title: In vivo biodistribution of siRNA and cisplatin administered using CD44-targeted hyaluronic acid nanoparticles.
abstract: Multidrug resistance (MDR) is a significant problem in the clinical management of several cancers. Overcoming MDR generally involves multi-modal therapeutic approaches that integrate enhancement of delivery efficiency using targeted nano-platforms as well as strategies that can sensitize cancer cells to drug treatments. We recently demonstrated that tandem delivery of siRNAs that downregulate anti-apoptotic genes overexpressed in cisplatin resistant tumors followed by therapeutic challenge using cisplatin loaded CD44 targeted hyaluronic acid (HA) nanoparticle (NP) induced synergistic antitumor response CD44 expressing tumors that are resistant to cisplatin. In the current study, a near infrared (NIR) dye-loaded HA NP was employed to image the whole body localization of NPs after intravenous (i.v.) injection into live mice bearing human lung tumors that were sensitive and resistant to cisplatin. In addition, we quantified the siRNA duplexes and cisplatin dose distribution in various tissues and organs using an ultra-sensitive quantitative PCR method and inductively coupled plasma-mass spectrometry (ICP-MS), respectively, after i.v. injection of the payload loaded HA NPs in tumor bearing mice. Our findings demonstrate that the distribution pattern of the siRNA and cisplatin using specifically engineered CD44 targeting HA NPs correlated well with the tumor targeting capability as well as the activity and efficacy obtained with combination treatments.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston 02115, USA; Novartis Institutes for Biomedical Research Inc., Cambridge 02139, USA.
authors.forename: Shanthi
authors.initials: S
authors.lastname: Ganesh
authors.forename: Arun K
authors.initials: AK
authors.lastname: Iyer
authors.forename: Florence
authors.initials: F
authors.lastname: Gattacceca
authors.forename: David V
authors.initials: DV
authors.lastname: Morrissey
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid; D002945:Cisplatin
keywords: Cisplatin; Hyaluronic acid; Multidrug resistance; Nanoparticles; Tumor targeting; siRNA