Synthesis and Characterization of a Methoxypolyethylene Glycol-Modified Bortezomib Prodrug

To overcome the challenges of low water solubility, nonspecific biodistribution, limited tumor penetration, and easy inactivation of bortezomib (BTZ) under physiological conditions, we designed and synthesized a novel methoxypolyethylene glycol-modified bortezomib prodrug (mPEG2000-DEA-BTZ). This prodrug employs diethanolamine as a linker and mPEG2000 as the polymer chain, synthesized through a three-step reaction, with its chemical structure confirmed by 1H NMR. Solubility studies demonstrated that in PBS buffer at pH 7.4, the solubility of mPEG2000-DEA-BTZ was ≥436.0 mg/mL, corresponding to a bortezomib solubility of ≥66.7 mg/mL, over 167-fold higher than that of free BTZ (399 μg/mL). In vitro release experiments showed that only approximately 2% of BTZ was released from the prodrug within 24 h at pH 7.4, indicating excellent physiological stability. In contrast, drug release was significantly accelerated under acidic conditions (pH 6.5 and pH 5.0), with the cumulative release exceeding 90% at pH 5.0 within 4 h and approaching complete release at 24 h. Compared to the previously reported mPEG5000-CA-BTZ prodrug, the lower molecular weight mPEG2000 and diethanolamine linker employed in this study significantly improved the drug release rate and completeness. This pH-sensitive prodrug is expected to enhance the pharmacokinetic profile of bortezomib and achieve acidic tumor microenvironment-triggered targeted release, demonstrating significant potential for clinical translation.