Antitumor activity of 5-fluorouracil polymeric nanogel synthesized by gamma radiation on a rat model of colon carcinoma: a proposed mechanism

Abstract

The use of 5-fluorouracil (5-FU) is associated with multifaceted challenges and poor pharmacokinetics. Accordingly, our study was designed to prepare 5-FU nanogel as a new form of the colon cancer chemotherapeutic drug 5-FU using polyacrylic acid and gelatin hybrid nanogel as efficient drug carriers. Alongside the in vivo chemotherapeutic evaluation, the anti-proliferative and anti-apoptotic efficacy were carried out for 5-FU nanogel against 1,2-dimethylhydrazine (DMH, 20 mg/kg) and γ-radiation (4 Gy)-prompted colon dysplasia in rats compared to 5-FU. The morphology and size of 5-FU nanogel were characterized by transmission electron microscopy (TEM) and dynamic light scattering (DLS) in addition to cytotoxicity assay. The expression of phosphoinositide-3-kinase (PI3K)/Akt, mammalian target of rapamycin (mTOR); Toll-like receptor2 (TLR2)/nuclear factor kappa B), adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream autophagy-related genes in addition to apoptotic markers were measured in colon tissues. Results: 5-FU nanogel reduced the levels of the TLR2/ NF-κβ as well as the expression of PI3K/AKT/mTOR. Moreover, it promoted autophagy through the activation of the AMPK and its downstream targets which consequently augmented the intrinsic and extrinsic apoptotic pathways. Conclusion: Collectively, these data might strengthen the therapeutic potential of 5-FU nanogel which can be used as an antitumor product for colon cancer.

Review of Prodrug and Nanodelivery Strategies to Improve the Treatment of Colorectal Cancer with Fluoropyrimidine Drugs

“…The extended release of 5-FU using a biodegradable nanogel was achieved by gamma irradiation of acrylic acid monomers and gelatin, and the resulting nanogel showed anticancer activity upon intra-peritoneal injection [ 89 ]. A micelle/hydrogel composite was developed by mixing 5-FU-loaded gelatin with hydrazide functionality (Gel-ADH) and a curcumin-loaded Pluronic F127-benzaldehyde (PF127-CHO) [ 90 ].…”

Towards Cancer Nanoradiopharmaceuticals—Radioisotope Nanocarrier System for Prostate Cancer Theranostics Based on Radiation-Synthesized Polymer Nanogels

“…An example of a radiation-derived nanostructure is a polymer nanogel-crosslinked polymer networks on the nanometer scale [31,32]. Their outstanding properties, such as biocompatibility, high water content, tailorable size, surface properties, and chemical reactivity, make them perfect candidates for drug delivery applications, and research interest in radiation-synthesized polymer nanogels is prominent [33][34][35]. Among many polymers that may be used to synthesize nanogels, poly(acrylic acid) (PAA) stands out as a particularly promising material.…”