Biodegradable Thermosensitive Hydrogel for SAHA and DDP Delivery: Therapeutic Effects on Oral Squamous Cell Carcinoma Xenografts

Background: OSCC is one of the most common malignancies and numerous clinical agents currently applied in combinative chemotherapy. Here we reported a novel therapeutic strategy, SAHA and DDP-loaded PECE (SAHA-DDP/PECE), can improve the therapeutic effects of intratumorally chemotherapy on OSCC cell xenografts. Objective/Purpose: The objective of this study was to evaluate the therapeutic efficacy of the SAHA-DDP/PECE in situ controlled drug delivery system on OSCC cell xenografts. Methods: A biodegradable and thermosensitive hydrogel was successfully developed to load SAHA and DDP. Tumorbeared mice were intratumorally administered with SAHA-DDP/PECE at 50 mg/kg (SAHA) +2 mg/kg (DDP) in 100 ul PECE hydrogel every two weeks, SAHA-DDP at 50 mg/kg(SAHA) +2 mg/kg(DDP) in NS, 2 mg/kg DDP solution, 50 mg/kg SAHA solution, equal volume of PECE hydrogel, or equal volume of NS on the same schedule, respectively. The antineoplastic actions of SAHA and DDP alone and in combination were evaluated using the determination of tumor volume, immunohistochemistry, western blot, and TUNEL analysis. Results: The hydrogel system was a free-flowing sol at 10uC, become gel at body temperature, and could sustain more than 14 days in situ. SAHA-DDP/PECE was subsequently injected into tumor OSCC tumor-beared mice. The results demonstrated that such a strategy as this allows the carrier system to show a sustained release of SAHA and DDP in vivo, and coul

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

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-<i>d</i>]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 <i>in vitro</i> and <i>in vivo</i>. 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 <i>in vivo</i> 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

Figure 3

<p><b>Antitumor activity of SAHA-DDP/PECE in vivo.</b> In the mice model of oral squamous cell carcinoma xenografts, the female nude mice received 2 × 10⁶ HSC-3 cells via subcutaneously into the right flank regions. (A) The mice were then treated with NS, PECE, SAHA, DDP, SAHA-DDP and SAHA-DDP/PECE every two weeks for a total of two doses starting on day 7 (n = 6 mice per group). Tumor volumes of mice from different groups of HSC-3 tumor model. (B) Representative tumors of OSCC mice model from NS, PECE, SAHA, DDP and SAHA-DDP control group and SAHA-DDP/PECE treated mice. Data are representative of at least two separate experiments. Bars, means ± SD (*P<0.05).(C) When tumors were palpable, the mice were randomly assigned to two independent treatment groups( n = 12 mice per group): mice treated with 100 ml combine SAHA with DDP (SAHA-DDP), or treated with 100 ml SAHA and DDP in thermosensitive hydrogel (SAHA-DDP/PECE). At the date of 1, 3, 7, 14 and 21 three mice were sacrificed separately. The ribonucleoprotein of the tumor tissues was extracted and the expression of acetyl-Histone H3 and Histone H3 was detected by western blot.</p