title: Synthesis and anticervical cancer activity of novel pH responsive micelles for oral curcumin delivery.
abstract: Curcumin (CM) has demonstrated safety and efficacy as a drug, but its pharmaceutical role is restricted as a result of extremely low aqueous solubility, rapid systemic elimination, inadequate tissue absorption and degradation at alkaline pH; properties that severely curtail its bioavailability. To address this issue, CM was encapsulated within pH responsive amphiphilic chitosan, resulting in the formation of 100 nm spontaneously self-assembled polymeric micelles in water. The amphiphilic chitosan, namely N-benzyl-N,O-succinyl chitosan (BSCS), was prepared by reductive N-benzylation and N,O-succinylation. The stability of micelles after being re-dispersed in water was investigated using glycine as a cryoprotectant, and the average sizes were shown to be maintained at a level lower than 200 nm for up to 4 months, at temperatures of 4°C and 25°C. In vitro drug release results showed that CM was slowly released from the micelles without any burst effect in the intestine (pH 5.5-7.4), with limited release in the stomach (pH 1.2). Cytotoxicity assays indicated that CM loaded micelles showed half maximal inhibitory concentrations (IC50) 4.7-, 3.6-, and 12.2-fold lower than that of free CM in HeLa, SiHa and C33a cervical cell lines, respectively. Cellular uptake of micelles was confirmed by confocal laser scanning microscopy and flow cytometry, with a 6-fold significant increase in the amount of CM loaded micelles compared to free CM in all cervical cancer cells. Notably, CM loaded micelles promoted an increase (30-55%) in the percentage of early apoptosis of HeLa, SiHa and C33a cells, compared to free CM. These results suggest that BSCS micelles may be a promising carrier for effective oral delivery of CM.
authors.affiliation: National Nanotechnology Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand. Electronic address: warayuth@nanotec.or.th.
authors.forename: Warayuth
authors.initials: W
authors.lastname: Sajomsang
authors.affiliation: National Nanotechnology Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
authors.forename: Pattarapond
authors.initials: P
authors.lastname: Gonil
authors.affiliation: National Nanotechnology Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
authors.forename: Somsak
authors.initials: S
authors.lastname: Saesoo
authors.affiliation: National Nanotechnology Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
authors.forename: Uracha Rangsadthong
authors.initials: UR
authors.lastname: Ruktanonchai
authors.affiliation: National Nanotechnology Center, National Science and Technology Development Agency, Pathum Thani 12120, Thailand.
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Srinuanchai
authors.affiliation: Department of Manufacturing Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand; Center of Excellence in Innovative Drug Delivery and Nanomedicine, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
authors.forename: Satit
authors.initials: S
authors.lastname: Puttipipatkhachorn
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D048271:Chitosan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D003474:Curcumin / Q000008:administration & dosage* / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry; D065546:Drug Liberation; D004355:Drug Stability; D005260:Female; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D010316:Particle Size; D013499:Surface Properties; D013501:Surface-Active Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000473:pathology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; C000600300:N-benzyl-N,O-succinyl chitosan; D013501:Surface-Active Agents; D048271:Chitosan; D003474:Curcumin
keywords: Anticervical cancer activity; Chitosan; Curcumin; Drug delivery system; pH responsive micelles