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Synergistic Effect of Retinoic Acid Polymeric Micelles and Prodrug for the Pharmacodynamic Evaluation of Tumor Suppression.

ABSTRACT: All-trans retinoic acid (ATRA) is an effective agent that induces differentiation, inhibits cell proliferation, and acts as an anticancer agent. ATRA was successfully conjugated with Pluronic F127 via esterification to enhance its anticancer effects. Pluronic-ATRA showed high cytotoxicity and inhibitory concentrations (IC50) 50% lower than those of ATRA in various breast cancer cell lines (4T1:31.16-8.57 ?g/mL; EMT6: 50.48-7.08 ?g/mL; MDA-MB-231:37.58-8.99 ?g/mL; BT474:25.27-9.09 ?g/mL). In combination with chemotherapy, Pluronic-ATRA synergistically enhanced the cytotoxic effects of cisplatin (CDDP). Pluronic-ATRA combined with CDDP effectively suppressed breast tumor growth in vivo. The results of this study demonstrate the potential of Pluronic-ATRA as an anticancer agent that can be used in combination therapy against solid tumors.

SUBMITTER: Zhu YH

PROVIDER: S-EPMC6531846 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Synergistic Effect of Retinoic Acid Polymeric Micelles and Prodrug for the Pharmacodynamic Evaluation of Tumor Suppression.

Zhu Yan-Hua YH Ye Ning N Tang Xin-Feng XF Khan Malik Ihsanullah MI Liu Hong-Liang HL Shi Ning N Hang Li-Feng LF

Frontiers in pharmacology 20190516

All-trans retinoic acid (ATRA) is an effective agent that induces differentiation, inhibits cell proliferation, and acts as an anticancer agent. ATRA was successfully conjugated with Pluronic F127 via esterification to enhance its anticancer effects. Pluronic-ATRA showed high cytotoxicity and inhibitory concentrations (IC<sub>50</sub>) 50% lower than those of ATRA in various breast cancer cell lines (4T1:31.16-8.57 μg/mL; EMT6: 50.48-7.08 μg/mL; MDA-MB-231:37.58-8.99 μg/mL; BT474:25.27-9.09 μg/m ...[more]

PMID: 31156425

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Project description:Background The prognosis of patients with advanced gastric cancer (GC) remains unsatisfactory owing to distant metastasis and resistance to concurrent systemic therapy. Cancer-associated fibroblasts (CAFs), as essential participators in the tumor microenvironment (TME), play a vital role in tumor progression. Thus, CAFs-targeting therapy is appealing for remodeling TME and sensitizing GC to conventional systemic therapy. Methods Amphiphilic SN38 prodrug polymeric micelles (PSN38) and encapsulated the hydrophobic esterase-responsive prodrug of Triptolide (TPL), triptolide-naphthalene sulfonamide (TPL-nsa), were synthesized to form PSN38@TPL-nsa nanoparticles. Then, CAFs were isolated from fresh GC tissues and immortalized. TPL at low dose concentration was used to investigate its effect on CAFs and CAFs-induced GC cells proliferation and migration. The synergistic mechanism and antitumor efficiency of SN38 and TPL co-delivery nanoparticle were investigated both in vitro and in vivo. Results Fibroblast activation protein (FAP), a marker of CAFs, was highly expressed in GC tissues and indicated poorer prognosis. TPL significantly reduced CAFs activity and inhibited CAFs-induced proliferation, migration and chemotherapy resistance of GC cells. In addition, TPL sensitized GC cells to SN38 treatment through attenuated NF-κB activation in both CAFs and GC cells. PSN38@TPL-nsa treatment reduced the expression of collagen, FAP, and α-smooth muscle actin (α-SMA) in tumors. Potent inhibition of primary tumor growth and vigorous anti-metastasis effect were observed after systemic administration of PSN38@TPL-nsa to CAFs-rich peritoneal disseminated tumor and patient-derived xenograft (PDX) model of GC. Conclusion TPL suppressed CAFs activity and CAFs-induced cell proliferation, migration and chemotherapy resistance to SN38 of GC. CAFs-targeted TPL and SN38 co-delivery nanoparticles exhibited potent efficacy of antitumor and reshaping TME, which was a promising strategy to treat advanced GC. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01127-5.

Project description:Oleanolic acid has been used only as a subsidiary agent in cosmetic products. The aim of the study is to show the effect of oleanolic acid as an active ingredient for the alleviation of wrinkles in humans and to develop a polymeric micelle formulation that enables poorly soluble oleanolic acid to be used as a main ingredient in cosmetic products for reducing wrinkles. The solubility of oleanolic acid was evaluated in solubilizers, surfactants, and polymers. The particle sizes and shapes of polymeric micelles containing oleanolic acid were evaluated by electrophoretic light scattering spectrophotometer and scanning electron cryomicroscopy. Encapsulation efficiency and skin permeation were measured by HPLC. Stability of the polymeric micelles stored at 40?°C for 3?months was evaluated by visual observation, particle size measurement, and oleanolic acid content measurement. Polymeric micelles in final product ampoule form were applied around the eyes of 23 female subjects for 8?weeks. Five skin parameters were evaluated by optical profilometry every 4?weeks for 8?weeks. In addition, professionals made visual observations of the skin and a human skin irritation study was conducted. Polymeric micelles of oleanolic acid with a particle size of less than 100?nm were prepared using Capryol 90® and poloxamer. The skin permeation rate of the oleanolic acid in the polymeric micelles was higher than that in the other solutions made of oleanolic acid dispersed in 2 different surfactants. No significant changes in particle size, color, or oleanolic acid content were observed, and the polymeric micelles stored at 40?°C for 3?months did not undergo phase separation. After 8?weeks of application, skin irritation had not developed and all five parameters evaluated by optical profilometry as well as the visual evaluation scores were significantly improved. This study showed that the polymeric micelles of oleanolic acid prepared in this study were stable and effective at alleviating wrinkles in humans as the principal active ingredient. Based on these findings, it is expected that polymeric micelles of oleanolic acid can be widely used in cosmetic applications.

Dataset Information

Synergistic Effect of Retinoic Acid Polymeric Micelles and Prodrug for the Pharmacodynamic Evaluation of Tumor Suppression.

Publications

Synergistic Effect of Retinoic Acid Polymeric Micelles and Prodrug for the Pharmacodynamic Evaluation of Tumor Suppression.

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