Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration

Publication date: Available online 8 March 2017
Source:Acta Biomaterialia
Author(s): Fakhar ud Din, Dong Wuk Kim, Ju Yeon Choi, Raj Kumar Thapa, Omer Mustapha, Dong Shik Kim, Yu-Kyoung Oh, Sae Kwang Ku, Yu Seok Youn, Kyung Taek Oh, Chul Soon Yong, Jong Oh Kim, Han-Gon Choi
Intramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. In this study, to solve this problem, a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinotecan was developed. This irinotecan-loaded DRTG was prepared by dispersing the irinotecan-loaded thermoreversible solid lipid nanoparticles (SLNs) in the thermoreversible hydrogel. In DRTG, the former was solid at 25 °C but converted to liquid at 36.5 °C; in contrast, the latter existed in a liquid form but transformed to gel state in the body. The DRTG was easily administered intramuscularly. Its particle size and drug content were not noticeably changeable, resulting that it was stable at 40 °C for at least 6 months. Compared to the irinotecan-loaded solution and conventional hydrogel, the DRTG significantly delayed drug release, leading to a reduced burst effect. Moreover, it showed decreased Cmax and maintained the sustained plasma concentrations at a relatively low level for the long period of 60 h in rats, resulting in ameliorated side effects of the anti-tumour drug. Furthermore, it gave significantly improved anti-tumour efficacy in tumour-bearing mice compared to the hydrogel but, unlike the conventional hydrogel, induced no body weight loss and local damage to the muscle. Thus, this DRTG with improved antitumor efficacy without initial burst effect and toxicity could provide a potential pharmaceutical system for the intramuscular administration of irinotecan.Statement of SignificanceIntramuscularly administered, anti-tumour drugs induce severe side effects due to their direct contact with body tissues and initial burst effect. To solve this problem, we developed a novel double-reversible thermogel system (DRTG) for the intramuscular administration of irinodecan. Unlike the conventional hydrogel, the DRTG is a dispersion of the irinotecan-loaded thermoreversible solid lipid nanoparticles in the thermoreversible hydrogel. In DRTG, the former was solid at 25°C but converted to liquid at 36.5°C; in contrast, the latter existed in a liquid form but transformed to gel state in the body. This DRTG gave significantly improved anti-tumour efficacy in tumour-bearing mice compared to the hydrogel but, unlike the conventional hydrogel, induced no body weight loss and local damage to the muscle.

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