N-Butyl-2-cyanoacrylate-based injectable and in situ-forming implants for efficient intratumoral chemotherapy

Abstract

The local delivery of chemotherapeutic drugs to tumor sites is an effective approach for achieving therapeutic drug concentrations in solid tumors. Injectable implants with the ability to form in situ represent one of the most promising technologies for intratumoral chemotherapy. However, many issues must be resolved before these implants can be applied in clinical practice. Herein, we report a novel injectable in situ-forming implant system composed of n-butyl-2-cyanoacrylate (NBCA) and ethyl oleate, and the sol-gel phase transition is activated by anions in body fluids or blood. This newly developed injectable NBCA ethyl oleate implant (INEI) is biodegradable, biocompatible, and non-toxic. INEI solidifies in several seconds after exposure to body fluids or blood, and the implant's in vivo degradation time can be controlled. In addition, the pore sizes formed by the polymerization of NBCA can be decreased by increasing the NBCA concentration in the implants. Therefore, the drug retention/ release time can be adjusted from a few weeks to several months by changing the concentration of NBCA in the implant formulation. Anti-tumor experiments in animal models showed that the average growth inhibition rate of xenografted human breast cancer cells by the paclitaxel-loaded INEI (40% NBCA) was 80%, and they also indicated that tumors in some of the mice were completely eliminated by just a single dosage injection. For the epirubicinloaded INEI (50% NBCA), the average growth inhibition rate of xenografted human liver cancer cells was 58%. Thus, the chemotherapeutic drug-loaded INEIs exhibited excellent therapeutic efficacy for local chemotherapy.

Developing protein arginine methyltransferase 1 (PRMT1) inhibitor TC-E-5003 as an antitumor drug using INEI drug delivery systems

“…It shows an excellent sustained-release effect with both hydrophobic and hydrophilic drugs. We have shown that the sol-gel phase transition, the relevant irregular particles polymerized by the NBCA, the inner hole of the implant, and the hardness of the implant pore changes of the implant as the concentration of NBCA increased (Wu et al, 2017).…”

“…The treatment efficacy was assessed by measuring the volume of the tumor with a caliper every 2 days. The living state, body weight, and tumor volume (V ¼ (length)Â(width) 2 /2, where length (mm) and width (mm) are the tumor dimensions at the longest point and the widest point) of the mice in each group were documented every two day (Wu et al, 2017). On day 28, all mice peripheral blood was gathered via cardiac puncture.…”

“…The irregular particles polymerized by the NBCA became smaller, the inner hole of the implant also became smaller, and the hardness of the implant increased with the increases in NBCA concentration. (Wu et al, 2017). We choose 40% NBCA to make the TC-E-5003-INEI in vitro.…”

In vitro and in vivo evaluation of the safety and efficacy of a novel liquid fiducial marker for image‑guided radiotherapy

“…The four treatment groups received different dilutions of NBCA/Lip and the control group received the same total volume (0.15 ml) of saline solution to allow comparisons of weight increase with the treatment groups. Sample size required in previous studies was usually 6-12 mice for four groups with the two-sided significant level of 0.05 and a power of 90%, however the present study was a type of multiple factorial exploration and a high power and effect size was needed for the credibility of the study (28)(29)(30)(31)(32). In addition, in the preliminary experiment, two mice died, which may have been caused by the blood vessel injections (14), therefore, the heterogeneity of variance could be decreased by 12 mice/group.…”

Implantation of In Situ Gelling Systems for the Delivery of Chemotherapeutic Agents

“…The paper by Wu Y et al [88] described the development of an in situ intratumor implant based on n-butyl-2-cyanoacrylate (NBCA) and ethyl oleate, and the sol-gel phase transition was activated by anions in body fluids or blood. The resulting implant solidified within seconds after contact with body fluids or blood, and the in vivo degradation time of the implant could be monitored.…”