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Tumor Stroma Targeting Nanoparticles Pro‐drug Approach for Treating Pancreatic Ductal Adenocarcinoma
Author(s) -
Alzhrani Rami,
Sau Samaresh,
Aboukameel Amro,
Alsaab Hashem,
Azmi Asfar,
Iyer Arun
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.09659
Subject(s) - stroma , cancer research , pancreatic cancer , chemistry , drug , cd44 , nanocarriers , drug delivery , gemcitabine , drug resistance , tumor microenvironment , cancer , medicine , pharmacology , in vitro , pathology , biology , tumor cells , biochemistry , immunohistochemistry , microbiology and biotechnology , organic chemistry
Pancreatic ductal adenocarcinoma (PDAC) is the third‐highest cause of cancer‐related death in the United States. The major challenges that limit the success of anti‐PDAC therapy are tumor heterogenicity and dense desmoplastic tumor stroma; that in turn promote drug resistance. Therefore, we developed nanoparticles (NP) pro‐drug that can overcome the stroma barrier and deliver the payload to the core of the tumor. We utilized nanoengineering technology to target dual CD44 and c‐Met biomarkers that have a crucial role in developing drug resistance in PDAC. Our western blot data analysis in several PDAC cell lines, such as PANC‐1, AsPc‐1, and BxPc3 revealed a high expression of CD44 and cMet. Thus, developing CD44/cMet dual‐targeted NP pro‐drug (C 44 MNPs) is expected to enhance drug delivery efficiency and efficacy. To test the tumor selectivity of C 44 MNPs on orthotopic PDAC model, near‐infrared (NIR) fluorescence dye was conjugated with C 44 MNPs, namely NIR‐C 44 MNPs. The biodistribution of NIR‐C 44 MNPs in the orthotopic model showed superior tumor accumulation with seven fold higher uptake than controls. Interestingly, NIR‐C 44 MNPs showed minimum liver accumulation, suggesting the ability of our NPs in overcoming liver toxicity (an observed problem with conventional NPs). Finally, C 44 MNPs was chemically conjugated with gemcitabine (GEM), namely C 44 MNPs ‐GEM pro‐drug, to improve the overall GEM therapeutic efficiency. In vitro data revealed that C 44 MNPs‐Gem pro‐drug has an excellent PDAC killing compared to free GEM. Moreover, C 44 MNPs‐GEM pro‐drug in combination with Everolimus showed extraordinary PDAC cell killing of D44M‐GEM with a high synergistic effect ( combination index [CI] value of 0.2–0.5). A significant tumor inhibition was achieved in an ASPC‐1 xenograft model by using combination therapy (C 44 MNPs‐GEM pro‐drug + EVR) compared with controls. Our current findings are highly encouraging and opens up a new avenue of using nanotherapeutics to overcome the current barriers of drug delivery for effective PDAC therapy.