pH/Thermal Dual-Sensitive Nanoparticle-Hydrogel Composite Based on Pluronic and Carboxymethyl Chitosan for In Situ Injection and Enhanced Chemo-Photothermal Antitumor Effect

The purpose of this paper is to develop a pH/thermal sensitive nanohydrogel composite for in situ injection and to achieve an enhanced chemo-photothermal synergistic antitumor effect. Pluronic F127 was oxidized to aldehyde-terminated (AF127) as the precursor of the thermally sensitive hydrogel. A series of hydrogels (HG) with different rheological behaviors were obtained by adjusting the ratio of AF127 to carboxymethyl chitosan (CMCS) (AF45/CM15, AF75/CM15, and AF90/CM15). By changing the ratio of AF127 micelles to CMCS, we can adjust the sol–gel transition time and temperature to facilitate in situ tumor injection. Indocyanine green (ICG) encapsulated AF127 micelles and doxorubicin (DOX)-loaded CMCS nanoparticles (NP-DOX) can form nanohydrogel composite (HG/ICG/NP-DOX) through dynamic Schiff base covalent bonds and physical entanglement. The nanohydrogel composite has good fluidity for injection at low temperatures and can quickly form hydrogel at 37 °C. Bromelain was introduced into the complex to improve the penetration of nanoparticles by hydrolyzing the dense extracellular matrix (ECM) in tumor tissue. ICG can produce a photothermal effect under 808 nm laser irradiation, further enhancing the antitumor effect of NP-DOX. HG/ICG/NP-DOX can remain in the tumor area for a long time, and it still shows an obvious photothermal effect even after 120 h. HG/ICG/NP-DOX with laser irradiation possesses an excellent chemo-photothermal synergistic antitumor effect, and the tumor growth inhibition rate reached 93.9%. These nanohydrogel composites have great potential in the field of in situ tumor injection as local drug delivery systems.