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, BxPC-3, Panc-1, 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.

PSMA targeted docetaxel-loaded superparamagnetic iron oxide nanoparticles for prostate cancer

“…The composition of SPION and SPION-Dtxl was evaluated using FTIR (Perkin Elmer Series Spectra 100, Waltham, MA) to affirm the drug encapsulation [37]. A Rigaku D/Max-B diffractometer (Rigaku Americas Corporation, The Woodlands, TX) was used to determine the crystalline behavior of SPION/SPION-Dtxl [26].…”

“…A Rigaku D/Max-B diffractometer (Rigaku Americas Corporation, The Woodlands, TX) was used to determine the crystalline behavior of SPION/SPION-Dtxl [26]. The thermal behavior of SPION and SPION-Dtxl was assessed using a Perkin Elmer Simultaneous Thermal Analyzer STA6000 [37]. …”

Microenvironment in determining chemo-resistance in pancreatic cancer: Neighborhood matters

“…In keeping with this concept, it can be argued that while depleting stroma in a tumor will result in relieving the interstitial pressure on the blood vessels and promote drug delivery to the tumor, the tumor cells need to be obliterated as well in order to prevent their extravasation and spread to a distant location. This hypothesis is supported by a recent publication on two experimental drugs: one of the studies published in 2015, showed that ormeloxifene, a non-hormonal, non-steroidal oral contraceptive to be effective in reducing desmoplasia as well as induce tumor cell death in pancreatic cancer 19–21 . The other study, also from 2015, evaluated a water-soluble diterpene triepoxide, Minnelide against both patient tumor derived xenografts as well as the spontaneous KPC model for pancreatic cancer.…”

Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy

“…Colony formation assay was performed to investigate the effect of miR-145-MNPF on the colony forming ability of pancreatic cancer cells, as described previously 15 . Briefly, HPAF-II and AsPC-1 cells were transfected with MNPF, NC-MNPF and miR-145-MNPF.…”