Hematoporphyrin (HP)
and protoporphyrin IX (PPIX) are useful porphyrin
photosensitizers with significant application values in photodynamic
therapy. Currently, many strategies have been developed to improve
their clinical performance, such as incorporating them with nanoparticle
(NP) carriers. In this work, we studied the possibility of using β-lactoglobulin
(BLG) as a potential NP carrier due to their hydrophobic affinity,
pH sensitivity, and low cost of extraction and preservation. The interaction
mechanisms of BLG with HP and PPIX were investigated using spectroscopic
techniques and molecular docking methods. The molecular docking results
agree well with the experimental results, which demonstrate that the
formations of HP-BLG and PPIX-BLG complexes are endothermic processes
and the main acting force is hydrophobic force. Furthermore, the opening–closure
states of EF loop have a great influence on the HP-BLG complex formation,
where the central hydrophobic cavity of β-barrel is available
for HP binding at pH 7.4 but not available at pH 6.2. However, the
formation of the PPIX-BLG complex is less dependent on the states
of the EF loop, and the binding sites of PPIX are both located on
the external surface of BLG under both pH 7.4 and 6.2 conditions.
All of our results would provide new insight into the mechanisms of
noncovalent interactions between BLG and HP/PPIX. It is believed that
this work indicated the potential application values of BLG in designing
pH-sensitive carriers for the delivery of HP and PPIX, as well as
other poorly soluble drugs.