RESUMEN
Cancer-associated fibroblasts (CAFs) are the majority cell population of tumor stroma, and they not only play important roles in tumor growth and metastasis, but they also form a protective physical barrier for cancer cells. Herein, we designed a fibroblast activation protein-α (FAP-α)-adaptive polymeric micelle based on hyaluronic acid and curcumin conjugates. The polymeric micelle is composed of a CD44-targeting shell and a FAP-α-cleavable polyethylene glycol (PEG) coating. When FAP-α is encountered on the surface of CAFs in the tumor microenvironment, the PEG layer is released, hyaluronic acid is recovered on the surface of nanoparticles, and the nanoparticles effectively inhibit the growth of tumor cells and CAFs through CD44-mediated endocytosis. The FAP-α-adaptive polymeric micelle exhibited potent anti-cancer efficacy by enhancing CAF apoptosis and reducing collagen in tumor tissues. Collectively, FAP-α-adaptive nanoparticles may be a promising method for antitumor anticancer treatments via reprogramming of stroma fibrosis.
Asunto(s)
Antineoplásicos , Micelas , Antineoplásicos/farmacología , Línea Celular Tumoral , Endopeptidasas , Fibroblastos , Fibrosis , Gelatinasas , Humanos , Proteínas de la Membrana , Serina EndopeptidasasRESUMEN
During the process of cancer metastasis, various enzymes, cytokines, and factors were involved, and upregulated cyclooxygenase-2(COX-2) in tumor cells led to proliferation and invasion of various tumors. Many nonsteroidal anti-inflammatory drugs (NSAIDs) were used as an anticancer adjuvant in chemotherapy, such as ibuprofen (BF) and celecoxib. NSAIDs could effectively inhibit local inflammation and decreased COX-2 expression. However, most of them have serious toxicity issues due to their limit selectivity against cancer and poor water solubility. Thus hyaluronic acid-ibuprofen (HA-ss-BF), which was sensitive to the reducing environment, was prepared by binding ibuprofen (BF) to the hyaluronic acid backbone through a disulfide bond, and the HA-ss-BF polymer could self-assemble into micelles and serve as carriers to delivery doxorubicin. These redox-sensitive prodrug polymeric micelles hold multiple therapeutic advantages, including on-demand BF release and disassembling micelles responding to redox stimuli, as well as desirable cellular uptake and favorable biodistribution. These advantages indicated the redox-responsive hyaluronic acid-ibuprofen prodrug could be a promising delivery system for metastatic breast cancer treatment.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Ácido Hialurónico/química , Ibuprofeno/química , Micelas , Profármacos/química , Animales , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Disulfuros/química , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Células 3T3 NIH , Oxidación-Reducción , Carga Tumoral/efectos de los fármacosRESUMEN
PEG coating was regarded as one effective method to improve the tumor-targeting efficiency of hyaluronic acid-based nanoparticles (HBN). However, the research of interaction between PEG coating and different receptors such as stabilin-2 and CD44 was limited. Herein, we synthesized a series of PEGylated hyaluronic acid with Curcumin (PHCs) to evaluate the role of PEG coating density in the interaction between HA and its receptors, which influenced tissues targeting activity, pharmacokinetic profiles and therapeutic efficacy of HBN. Compared with other counterparts, PHC HBN with about 5% PEG coating density preferably accumulated in the tumor mass, rather than in the liver, and hold desirable anti-cancer effect. These results indicated that to obtain optimized anticancer effect of HBN, the cellular uptake efficiency between different types of the cells should be carefully balanced by different PEG densities.
