title: Nanoparticle formulation of ormeloxifene for pancreatic cancer.
abstract: Pancreatic cancer is the fourth most prevalent cancer with about an 85% mortality rate; thus, an utmost need exists to discover new therapeutic modalities that would enhance therapy outcomes of this disease with minimal or no side effects. Ormeloxifene (ORM), a synthetic molecule, has exhibited potent anti-cancer effects through inhibition of important oncogenic and proliferation signaling pathways. However, the anti-cancer efficacy of ORM can be further improved by developing its nanoformulation, which will also offer tumor specific targeted delivery. Therefore, we have developed a novel ORM encapsulated poly(lactic-co-glycolic acid) nanoparticle (NP) formulation (PLGA-ORM NP). This formulation was characterized for particle size, chemical composition, and drug loading efficiency, using various physico-chemical methods (TEM, FT-IR, DSC, TGA, and HPLC). Because of its facile composition, this novel formulation is compatible with antibody/aptamer conjugation to achieve tumor specific targeting. The particle size analysis of this PLGA-ORM formulation (∼100 nm) indicates that this formulation can preferentially reach and accumulate in tumors by the Enhanced Permeability and Retention (EPR) effect. Cellular uptake and internalization studies demonstrate that PLGA-ORM NPs escape lysosomal degradation, providing efficient endosomal release to cytosol. PLGA-ORM NPs showed remarkable anti-cancer potential in various pancreatic cancer cells (HPAF-II, AsPC-1, BxPC-3, Panc-1, and MiaPaca) and a BxPC-3 xenograft mice model resulting in increased animal survival. PLGA-ORM NPs suppressed pancreatic tumor growth via suppression of Akt phosphorylation and expression of MUC1, HER2, PCNA, CK19 and CD31. This study suggests that the PLGA-ORM formulation is highly efficient for the inhibition of pancreatic tumor growth and thus can be valuable for the treatment of pancreatic cancer in the future.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Sheema
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Chauhan
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Murali M
authors.initials: MM
authors.lastname: Yallapu
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, SD, USA.
authors.forename: Mara C
authors.initials: MC
authors.lastname: Ebeling
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Swathi
authors.initials: S
authors.lastname: Balakrishna
authors.affiliation: College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Ellis
authors.affiliation: Methodology and Data Analysis Center, Sanford Research, Sioux Falls, SD, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Department of Pharmaceutical Sciences and Plough Center for Sterile Drug Delivery Systems, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Balabathula
authors.affiliation: Department of Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Behrman
authors.affiliation: Department of Pathology, University of Tennessee at Memphis, Memphis, TN, USA.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Zafar
authors.affiliation: Saraswati Dental College, Lucknow, Uttar Pradesh, India.
authors.forename: Man M
authors.initials: MM
authors.lastname: Singh
authors.affiliation: Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD, 57007, USA.
authors.forename: Fathi T
authors.initials: FT
authors.lastname: Halaweish
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA. Electronic address: schauha1@uthsc.edu.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000008:administration & dosage* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004337:Drug Carriers; D005260:Female; D006801:Humans; D019344:Lactic Acid; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D023041:Xenograft Model Antitumor Assays
chemical_list: D001578:Benzopyrans; D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C508548:ormeloxifene
keywords: Cancer therapeutics; Drug delivery; Nanoparticles; Ormeloxifene; Pancreatic cancer; Sonic hedgehog