Enhanced photo/chemo combination efficiency against bladder tumor by encapsulation of DOX and ZnPC into in situ-formed thermosensitive polymer hydrogel

Abstract

BackgroundChemotherapy after transurethral resection is commonly recommended for bladder cancer. However, studies have shown that chemotherapy solely can hardly decrease progression rates of bladder cancer. The combination of chemotherapeutic agents with photo-dynamic therapy (PDT), a new promising localized therapy, may become a workable strategy for combating bladder cancer. This study reports the combination of doxorubicin (DOX)-based chemotherapy and zinc phthalocyanine (ZnPC)-based PDT using in situ-formed thermal-responsive copolymer hydrogel.Materials and methodsThe copolymer was synthesized by polymerization of 3-caprolactone, 1,4,8-trioxa[4.6]spiro-9-undecanone and poly(ethylene glycol) and was abbreviated as PCL-PTSUO-PEG. The thermal-responsive nanoparticles (TNPs) were prepared by the nanoprecipitation technology. The thermal-responsive hydrogel was formed after 37°C heating of TNP solution. The size, morphology and dynamic viscosity of hydrogel were detected. The in vitro drug release profile of TNP/DOX/ZnPC was performed. Cell uptake, cell inhibition and ROS generation of TNP/DOX/ZnPC were studied in 5637 cells. The in vivo antitumor activity of TNP/DOX/ZnPC was evaluated in nude mice bearing 5637 cells xenograft.ResultsTNP/DOX and TNP/ZnPC had an average diameter of 102 and 108 nm, respectively. After being heated at 37°C for 5 minutes, TNP/DOX and TNP/ZnPC solution turned uniform light red and dark green hydrogel. ZnPC encapsulation designed by TNP could significantly improve its aqueous solubility to 1.9 mg/mL. Cell inhibition showed that the best cell inhibition was found, with cell viability of 18.5%, when the weight ratio of DOX and ZnPC encapsulated in the TNP reached about 1:5. TNP/DOX/ZnPC generated relative high level of ROS with 4.8-fold of free ZnPC and 1.6-fold of TNP/ZnPC. TNP/DOX/ZnPC showed only 8-fold of relative tumor growth without obvious toxicity to the mice.ConclusionThermosensitive thermal-responsive hydrogel reported in this contribution are promising in situ-formed matrix for DOX- and ZnPC-based photo/chemo combination treatment for bladder cancer therapy.

Zinc(II) phthalocyanines as photosensitizers for antitumor photodynamic therapy

“…Thus, PDT coupled with chemotherapy agents has proven to be a promising combination treatment for some kinds of tumors (Brodin et al, 2015). The encapsulation of ZnPc and doxorubicin (DOX) into nanovehicles linked to folic acid achieved a synergistic chemotherapy-PDT in tumor cells overexpressing folic acid receptors (Liang et al, 2015;Flak et al, 2017;Huang et al, 2018). ZnPc and DOX were also conjugated through acid-labile and redox-responsive disulfide linkers in polymeric micelles.…”

Stimuli-Responsive Hydrogels for Local Post-Surgical Drug Delivery

“…The other in situ thermo-gelation system was achieved through the co-polymerization of 3-caprolactone,1,4,8-trioxa [4.6] spiro-9-undecanone and poly (ethylene glycol), through which chemotherapeutic drug-loaded nanoparticles were assembled and formed a hydrogel at 37 • C ( Figure 4A). As depicted in Figure 4B, this hydrogel was an effective drug carrier for the ablation of bladder tumors in mice models so that relatively high levels of reactive oxygen species (ROS) (a 4.8-fold increase) were generated, in comparison to free drug [77].…”

“…Doxorubicin and zinc phthalocyanine loaded TNP polymer solution is transformed to gel state after injecting, to be used for localized photodynamic therapy. Adapted with permission from Huang et al[77]; (B) relative tumor volume of the mice model in different treatment conditions showing the significance of concurrent localized chemo/PDT therapy. Adapted with permission from Huang et al[77].…”

“…Adapted with permission from Huang et al[77]; (B) relative tumor volume of the mice model in different treatment conditions showing the significance of concurrent localized chemo/PDT therapy. Adapted with permission from Huang et al[77]. (C) Thermal fluctuations and corresponding on/off switch release of drug from thermo-responsive PIPAAm-PBMA micelles through the low critical solution temperature (LCST).…”

One-Step Microfluidic Fabrication of Multi-Responsive Liposomes for Targeted Delivery of Doxorubicin Synergism with Photothermal Effect

“…As such, there are still several critical challenges that need to be addressed to improve the targeting effect and drug concentration in intravesical treatment. 5,6,[9][10][11] Nanocarrier-based chemotherapy has been extensively applied to improve traditional cancer chemotherapy strategies. [12][13][14] However, due to the lack of specific targeting, there are difficulties in accumulating enough chemotherapy agents at the tumor site.…”