently, Phe-PEAs were formulated into NPs for doxorubicin (DOX) delivery in prostate cancer therapy. Results: Small adjustments in polymer structure induced the changes in the hydrophobicity and thermal properties of the PEAs, consequently NP size, drug loading capacity, cellular uptake efficacy, and cytotoxicity. Additionally, DOX-loaded Phe-PEA NPs demonstrated enhanced tumor suppression and reduced side effects in prostate tumor-bearing mice. Conclusion: Phe-PEAs, with their finely tunable structures, show great promise as effective and customizable nanocarriers for cancer therapy.