Self-Assembling Monomeric Nucleoside Molecular Nanoparticles Loaded with 5-FU Enhancing Therapeutic Efficacy against Oral Cancer

Abstract

Conventional oligonucleotide based drug delivery systems suffer from lengthy synthetic protocols, high cost, and poor chemical or enzymatic stability under certain circumstances. Canonical free individual nucleosides cannot form stable nanostructures in aqueous solution as drug vehicles. Here, we report the development of a monomeric self-assembled nucleoside nanoparticle (SNNP) into an efficient drug delivery system which has currently no parallel in such field. This was achieved using a l-configurational pyrimido[4,5-d]pyrimidine nucleoside building block that can form robust discrete nanoparticles in just one step with water as the sole solvent. Its high biocompatibility and low toxicity was demonstrated in vitro and in vivo. In mouse xenograft model of oral squamous cell carcinoma (OSCC), SNNP loaded with 5-fluoro-uracile (5-FU-SNNP) remarkably retarded the tumor growth compared with free 5-FU, albeit SNNP alone showed no antitumor effect. The stability in blood circulation and the effective concentration of 5-FU in tumor tissue were increased upon the loading with SNNP. TUNEL and immunohistochemistry analyses further indicated that the superior in vivo antitumor efficacy of 5-FU-SNNP compared to free 5-FU was associated with an enhanced degree of inhibition of cell proliferation and stimulation of cell apoptosis. Furthermore, SNNP alleviated the toxic side effects of 5-FU. These findings suggested that when loaded with SNNP, 5-FU has better antitumor efficacy and lower side effects, indicating that SNNP can efficiently act as a readily accessible, robust, biocompatible and low-toxic nanobiomaterial which may find wide therapeutic applications clinically in the future.

Biogenic (R)‐(+)‐Lipoic Acid Only Constructed Cross‐Linked Vesicles with Synergistic Anticancer Potency

“…Hemagglutination Assay : The hemagglutination test was also used to evaluate the blood compatibility. In brief, 950 µL of cLAVs solution at concentrations of 30.0, 20.0, 10.0, 5.0, and 1.0 mg mL −1 was added to 50 µL of 2% (v/v) RBC suspension in 24‐well plates, respectively, and incubated for 2 h at room temperature allowing hemagglutination to occur.…”

“…Acute Toxicity Test : The acute toxicity test was used to evaluate in vivo biocompatibility/biosafety. In this study, physiological state of mice, complete blood count (CBC), serum biochemical analysis and histopathological study were used to evaluate the acute toxicity of cLAVs.…”

Nanomedicine, an emerging therapeutic strategy for oral cancer therapy

“…Zhao et al [49] synthesized 5FU-monomeric self-assembled nucleoside NPs (5-FU-SNNP) and evaluated their anti-tumor effect in vitro and in vivo. In the in vitro study, normal human oral cells were also used as controls.…”

Polymeric drug delivery systems for intraoral site‐specific chemoprevention of oral cancer

“…The chemoprevention of oral cancer using nanosized drug delivery systems has received considerable attention in recent decades. The feasibility and efficacy of different types of nanosized delivery systems (see below) have been evaluated for the delivery of cytotoxic drugs against oral cancer . The key characteristics (e.g., polymers used, drugs encapsulated, drug loading capacity/efficiency, and size) of different nanosized carriers are provided in Table .…”

“…Nanoparticles based on numerous polymers have been demonstrated for the delivery of chemopreventive agents. Different techniques, such as nanoprecipitation, emulsification, diafiltration/dialysis, ionotropic gelation, and self‐assembly, are available for the preparation of nanoparticles . The procedures involved in the preparation of nanoparticles by these methods are provided in Supporting Information, Table SIV.…”