title: Hyaluronic acid-conjugated polyamidoamine dendrimers for targeted delivery of 3,4-difluorobenzylidene curcumin to CD44 overexpressing pancreatic cancer cells.
abstract: The current study was aimed to develop a targeted dendrimer formulation of 3, 4-difluorobenzylidene curcumin (CDF) and evaluate its potential in CD44 targeted therapy for pancreatic cancer. Using amine terminated fourth generation poly(amidoamine) (PAMAM) dendrimer nanocarrier and hyaluronic acid (HA) as a targeting ligand, we engineered a CD44-targeted PAMAM dendrimer (HA-PAMAM) formulation of CDF. The resulting dendrimer nanosystem (HA-PAMAM-CDF) had a particle size and surface charge of 9.3 ± 1.5 nm and -7.02 ± 9.53 mV, respectively. When CD44 receptor overexpressing MiaPaCa-2 and AsPC-1 human pancreatic cancer cells were treated with HA-PAMAM-CDF, a dose-dependent cytotoxicity was observed. Furthermore, blocking the CD44 receptors present on the MiaPaCa-2 cells using free excess soluble HA prior to treatment with HA-PAMAM-CDF nano-formulation resulted in 1.71 fold increase in the IC50 value compared to non-targeted formulation (PAMAM-CDF), confirming target specificity of HA-PAMAM-CDF. Additionally, HA-PAMAM-CDF formulation when compared to PAMAM-CDF, displayed higher cellular uptake in MiaPaCa-2 cancer cell lines as shown by fluorescence studies. In summary, the novel CD44 targeted dendrimer based nanocarriers appear to be proficient in mediating site-specific delivery of CDF via CD44 receptors, with an improved therapeutic margin and safety.
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 Ave, Detroit, MI 48201, USA.
authors.forename: Prashant
authors.initials: P
authors.lastname: Kesharwani
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, 5050 Anthony Wayne Drive, Detroit, MI 48202, USA.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University, School of Medicine, 740 HWCRC, Detroit, MI 48201, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Chemical Engineering and Materials Science, College of Engineering, Wayne State University, 5050 Anthony Wayne Drive, Detroit, MI 48202, USA.
authors.forename: Guangzhao
authors.initials: G
authors.lastname: Mao
authors.affiliation: ISTRA, Department of Chemistry, MCE Society's Abeda Inamdar Senior College of Arts, Science and Commerce, University of Pune, Pune 411001, India.
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.affiliation: Department of Pathology, Barbara Ann Karmanos Cancer Center, Wayne State University, School of Medicine, 740 HWCRC, Detroit, MI 48201, USA.
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
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 Ave, Detroit, MI 48201, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI 48201, USA. Electronic address: arun.iyer@wayne.edu.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Iyer
mesh_terms: D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D050091:Dendrimers / Q000737:chemistry*; D036381:Diarylheptanoids; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D006820:Hyaluronic Acid / Q000737:chemistry*; D018625:Microscopy, Atomic Force; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: C000611228:3,4-difluorobenzylidenecurcumin; D050091:Dendrimers; D036381:Diarylheptanoids; D018960:Hyaluronan Receptors; C104700:PAMAM Starburst; D006820:Hyaluronic Acid; D003474:Curcumin
keywords: 3, 4-Difluorobenzylidene curcumin; CD44 targeting; Drug delivery; Hyaluronic acid; PAMAM dendrimer; Pancreatic cancer