title: Irinotecan-loaded double-reversible thermogel with improved antitumor efficacy without initial burst effect and toxicity for intramuscular administration.
abstract: 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 6months. 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 Cmaxand maintained the sustained plasma concentrations at a relatively low level for the long period of 60h 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.
  
  
  
  Intramuscularly 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 irinotecan. 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.
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea; Department of Pharmacy, Quaid-I-Azam University, Islamabad 45320, Pakistan.
authors.forename: Fakhar Ud
authors.initials: FU
authors.lastname: Din
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Dong Wuk
authors.initials: DW
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Thapa
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Omer
authors.initials: O
authors.lastname: Mustapha
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea.
authors.forename: Dong Shik
authors.initials: DS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Ku, Seoul 151-742, Republic of Korea.
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.affiliation: College of Oriental Medicine, Daegu Haany University, Gyongsan 712-715, Republic of Korea.
authors.forename: Sae Kwang
authors.initials: SK
authors.lastname: Ku
authors.affiliation: School of Pharmacy, Sungkyunkwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, Republic of Korea.
authors.forename: Yu Seok
authors.initials: YS
authors.lastname: Youn
authors.affiliation: College of Pharmacy, Chung-Ang University, 221 Heuksuk-dong Dongjak-gu, Seoul 156-756, Republic of Korea.
authors.forename: Kyung Taek
authors.initials: KT
authors.lastname: Oh
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea.
authors.forename: Chul Soon
authors.initials: CS
authors.lastname: Yong
authors.affiliation: College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, Republic of Korea. Electronic address: jongohkim@yu.ac.kr.
authors.forename: Jong Oh
authors.initials: JO
authors.lastname: Kim
authors.affiliation: College of Pharmacy & Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Sangnok-gu, Ansan 426-791, Republic of Korea. Electronic address: hangon@hanyang.ac.kr.
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D020100:Hydrogels / Q000737:chemistry / Q000494:pharmacology; D007273:Injections, Intramuscular; D000077146:Irinotecan; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D020100:Hydrogels; D008055:Lipids; D000077146:Irinotecan; D002166:Camptothecin
keywords: Anti-tumour efficacy; Burst effect; Double-reversible thermogel; Irinotecan; Toxicity