Polymeric Micelles Encapsulating Fisetin Improve the Therapeutic Effect in Colon Cancer

Abstract

The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) was discovered to possess antitumor activity, revealing its potential value in future chemotherapy. However, its poor water solubility makes it difficult for intravenous administration. In this study, the monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) copolymer was applied to prepare nanoassemblies of fisetin by a self-assembly procedure. The prepared fisetin micelles gained a mean particle size of 22 ± 3 nm, polydisperse index of 0.163 ± 0.032, drug loading of 9.88 ± 0.14%, and encapsulation efficiency of 98.53 ± 0.02%. Compared with free fisetin, fisetin micelles demonstrated a sustained and prolonged in vitro release behavior, as well as enhanced cytotoxicity, cellular uptake, and fisetin-induced apoptosis in CT26 cells. As for in vivo studies, fisetin micelles were more competent for suppressing tumor growth and prolonging survival time than free fisetin in the subcutaneous CT26 tumor model. Furthermore, histological analysis, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, immunohistochemical detection of Ki-67, and microvessel density detection were conducted, demonstrating that fisetin micelles gained increased tumor apoptosis induction, proliferation suppression, and antiangiogenesis activities. In conclusion, we have successfully produced a MPEG-PCL-based nanocarrier encapsulating fisetin with enhanced antitumor activity.

Polymeric nanoparticles for colon cancer therapy: overview and perspectives

“…The results of in vivo studies also revealed significantly induced tumor growth and an increased survival time in the CT26 tumor model. 79 ShinYu Lee et al utilized cationic PDMA-block-poly(e-caprolactone) (PDMA-b-PCL) micelles to load SN-38, ultra-small super paramagnetic iron oxide (USPIO) nanoparticles and small interference RNA to form a multifunctional micellar drug delivery system. The results revealed that the SN-38/USPIO-loaded siRNA-PEG mixed micelles can passively target tumor areas, suppress the action of VEGF while simultaneously supplying a chemotherapeutic, hence significantly reducing the tumor growth via a multi-dose therapy.…”

Exploring the molecular targets of dietary flavonoid fisetin in cancer

“…Recently, fisetin was shown to inhibit growth and proliferation of human melanoma cells both in vitro and in vivo in combination with the BRAF inhibitor sorafenib [33]. Fisetin has also shown strong negative impact on the growth and proliferation of diverse cancer cell types including breast [34–36] cervical [37,38] and colon [39–43]. …”

The Natural Flavonoid Fisetin Inhibits Cellular Proliferation of Hepatic, Colorectal, and Pancreatic Cancer Cells through Modulation of Multiple Signaling Pathways

“…Previously, fisetin has shown anti-proliferative, anticancer, neuroprotective, and antioxidant activities [10–12]. In recent years, Fisetin has been reported to inhibit cell proliferation, migration and invasion, and induce apoptosis in several cancer types, such as colon cancer [13], glioma cancer [14], lung cancer [15], nasopharyngeal carcinoma [16], prostate cancer [17], and bladder cancer [18] and cervical carcinoma[19]. It also inhibits micro-ophthalmia associated transcription factor (MITF) in melanoma cells and inhibits invasion of melanoma cells via modulation of the MAPK and NF-κB pathways [20–22].…”