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Formulation and Delivery - Chemical

(T1530-08-51) Synthesis and Characterization of Biodegradable Polymer Backbone for the Development of Dual-Drug Polymer Conjugate for Pancreatic Cancer Treatment

Tuesday, November 11, 2025
3:30 PM - 4:30 PM CT
Purpose: Polymer-drug conjugates (PDCs) are macromolecular delivery systems with the cytotoxic agents covalently bound to the backbone via stimuli-sensitive linkers. In the design of polymer-drug conjugates, the choice of polymer backbone is essential.  Polymer backbones that are conformationally flexible with essential functional groups necessary for conjugation, biodegradable and can afford high drug loading efficiency are desired. This study aims to synthesize and characterize a linear and biodegradable polymer backbone suitable for the development of multi-drug polymer conjugate system.

Methods: An azide terminated peptide N3-PEG4-Lys-Gly-Phe-Leu-Gly-Lys-PEG2-NH2 was synthesized using by 9-fluorenyl-methoxycarbonyl solid phase peptide chemistry to obtain an intermediate for the polymer backbone. A bis-azido-terminated polymer backbone was synthesized by reacting the intermediate with ethylenediaminetetraacetic (EDTA) dianhydride. The synthesis of the polymer backbone EDTA-(azido-PEG4-KGFLGK-PEG2)2 and intermediate were confirmed using analytical HPLC, mass spectrometry and Fourier-transform infrared (FT-IR) spectroscopy. The cleavage of the synthesized polymer intermediate in the presence of exogenous cathepsin B was performed and analyzed by analytical HPLC. The stability of the conjugate in phosphate buffer saline at pH 7.4 was evaluated.

Results: The intermediate N3-PEG4-Lys-Gly-Phe-Leu-Gly-Lys-PEG2-NH2 and polymer backbone EDTA-(azido-PEG4-KGFLGK-PEG2)2 were successfully synthesized and characterized. The polymer backbone has two free carboxylic acid and protected amino groups for subsequent drug coupling. The terminal azide group is designed for end-to-end strain-promoted alkyne-azide cycloaddition-mediated polymerization. Mass spectrometry of the intermediate and polymer backbone showed m/z 1343.13 (m/z calculated: 1342.64) and m/z 2942.96 (m/z calculated: 2941.50), respectively. FT-IR spectroscopy showed the expected azide and carboxylic acid– O-H stretch at 2110.4 cm-1 and 3303 cm-1, respectively. The cleavage profile showed the requirement of cathepsin B for the specific cleavage of the backbone and confirmed the degradability. The lack of cleavage in the absence of cathepsin B and buffer at physiological pH confirmed the backbone’s stability.

Conclusion: A biodegradable polymer backbone was synthesized for the development of dual-drug polymer conjugate. This backbone offers flexibility, stability and high drug loading capacity. Two cytotoxic agents will be conjugated to the backbone and will be subjected to strain-promoted alkyne-azide cycloaddition click chemistry to obtain dual-drug polymer conjugate. The anticancer effect of the conjugate will be evaluated in pancreatic cancer cell lines.