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.
Background: Gastric cancer (GC) remains a major public health problem. Ursolic acid (UA) is reported to be effective in inhibiting GC; however, its low solubility and poor biocompatibility have greatly hindered its clinical application. Results: Herein, an innovative ROS-sensitive UA dimeric prodrug is developed by coupling two UA molecules via a ROS-cleavable linkage, which can self-assemble into stable nanoparticles in the presence of surfactant. This new UA-based delivery system comprises the following major components: Ⅰ) dimeric prodrug inner core that can achieve high drug-loading (55%, w/w) and undergo rapid and selective conversion into intact drug molecules in response to ROS; Ⅱ) a polyethylene glycol (PEG) shell to improve colloid stability and extend blood circulation, and Ⅲ) surface-modified iRGD to increase tumor targeting. Conclusion: Enhancement of the antitumor effect of this delivery system was demonstrated against GC tumors in vitro and in vivo. This novel approach offers the potential for clinical applications of UA.
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