Pancreatic cancer is one of the most chemotherapy-resistant cancers and a leading cause of cancer-related mortality with a dismal 5-year survival rate of 8 to 10%. Most patients with pancreatic cancer are present with metastatic or inoperable disease, and therefore, systemic polychemotherapy remains the treatment of choice. The median survival of patients with metastatic pancreatic cancer is still less than a year with either FOLFIRINOX or GEM and nab-paclitaxel (6, 7). Therefore, safer and more effective combination of GEM and novel drugs further need to be developed particularly for older or less fit patients or those with significant comorbidities, who cannot tolerate intensive chemotherapy.Most patients with pancreatic cancer are present with metastatic or inoperable disease, and therefore, systemic polychemotherapy remains the treatment of choice. The median survival of patients with metastatic pancreatic cancer is still less than a year with either FOLFIRINOX or GEM and nab-paclitaxel (6, 7). Therefore, a safer and more effective combination of GEM and novel drugs further need to be developed particularly for older or less fit patients or those with significant comorbidities, who cannot tolerate intensive chemotherapy. Desmoplasia produces hypoxic microenvironment, stimulating hypoxia-inducible factor-1α (HIF-1α), which, in turn, modulates tumor metabolism, induces profibrotic and angiogenic responses. Hypoxia is responsible for an increase in sonic hedgehog (SHH) signaling and smoothened (SMO) expression in pancreatic cancer and activation of the transcription factor glioma-associated oncogene (GLI) (12). These changes result in further generation of fibrosis and a decrease in blood flow, creating a desmoplasia-hypoxia vicious cycle.
Visodegib, an inhibitor of Hh pathway component smoothened (Smo) has shown promise in the treatment of various cancers including pancreatic cancer. However, the emergence of resistance during vismodegib treatment with numerous side effects limits its use. Therefore, here we designed a novel vismodegib analogs using N-[3-(2-pyridinyl) phenyl] benzamide scaffold. Cell-based screening followed by molecular simulation revealed 2-chloro-N 1-[4-chloro-3-(2-pyridinyl)phenyl]-N 4,N 4-bis(2-pyridinylmethyl)-1,4-benzenedicarboxamide (MDB5) as most potent analog, binding with an extra interactions in seven-transmembrane (7-TM) domain of Smo due to an additional 2-pyridylmethyl group than GDC-0449. Moreover, MDB5 was more efficient in inhibiting Hh pathway components as measured by Gli-1 and Shh at transcriptional and translational levels. In a pancreatic tumor mouse model, MDB5 containing nanoparticles treated group showed significant inhibition of tumor growth without loss in body weight.
Various drug delivery systems like liposomes, nanoparticles and micelles fail to improve drug concentration in the core of pancreatic cancer and show premature release.
Epidermal growth factor receptor (EGFR) is overexpressed in the pancreatic tumor. Full-length EGFR natural ligands, such as EGF and monoclonal antibody cetuximab conjugated nanoparticles, have been shown to enhance the receptor-mediated endocytosis of GEM by pancreatic tumor cells. However, the high mitogenic and pro-angiogenic capability of full-length EGFR ligands retard their clinical translation. Alternatively, GE11 peptide (YHWYGYTPQNVI) ligand has been shown its specific binding to EGFR with low mitogenic activity. We successfully conjugated GE11 peptide to the surface of malemido-poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft-dodecanol (GE11-PEG-PCD) and synthesized methoxy-poly(ethylene glycol)-block-poly(2-methyl-2-carboxylpropylene carbonate-graft-gemcitabine-graft-dodecanol (mPEG-b-PCC-g-GEM-g-DC) to prepare mixed micelles for enhanced GEM delivery to EGFR expressing pancreatic cancer cells. We were able to show that GE11 linked mixed micelles exhibited a better therapeutic effect than nontargeted mixed micelles in vitro and in MIA PaCa-2 cells derived orthotopic pancreatic tumor bearing mice.