Acute toxicity evaluation of biodegradable in situ gel‐forming controlled drug delivery system based on thermosensitive PEG‐PCL‐PEG hydrogel

Abstract

In this work, a biodegradable poly(ethylene glycol)-poly(epsilon-caprolactone)-poly (ethylene glycol) (PEG-PCL-PEG, PECE) triblock copolymer was successfully synthesized. The aqueous solution of such PECE copolymer displayed special sol-gel-sol transition as temperature increase, which is a flowing sol at low-temperature and turns into a nonflowing gel at body temperature. The cytotoxicity of PECE copolymer was evaluated by cell viability assay using HEK 293 cells. In vivo gel formation and degradation test based on intraperitoneal and subcutaneous administration was conducted, respectively. The acute toxicity test and histopathological study were performed in BALB/c mice by intrapleural, intraperitoneal, or subcutaneous administration of PECE hydrogel (30 Wt %), respectively. The dose of intrapleural, intraperitoneal, or subcutaneous administration was up to 10 g/kg body weight (b.w.), 25 g/kg b.w., and 25 g/kg b.w., respectively, and the mice were observed continuously for 14 days. For histopathologic study, samples including heart, liver, lung, kidneys, spleen, stomach, intestine, and tissue of injection site were prepared for histochemical analysis and were stained with hematoxylin-eosin. No mortality or significant signs of acute toxicity was observed during the whole observation period and there is no significant lesion to be shown in histopathologic study of major organs. Therefore, the maximum tolerance dose of PECE hydrogel by intrapleural, intraperitoneal, or subcutaneous administration was calculated to be higher than 10 g/kg b.w., 25 g/kg b.w., and 25 g/kg b.w., respectively. The results indicated that the prepared PECE hydrogel was nontoxic after intrapleural, intraperitoneal, or subcutaneous administration, and it could be a safe candidate for in situ gel-forming controlled drug delivery system.

Prevention of abdominal adhesion formation by thermosensitive PECE‐hydrogel in a rat uterine horn model

“…8,9 In our pervious work, the PECE hydrogel has been proven to be injectable, biocompatible, and bioabsorbable. 19,20 Our results showed that this thermosensitive hydrogel could conform to the uterine and abdominopelvic surfaces, and it remains adherent to the tissue, even in a vertical position, for a suitable time before degradation. Therefore, it possesses a high efficacy of antiadhesion function.…”

“…19 In our pervious researches, the prepared PECE hydrogels were proved to be thermosensitive, biocompatible, and bioabsorbable. 19,20 Here, as a candidate of antiadhesion barrier, we aimed to assess its antiadhesion efficacy and dynamically observe its degradation and the peritoneal healings in rat model of sidewall defect-uterine horns abrasion.…”

Preventing postoperative abdominal adhesions in a rat model with PEG-PCL-PEG hydrogel

“…11,12 In previous work, the PECE hydrogel was proven to be injectable, biocompatible, and bioabsorbable. 22,23 Results showed that the hydrogel could not only be adhered to the peritoneal wounds even with punctate hemorrhage but also effectively prevent postsurgical intra-abdominal adhesions. The key for preventing adhesions is the reconstruction of the neo-mesothelial cell layer.…”

“…22 The prepared PECE hydrogels were proved to be thermosensitive, biocompatible, and bioabsorbable. 22,23 In this present study, the aim was to assess its potential anti-adhesion efficacy and mechanisms in a rat model of surgical adhesion formation. Its potential toxicity was also investigated in vivo by histopathological observations.…”

PEG-<em>b</em>-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish

“…Based on this property, increasing efforts have been made to encapsulate some antitumor drugs with poor water solubility, such as curcumin and doxorubicin into PEG-b-PCL nano-micelles to improve therapeutic activities. 4,5 Despite that PEG and PCL are biocompatible and approved by US FDA in the form of microspheres and implants (containing hydrogels), as well as that PEG-b-PCL nano-micelle shows advantages and potentials in DDS, 6 there are open questions and concerns over the biological behaviors and safety of the nano-sized PEG-PCL, 7,8 which restricts their further application in clinical therapeutics. The most attractive properties of nanoparticles, such as smaller size and larger surface-to-volume ratio, are also the factors leading to systematic or local toxicity.…”