title: Doxorubicin and siRNA Codelivery via Chitosan-Coated pH-Responsive Mixed Micellar Polyplexes for Enhanced Cancer Therapy in Multidrug-Resistant Tumors.
abstract: This study investigated the potential of chitosan-coated mixed micellar nanocarriers (polyplexes) for codelivery of siRNA and doxorubicin (DOX). DOX-loaded mixed micelles (serving as cores) were prepared by thin film hydration method and coated with chitosan (CS, serving as outer shell), and complexed with multidrug resistance (MDR) inhibiting siRNA. Selective targeting was achieved by folic acid conjugation. The polyplexes showed pH-responsive enhanced DOX release in acidic tumor pH, resulting in higher intracellular accumulation, which was further augmented by downregulation of mdr-1 gene after treatment with siRNA-complexed polyplexes. In vitro cytotoxicity assay demonstrated an enhanced cytotoxicity in native 4T1 and multidrug-resistant 4T1-mdr cell lines, compared to free DOX. Furthermore, in vivo, polyplexes codelivery resulted in highest DOX accumulation and significantly reduced the tumor volume in mice with 4T1 and 4T1-mdr tumors as compared to the free DOX groups, leading to improved survival times in mice. In conclusion, codelivery of siRNA and DOX via polyplexes has excellent potential as targeted drug nanocarriers for treatment of MDR cancers.
authors.affiliation: Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia.
authors.forename: Adeel Masood
authors.initials: AM
authors.lastname: Butt
authors.affiliation: Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia.
authors.forename: Mohd Cairul Iqbal Mohd
authors.initials: MC
authors.lastname: Amin
authors.affiliation: Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, Kuala Lumpur 50300, Malaysia.
authors.forename: Haliza
authors.initials: H
authors.lastname: Katas
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM) , Jalan Ya'acob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Nor Azian
authors.initials: NA
authors.lastname: Abdul Murad
authors.affiliation: UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM) , Jalan Ya'acob Latiff, Bandar Tun Razak, Cheras, Kuala Lumpur 56000, Malaysia.
authors.forename: Rahman
authors.initials: R
authors.lastname: Jamal
authors.affiliation: Use-inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University , 259 Mack Avenue, Detroit, Michigan 48201, United States.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kesharwani
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry*; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D011108:Polymers; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D004317:Doxorubicin; D048271:Chitosan
keywords: breast cancer; cytotoxicity; doxorubicin siRNA codelivery; multidrug resistance; nanoparticles; polymeric micelles; simultaneous delivery