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 ?. 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.

Abstract Purpose To analyze the clinical efficacy of total laparoscopic π-shaped esophageal jejunostomy and laparoscopic assisted Roux en-Y esophago-jejunostomy for cardiac cancer and their effects on traumatic stress. Methods We collected clinical data from 72 patients with adenocarcinoma of the esophagogastric junction who were treated in our department between June 2020 and July 2022. All patients underwent laparoscopic total gastrectomy + D2 lymphadenectomy, in whom 38 patients underwent total laparoscopic total gastrectomy with π-shaped esophageal jejunostomy and 34 patients underwent laparoscopic-assisted total gastrectomy with Roux en-Y esophago-jejunostomy. The short-term therapeutic effects, safety and effects on stress response indicators of different surgical methods were analyzed. Results There were no significant differences in baseline clinical and pathological data between the two groups (P > 0.05). The mean operation duration was 201.7 ± 80.3 minutes in the total endoscopic π-shaped esophageal jejunostomy group, which was longer than 166.9 ± 26.9 minutes in the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P < 0.05). The length of the surgical incision in the total endoscopic π-shaped esophageal jejunostomy group was significantly shorter, measuring 4.6 ± 2.1 cm, compared to the Roux-en-Y anastomosis group, which had an average length of 10.4 ± 2.1 cm (P < 0.01). In terms of intraoperative bleeding, the intraoperative bleeding volume of 130.3 ± 50.3 ml in the total endoscopic π-shaped esophageal jejunostomy group was significantly lower than that of 167.2 ± 72.8 ml in the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P < 0.05). Postoperative recovery time to exhaust was 3.8 ± 1.2 days in total endoscopic π-shaped esophageal jejunostomy group, significantly lower than 5.0 ± 2.0 days in laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P = 0.003). In terms of postoperative extubation time, postoperative hospital stay, postoperative complications and the number of dissected lymph nodes, there were no significant differences between the total endoscopic π-shaped esophageal jejunostomy group and the laparoscopic-assisted Roux en-Y esophago-jejunostomy group (P > 0.05). In terms of stress indicators, there were no significant differences in stress indicators between the two groups before surgery, and the serum levels of CRP, cortisol (COR) and IL-6 in the π anastomosis group were significantly lower than those in the Roux en-Y esophago-jejunostomy group on postoperative days 3 and 5 (P < 0.05). Conclusion Total laparoscopic total gastrectomy with π-shaped esophageal jejunostomy demonstrates safety and feasibility. This surgical approach effectively reduces intraoperative bleeding, accelerates patient recovery time, minimizes postoperative pain, lowers the risk of complications, and minimally impacts the body's traumatic stress response.

Dynamic carrier-free theranostic nanodrugs are in great demand, owing to their extraordinary high drug loading, enhanced targeting therapy, and panoramic tracking of the drug behaviors. Herein, this work highlights a successful development of pH-triggered dynamic carrier-free nanodrugs for precise tumoral targeting theragnostic, which are established through self-assembly between dasatinib (DAS) and chlorambucil (CLB). The study has proved the structure, change in particle size and zeta potential, fluorescence transition, cellular uptake, cytotoxicity as well as biosafety of the carrier-free nanodrugs. The nanodrugs are characterized by Fourier transform infrared spectroscopy, 1H nuclear magnetic resonance, X-ray diffraction, Dynamic light scattering, and Microplate reader. Cellular uptake and cytotoxicity assay are conducted for free drugs and their nanodrugs using tumor cell lines including A549, HepG2, K562, and THP1. ICR mice are applied to evaluate the biosafety of nanodrugs. The introduction of CLB into DAS nanoparticles can successfully redshift the emission wavelength from 420 to 810 nm. Moreover, the nanodrugs exhibit a dynamic fluorescence intensity conversion via tumoral intracellular gradual quenching of Aggregation-induced emission (AIE). This characteristic is beneficial to the precise monitoring of tumoral intracellular drug behaviors. Furthermore, the nanodrugs show a small-to-large size transition from 175 nm to more than 500 nm in 12 h and surficial charge reversal from −2.3 mV to more than 0.2 mV by protonation at tumoral pHs. These superior properties facilitate the improved cellular uptake and synergistic cytotoxicity on various types of tumor cells. The study shows that nanodrugs made of DAS and CLB that can self-assemble without carriers under different pH levels may be ready for testing in tumor targeting, and might someday be helpful for diagnosis and treatment in the future.

BackgroundThis study aims to investigate the effects of ω-3, ω-6 polyunsaturated fatty acids (PUFAs), and their middle metabolites prostaglandin (PGE)2 and PGE3 on proliferation, invasion, and angiogenesis formation of gastric cancer cells and to explore associated mechanism.MethodsRT-PCR and ELISA were used to detect the expression of cyclooxygenase (COX)-1 and COX-2 in gastric cancer cell lines. The effect of ω-3, ω-6, PGE2, and PGE3 on the proliferation, invasion, and angiogenesis of gastric cancer cells were measured by cell proliferation, invasion, and angiogenesis assay in vitro. COX-2 small interfering RNA (siRNA) was transfected into gastric cancer cells, and the expression of COX-2 protein was detected by Western blot. COX-2 gene silencing influencing proliferation, invasion, and angiogenesis potential of gastric cancer cells was detected by WST-1, transwell chamber, and angiogenesis assay, respectively.ResultsCOX-2 was only expressed in MKN74 and MKN45 cells. In gastric cancer cell lines with positive COX-2 expression, ω-6 and PGE2 could significantly enhance the proliferation, invasion, and angiogenesis of gastric cancer cells, and after transfection with COX-2 siRNA, the effects of ω-6 and PGE2 on enhancing the proliferation, invasion, and angiogenesis of gastric cancer cells were significantly attenuated; ω-3 and PEG3 could inhibit the proliferation, invasion, and angiogenesis of gastric cancer cells. In gastric cancer cell lines with negative COX-2 expression, ω-6 and PGE2 had no significant effect on the proliferation, invasion, and angiogenesis of gastric cancer; ω-3 and PGE3 could significantly inhibit the proliferation, invasion, and angiogenesis of gastric cancer.Conclusionω-6 PUFAs reinforce the metastatic potential of gastric cancer cells via COX-2/PGE2; ω-3 PUFAs inhibit the metastatic potential of gastric cancer via COX-1/PGE3 signaling axis.