pH-sensitive polymer-drug conjugate: An approach to evaluate the effect of the linker on doxorubicin release.

Conventional chemotherapy with doxorubicin (Dox) is limited by poor selectivity and systemic toxicity. Polymeric micelles based on Pluronic F127 offer a versatile platform for drug delivery, but their stability and responsiveness to tumor-specific stimuli remain critical challenges. To address these issues, two pH-sensitive F127-Dox conjugates were synthesized using cis-aconitic (Cis) and succinic (Suc) linkers. The conjugates were structurally characterized by FTIR and 1H NMR, and their micellization behavior was studied via pyrene fluorescence. Dynamic light scattering was employed to analyze micelle size and pH responsiveness, while UV-Vis spectrophotometry was used to quantify drug loading (DL%) and encapsulation efficiency (EE%). Drug release kinetics were evaluated using the dialysis method at pH 7.4 and 5.5. Conjugation reduced the CMC of F127 from 112 μg/mL to 89 μg/mL (Cis-Dox) and 75 μg/mL (Suc-Dox), enhancing micellar stability. F127-Cis-Dox achieved higher drug loading (5.54%) and encapsulation efficiency (61.8%) compared to F127-Suc-Dox (3.42%, 37.0%) and physically loaded F127-Dox micelles (4.94%, 60.3%). In vitro release showed pronounced pH sensitivity: F127-Cis-Dox released 80.7% of Dox at pH 5.5, compared with 25.2% at pH 7.4, whereas F127-Suc-Dox released 65.0% versus 33.9%, respectively. By contrast, F127-Dox exhibited rapid, nonspecific release (∼85% at pH 7.4, 144 h). These results highlight the importance of linker chemistry in tuning micelle stability and drug release. F127-Cis-Dox, in particular, demonstrates superior pH-responsiveness and drug-loading capacity, making it a promising candidate for tumor-targeted doxorubicin delivery.