title: Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors.
abstract: Anticancer therapeutics employing RNA interference mechanism holds promising potentials for sequence-specific silencing of target genes. However targeted delivery of siRNAs to tumor tissues and cells and more importantly, their intracellular release at sites of interest still remains a major challenge that needs to be addressed before this technique could become a clinically viable option. In the current study, we have engineered and screened a series of CD44 targeting hyaluronic acid (HA) based self-assembling nanosystems for targeted siRNA delivery. The HA polymer was functionalized with lipids of varying carbon chain lengths/nitrogen content, as well as polyamines for assessing siRNA encapsulation. From the screens, several HA-derivatives were identified that could stably encapsulate/complex siRNAs and form self-assembled nanosystems, as determined by gel retardation assays and dynamic light scattering. Many HA derivatives could transfect siRNAs into cancer cells overexpressing CD44 receptors. Interestingly, blocking the CD44 receptors on the cells using free excess soluble HA prior to incubation of cy3-labeled-siRNA loaded HA nano-assemblies resulted in >90% inhibition of the receptor mediated uptake, confirming target specificity. In addition, SSB/PLK1 siRNA encapsulated in HA-PEI/PEG nanosystems demonstrated dose dependent and target specific gene knockdown in both sensitive and resistant A549 lung cancer cells overexpressing CD44 receptors. More importantly, these siRNA encapsulated nanosystems demonstrated tumor selective uptake and target specific gene knock down in vivo in solid tumors as well as in metastatic tumors. The HA based nanosystems thus portend to be promising siRNA delivery vectors for systemic targeting of CD44 overexpressing cancers including tumor initiating (stem-) cells and metastatic lesions.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115, USA.
authors: Shanthi
authors: S
authors: Ganesh
authors: Arun K
authors: AK
authors: Iyer
authors: David V
authors: DV
authors: Morrissey
authors: Mansoor M
authors: MM
authors: Amiji
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004705:Endocytosis; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D011094:Polyethyleneimine / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D011094:Polyethyleneimine; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D000097869:Polo-Like Kinase 1