title: Potential of amphiphilic graft copolymer α-tocopherol succinate-g-carboxymethyl chitosan in modulating the permeability and anticancer efficacy of tamoxifen.
abstract: Recent studies showed an enhanced oral bioavailability of tamoxifen (TMX) by hydrophobically modified α-tocopherol succinate-g-carboxymethyl chitosan (Cmc-TS) micelles. As a continued effort, here we evaluated TMX-loaded polymeric micelles (TMX-PMs) for its enhanced permeability with increased anticancer efficacy and decreased hepatotoxicity. We employed co-solvent evaporation technique to encapsulate TMX into Cmc-TS. Apparent permeability assay of TMX-PMs was performed on Caco-2 cell line. The absorptive transport of TMX increased significantly about 3.8-fold when incorporated into Cmc-TS PMs. Cytotoxicity of Cmc-TS PMs was studied on MCF-7 cell line by MTT and; confocal microscopy was used for cellular uptake. Confocal microscopy revealed that Cmc-TS PMs could effectively accumulate in the cytosol of MCF-7 cell lines. In vitro data was further validated using N-methyl-N-nitrosourea (MNU)-induced mammary carcinogenesis model in Sprague-Dawley rats. Hepatotoxicity profiles of TMX-PMs at three different doses were also evaluated against the free drug TMX. TMX-PMs were more effective in suppressing breast tumor in MNU-induced mammary carcinoma model than free TMX with better safety profile. In addition, histological data shows that tumors are "benign" in TMX-PMs treated group compared with "malignant" tumors in free TMX treated and control groups. Overall, the results implicate that our Cmc-TS PMs may serve as a promising carrier for the intracellular delivery of anticancer drug molecules via oral route.
authors.affiliation: Department of Pharmaceutical Technology (Formulations), National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Jena
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Sanjaya K
authors.initials: SK
authors.lastname: Samal
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Shamandeep
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Chand
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, Punjab 160062, India. Electronic address: abhays@niper.ac.in.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D008823:Micelles; D010539:Permeability / Q000187:drug effects*; D011108:Polymers / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; C514968:carboxymethyl-chitosan; D013629:Tamoxifen; D048271:Chitosan; D024502:alpha-Tocopherol
keywords: Antitumor; Carboxymethyl chitosan; Hepatotoxicity; Polymeric micelles; Tamoxifen