This paper focuses on the synthesis and characterization of new bivalent folate-targeted PEGylated doxorubicin (FA2-dPEG-DOX2) made by modular chemo-enzymatic processes using Candida antarctica lipase B (CALB) as biocatalyst. Unique features are the use of monodisperse PEG (dPEG) and the synthesis of FA-SH yielding exclusive γ-conjugation of folic acid (FA). In comparison, conjugates in the literature use the activated ester method to attach FA to polymers that gives a mixture of products that need to be purified to separate the biologically active γ-conjugate. The synthetic strategies are shown in Figure 1. DOX fluoresces in the red so it has dual properties as both a diagnostic and therapeutic agent. It does not interfere with live tissue fluorescence. The modular approach with enzyme catalysis leads to selectivity, full conversion and high yield, and no transition metal catalyst residues. Flow cytometry analysis showed that at 10 µM concentration, both free DOX and FA2-dPEG-DOX2 would be taken up by 99.9% of triple-negative breast cancer cells in 2 h. Fluorescence was detected for 5 days after injecting compound IV into mice. Preliminary results showed that intra-tumoral injection seemed to delay tumor growth more than intravenous delivery.

Synthesis and characterization of folate-targeted monodisperse PEG-based conjugates made by chemo-enzymatic methods for cancer diagnosis and treatment

ACS Spring 2022

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