Release kinetics approach of stimuli-responsive mesoporous silica nanocarriers: pH-sensitive linker versus pH-sensitive framework

Silica-based stimuli-responsive nanomaterials have attracted significant attention in the field of drug delivery because they can achieve controlled release of anticancer drugs. For this, a gatekeeper is usually used, thus avoiding unwanted leakage at pH 7.4, while modulating the release under more acidic pH conditions in the tumor cell microenvironment. To optimize the efficiency of these nanostructures, it is crucial to study the release kinetics of anticancer drugs, predict their behavior, and modify the transport process mechanism. In the present study, we synthesized and characterized two types of pH-responsive mesoporous silica nanocarriers, which have transferrin conjugates on the surface serving as a gatekeeper. One nanocarrier was a conventional mesoporous silica nanoparticle (MSN) with transferrin attached through a pH-sensitive linker (MSN-Tf), while the other had a pH-sensitive diimine bridge in its framework, giving it degradable characteristic (dMSN-Tf). The use of conventional mathematical models and a three-parameter model that considers the drug-matrix interaction allowed the evaluation and elucidation of the different mechanisms involved in the kinetics of doxorubicin release from both materials at pH 7.4 and pH 5.0. The change in the kinetics of doxorubicin release from zero-order to first order when it is in a degradable system such as dMSN-Tf, can be very useful for rapid drug delivery in acidic media such as inside cancer cells. Cell viability experiments in lung cancer cell lines A549 and H1299, showed enhanced anticancer activity by the nanomaterial with the pH-sensitive framework compared to the material that has a pH-sensitive linker. Overall, these findings provide important insights for optimizing the delivery of anticancer drugs.