title: Development of polymeric irinotecan nanoparticles using a novel lactone preservation strategy.
abstract: Irinotecan (IRT) is an important part of the first- and second-line regimen for metastatic colorectal and some other cancers. However, IRT suffers the constraints of pH-dependent conversion of active lactone form to inactive carboxylate form, burst release owing to its aqueous solubility, short half-life and dose-dependent side effects. In this study, we developed polymeric nanoparticles (NPs) that not only deliver IRT to tumor sites, but also overcome its drawbacks by preserving active lactone conformation, prolonging the plasma circulation time, and by providing sustained release. IRT complex was rendered hydrophobic by ion-pairing with anions (docusate sodium, sodium lauryl sulfate, and sodium tripolyphosphate), and loaded in PEG-PLGA NPs via water/oil/water double emulsification method. The NPs were spherical, ∼60nm, monodispersed, and had shell-core morphology. They retained >80% lactone form for more than 1 month of storage and exhibited sustained release characteristics. In addition, sub -100nm size of NPs offered elevated cellular internalization. Owing to the presence of hydrophilic PEG outer layer and drug-loaded hydrophobic PLGA core, NPs conferred excellent plasma stability and prolonged the retention time of IRT by more than 10-fold as compared to free IRT. Therefore, this system could provide an excellent platform for efficient and sustained delivery of IRT and similar labile drugs to the tumor site, while maintaining their chemical integrity.
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea.
authors: Bijay Kumar
authors: BK
authors: Poudel
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea.
authors: Biki
authors: B
authors: Gupta
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea.
authors: Thiruganesh
authors: T
authors: Ramasamy
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea.
authors: Raj Kumar
authors: RK
authors: Thapa
authors: School of Pharmacy, SungKyunKwan University, 300 Cheoncheon-dong, Jangan-gu, Suwon 440-746, South Korea.
authors: Yu Seok
authors: YS
authors: Youn
authors: College of Pharmacy, Hanyang University, 55, Hanyangdaehak-Ro, Sangnok-gu, Ansan 426-791, South Korea.
authors: Han-Gon
authors: HG
authors: Choi
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea. Electronic address: csyong@yu.ac.kr.
authors: Chul Soon
authors: CS
authors: Yong
authors: College of Pharmacy, Yeungnam University, 214-1, Dae-dong, Gyeongsan 712-749, South Korea. Electronic address: jongohkim@yu.ac.kr.
authors: Jong Oh
authors: JO
authors: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D004355:Drug Stability; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D000077146:Irinotecan; D007783:Lactones / Q000737:chemistry*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D012995:Solubility
chemical_list: D003692:Delayed-Action Preparations; D007783:Lactones; D011091:Polyesters; D011108:Polymers; C000589473:polyethylene glycol-poly(lactide-co-glycolide); D011092:Polyethylene Glycols; D000077146:Irinotecan; D002166:Camptothecin
keywords: Emulsification; Ion-pairing; Irinotecan; PLGA; Stability